Formononetin attenuates Aβ25-35-induced cytotoxicity in HT22 cells via PI3K/Akt signaling and non-amyloidogenic cleavage of APP.

PubMed

Chen, Lizhi; Ou, Shanshan; Zhou, Lingqi; Tang, Hai; Xu, Jie; Guo, Kaihua

2017-02-03

Amyloid beta (Aβ) is the main component of the amyloid plaques that accumulate in the brains of Alzheimer patients. Here, we reported the protective role of Formononetin (Form) against Aβ 25-35 -induced neurotoxicity in HT22 cells. We found that Form significantly increased the viability of HT22 cells but decreased the cell apoptosis when challenging with Aβ 25-35. The inhibitory effects of Form were associated with PI3K/Akt signaling pathway as PI3K inhibitor (LY294002) or ERα specific inhibitor (MPP) blocked the effects. Form also accelerated the non-amyloidogenic process of amyloid precursor protein (APP) by enhancing α-secretase activity and sAPPα release. Altogether, our findings may provide a novel therapeutic target to treat AD sufferers. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Total flavonoid extract from Dracoephalum moldavica L. attenuates β-amyloid-induced toxicity through anti-amyloidogenesic and neurotrophic pathways.

PubMed

Liu, Qing-Shan; Jiang, Hai-Lun; Wang, Yu; Wang, Lin-Lin; Zhang, Jun-Xia; He, Cheng-Hui; Shao, Shuai; Zhang, Tian-Tai; Xing, Jian-Guo; Liu, Rui

2018-01-15

Alzheimer's disease (AD) is an incurable neurodegenerative disorder characterized by global cognitive impairment that involves accumulation of amyloid-beta peptides (Aβ) in the brain. Herbal approaches can be used as alternative medicines to slow the progression of AD. This study aimed to determine the beneficial effects and potential underlying mechanisms of total flavonoid extract from Dracoephalum moldavica L. (TFDM) for attenuating Alzheimer-related deficits induced by Aβ. We used amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice and copper-injured APP Swedish mutation overexpressing SH-SY5Y cells to evaluate the beneficial effects of TFDM. Further, identifying the mechanisms of action was conducted on anti-amyloidogenic and neurotrophic transductions. Our results indicated that TFDM treatment ameliorated cognitive impairments and neurodegeneration and improved the antioxidant defense system in APP/PS1 mice. TFDM also reduced Aβ burden by relieving Aβ deposition, decreasing insoluble Aβ levels, and inhibiting β-amyloidogenic processing pathway involving downregulation of β-secretase and β-C-terminal fragment in the brain. In the in vitro model of AD, TFDM treatment protected injured cells, and combined with the beneficial effects of decreasing APP levels, lowered Aβ 1-42 and regulated the redox imbalance. Moreover, TFDM preserved the extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway both in vitro and in vivo. In conclusion, TFDM clearly demonstrated neuroprotective effects by restoring the anti-amyloidogenic and neurotrophic transductions in the context of AD-associated deficits. These findings indicate the potential use of herb-based substances as supplements or potential alternative supplements for attenuating the progression of AD. Copyright © 2017. Published by Elsevier Inc.

Huperzine A alleviates synaptic deficits and modulates amyloidogenic and nonamyloidogenic pathways in APPswe/PS1dE9 transgenic mice.

PubMed

Wang, Ying; Tang, Xi Can; Zhang, Hai Yan

2012-02-01

Huperzine A (HupA) is a potent acetylcholinesterase inhibitor (AChEI) used in the treatment of Alzheimer's disease (AD). Recently, HupA was shown to be active in modulating the nonamyloidogenic metabolism of β-amyloid precursor protein (APP) in APP-transfected human embryonic kidney cell line (HEK293swe). However, in vivo research concerning the mechanism of HupA in APP transgenic mice has not yet been fully elucidated. The present study indicates that the loss of dendritic spine density and synaptotagmin levels in the brain of APPswe/presenilin-1 (PS1) transgenic mice was significantly ameliorated by chronic HupA treatment and provides evidence that this neuroprotection was associated with reduced amyloid plaque burden and oligomeric β-amyloid (Aβ) levels in the cortex and hippocampus of APPswe/PS1dE9 transgenic mice. Our findings further demonstrate that the amelioration effect of HupA on Aβ deposits may be mediated, at least in part, by regulation of the compromised expression of a disintegrin and metalloprotease 10 (ADAM10) and excessive membrane trafficking of β-site APP cleavage enzyme 1 (BACE1) in these transgenic mice. In addition, extracellular signal-regulated kinases 1/2 (Erk1/2) phosphorylation may also be partially involved in the effect of HupA on APP processing. In conclusion, our work for the first time demonstrates the neuroprotective effect of HupA on synaptic deficits in APPswe/PS1dE9 transgenic mice and further clarifies the potential pharmacological targets for this protective effect, in which modulation of nonamyloidogenic and amyloidogenic APP processing pathways may be both involved. These findings may provide adequate evidence for the clinical and experimental benefits gained from HupA treatment. Copyright © 2011 Wiley Periodicals, Inc.

Turnover of C99 is Controlled by a Crosstalk between ERAD and Ubiquitin-Independent Lysosomal Degradation in Human Neuroglioma Cells

PubMed Central

Bustamante, Hianara A.; Rivera-Dictter, Andrés; Cavieres, Viviana A.; Muñoz, Vanessa C.; González, Alexis; Lin, Yimo; Mardones, Gonzalo A.; Burgos, Patricia V.

2013-01-01

Alzheimer’s disease (AD) is characterized by the buildup of amyloid-β peptides (Aβ) aggregates derived from proteolytic processing of the β-amyloid precursor protein (APP). Amyloidogenic cleavage of APP by β-secretase/BACE1 generates the C-terminal fragment C99/CTFβ that can be subsequently cleaved by γ-secretase to produce Aβ. Growing evidence indicates that high levels of C99/CTFβ are determinant for AD. Although it has been postulated that γ-secretase-independent pathways must control C99/CTFβ levels, the contribution of organelles with degradative functions, such as the endoplasmic reticulum (ER) or lysosomes, is unclear. In this report, we investigated the turnover and amyloidogenic processing of C99/CTFβ in human H4 neuroglioma cells, and found that C99/CTFβ is localized at the Golgi apparatus in contrast to APP, which is mostly found in endosomes. Conditions that localized C99/CTFβ to the ER resulted in its degradation in a proteasome-dependent manner that first required polyubiquitination, consistent with an active role of the ER associated degradation (ERAD) in this process. Furthermore, when proteasomal activity was inhibited C99/CTFβ was degraded in a chloroquine (CQ)-sensitive compartment, implicating lysosomes as alternative sites for its degradation. Our results highlight a crosstalk between degradation pathways within the ER and lysosomes to avoid protein accumulation and toxicity. PMID:24376644

Turnover of C99 is controlled by a crosstalk between ERAD and ubiquitin-independent lysosomal degradation in human neuroglioma cells.

PubMed

Bustamante, Hianara A; Rivera-Dictter, Andrés; Cavieres, Viviana A; Muñoz, Vanessa C; González, Alexis; Lin, Yimo; Mardones, Gonzalo A; Burgos, Patricia V

2013-01-01

Alzheimer's disease (AD) is characterized by the buildup of amyloid-β peptides (Aβ) aggregates derived from proteolytic processing of the β-amyloid precursor protein (APP). Amyloidogenic cleavage of APP by β-secretase/BACE1 generates the C-terminal fragment C99/CTFβ that can be subsequently cleaved by γ-secretase to produce Aβ. Growing evidence indicates that high levels of C99/CTFβ are determinant for AD. Although it has been postulated that γ-secretase-independent pathways must control C99/CTFβ levels, the contribution of organelles with degradative functions, such as the endoplasmic reticulum (ER) or lysosomes, is unclear. In this report, we investigated the turnover and amyloidogenic processing of C99/CTFβ in human H4 neuroglioma cells, and found that C99/CTFβ is localized at the Golgi apparatus in contrast to APP, which is mostly found in endosomes. Conditions that localized C99/CTFβ to the ER resulted in its degradation in a proteasome-dependent manner that first required polyubiquitination, consistent with an active role of the ER associated degradation (ERAD) in this process. Furthermore, when proteasomal activity was inhibited C99/CTFβ was degraded in a chloroquine (CQ)-sensitive compartment, implicating lysosomes as alternative sites for its degradation. Our results highlight a crosstalk between degradation pathways within the ER and lysosomes to avoid protein accumulation and toxicity.

Oxidative Stress and Hypoxia Contribute to Alzheimer's Disease Pathogenesis: Two Sides of the Same Coin

PubMed Central

Guglielmotto, Michela; Tamagno, Elena; Danni, Oliviero

2009-01-01

While it is well established that stroke and cerebral hypoperfusion are risk factors for Alzheimer's disease (AD), the molecular link between ischemia/hypoxia and amyloid precursor protein (APP) processing has only been recently established. Here we review the role of the release of reactive oxygen species (ROS) by the mitochondrial electron chain in response to hypoxia, providing evidence that hypoxia fosters the amyloidogenic APP processing through a biphasic mechanism that up-regulates β-secretase activity, which involves an early release of ROS and an activation of HIF-1α. PMID:19705038

Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes.

PubMed

Vetrivel, Kulandaivelu S; Cheng, Haipeng; Lin, William; Sakurai, Takashi; Li, Tong; Nukina, Nobuyuki; Wong, Philip C; Xu, Huaxi; Thinakaran, Gopal

2004-10-22

Alzheimer's disease-associated beta-amyloid peptides (Abeta) are generated by the sequential proteolytic processing of amyloid precursor protein (APP) by beta- and gamma-secretases. There is growing evidence that cholesterol- and sphingolipid-rich membrane microdomains are involved in regulating trafficking and processing of APP. BACE1, the major beta-secretase in neurons is a palmitoylated transmembrane protein that resides in lipid rafts. A subset of APP is subject to amyloidogenic processing by BACE1 in lipid rafts, and this process depends on the integrity of lipid rafts. Here we describe the association of all four components of the gamma-secretase complex, namely presenilin 1 (PS1)-derived fragments, mature nicastrin, APH-1, and PEN-2, with cholesterol-rich detergent insoluble membrane (DIM) domains of non-neuronal cells and neurons that fulfill the criteria of lipid rafts. In PS1(-/-)/PS2(-/-) and NCT(-/-) fibroblasts, gamma-secretase components that still remain fail to become detergent-resistant, suggesting that raft association requires gamma-secretase complex assembly. Biochemical evidence shows that subunits of the gamma-secretase complex and three TGN/endosome-resident SNAREs cofractionate in sucrose density gradients, and show similar solubility or insolubility characteristics in distinct non-ionic and zwitterionic detergents, indicative of their co-residence in membrane microdomains with similar protein-lipid composition. This notion is confirmed using magnetic immunoisolation of PS1- or syntaxin 6-positive membrane patches from a mixture of membranes with similar buoyant densities following Lubrol WX extraction or sonication, and gradient centrifugation. These findings are consistent with the localization of gamma-secretase in lipid raft microdomains of post-Golgi and endosomes, organelles previously implicated in amyloidogenic processing of APP.

Association of γ-Secretase with Lipid Rafts in Post-Golgi and Endosome Membranes*

PubMed Central

Vetrivel, Kulandaivelu S.; Cheng, Haipeng; Lin, William; Sakurai, Takashi; Li, Tong; Nukina, Nobuyuki; Wong, Philip C.; Xu, Huaxi; Thinakaran, Gopal

2005-01-01

Alzheimer’s disease-associated β-amyloid peptides (Aβ) are generated by the sequential proteolytic processing of amyloid precursor protein (APP) by β- and γ-secretases. There is growing evidence that cholesterol- and sphingolipid-rich membrane microdomains are involved in regulating trafficking and processing of APP. BACE1, the major γ-secretase in neurons is a palmi-toylated transmembrane protein that resides in lipid rafts. A subset of APP is subject to amyloidogenic processing by BACE1 in lipid rafts, and this process depends on the integrity of lipid rafts. Here we describe the association of all four components of the γ-secretase complex, namely presenilin 1 (PS1)-derived fragments, mature nicastrin, APH-1, and PEN-2, with cholesterol-rich detergent insoluble membrane (DIM) domains of non-neuronal cells and neurons that fulfill the criteria of lipid rafts. In PS1−/−/PS2−/− and NCT−/− fibroblasts, γ-secretase components that still remain fail to become detergent-resistant, suggesting that raft association requires γ-secretase complex assembly. Biochemical evidence shows that subunits of the γ-secretase complex and three TGN/endosome-resident SNAREs cofractionate in sucrose density gradients, and show similar solubility or insolubility characteristics in distinct non-ionic and zwitterionic detergents, indicative of their co-residence in membrane microdomains with similar protein-lipid composition. This notion is confirmed using magnetic immunoisolation of PS1- or syntaxin 6-positive membrane patches from a mixture of membranes with similar buoyant densities following Lubrol WX extraction or sonication, and gradient centrifugation. These findings are consistent with the localization of γ-secretase in lipid raft microdomains of post-Golgi and endosomes, organelles previously implicated in amyloidogenic processing of APP. PMID:15322084

Amyloid-β Peptide Exacerbates the Memory Deficit Caused by Amyloid Precursor Protein Loss-of-Function in Drosophila

PubMed Central

Bourdet, Isabelle; Lampin-Saint-Amaux, Aurélie; Preat, Thomas; Goguel, Valérie

2015-01-01

The amyloid precursor protein (APP) plays a central role in Alzheimer’s disease (AD). APP can undergo two exclusive proteolytic pathways: cleavage by the α-secretase initiates the non-amyloidogenic pathway while cleavage by the β-secretase initiates the amyloidogenic pathway that leads, after a second cleavage by the γ-secretase, to amyloid-β (Aβ) peptides that can form toxic extracellular deposits, a hallmark of AD. The initial events leading to AD are still unknown. Importantly, aside from Aβ toxicity whose molecular mechanisms remain elusive, several studies have shown that APP plays a positive role in memory, raising the possibility that APP loss-of-function may participate to AD. We previously showed that APPL, the Drosophila APP ortholog, is required for associative memory in young flies. In the present report, we provide the first analysis of the amyloidogenic pathway’s influence on memory in the adult. We show that transient overexpression of the β-secretase in the mushroom bodies, the center for olfactory memory, did not alter memory. In sharp contrast, β-secretase overexpression affected memory when associated with APPL partial loss-of-function. Interestingly, similar results were observed with Drosophila Aβ peptide. Because Aβ overexpression impaired memory only when combined to APPL partial loss-of-function, the data suggest that Aβ affects memory through the APPL pathway. Thus, memory is altered by two connected mechanisms—APPL loss-of-function and amyloid peptide toxicity—revealing in Drosophila a functional interaction between APPL and amyloid peptide. PMID:26274614

Modulation of Gamma-Secretase for the Treatment of Alzheimer's Disease

PubMed Central

McKee, Timothy D.; Loureiro, Robyn M. B.; Dumin, Jo Ann; Xia, Weiming; Pojasek, Kevin; Austin, Wesley F.; Fuller, Nathan O.; Hubbs, Jed L.; Shen, Ruichao; Jonker, Jeff; Ives, Jeff; Bronk, Brian S.

2012-01-01

The Amyloid Hypothesis states that the cascade of events associated with Alzheimer's disease (AD)—formation of amyloid plaques, neurofibrillary tangles, synaptic loss, neurodegeneration, and cognitive decline—are triggered by Aβ peptide dysregulation (Kakuda et al., 2006, Sato et al., 2003, Qi-Takahara et al., 2005). Since γ-secretase is critical for Aβ production, many in the biopharmaceutical community focused on γ-secretase as a target for therapeutic approaches for Alzheimer's disease. However, pharmacological approaches to control γ-secretase activity are challenging because the enzyme has multiple, physiologically critical protein substrates. To lower amyloidogenic Aβ peptides without affecting other γ-secretase substrates, the epsilon (ε) cleavage that is essential for the activity of many substrates must be preserved. Small molecule modulators of γ-secretase activity have been discovered that spare the ε cleavage of APP and other substrates while decreasing the production of Aβ 42. Multiple chemical classes of γ-secretase modulators have been identified which differ in the pattern of Aβ peptides produced. Ideally, modulators will allow the ε cleavage of all substrates while shifting APP cleavage from Aβ 42 and other highly amyloidogenic Aβ peptides to shorter and less neurotoxic forms of the peptides without altering the total Aβ pool. Here, we compare chemically distinct modulators for effects on APP processing and in vivo activity. PMID:23320246

BRI2 (ITM2b) Inhibits Aβ Deposition in Vivo

PubMed Central

Kim, Jungsu; Miller, Victor M.; Levites, Yona; West, Karen Jansen; Zwizinski, Craig W.; Moore, Brenda D.; Troendle, Fredrick J.; Bann, Maralyssa; Verbeeck, Christophe; Price, Robert W.; Smithson, Lisa; Sonoda, Leilani; Wagg, Kayleigh; Rangachari, Vijayaraghavan; Zou, Fanggeng; Younkin, Steven G.; Graff-Radford, Neill; Dickson, Dennis; Rosenberry, Terrone; Golde, Todd E.

2008-01-01

Analyses of the biologic effects of mutations in the BRI2 (ITM2b) and the amyloid β precursor protein (APP) genes support the hypothesis that cerebral accumulation of amyloidogenic peptides in familial British and familial Danish dementias and Alzheimer’s disease (AD) is associated with neurodegeneration. We have used somatic brain transgenic technology to express the BRI2 and BRI2-Aβ1-40 transgenes in amyloid β protein precursor (APP) mouse models. Expression of BRI2-Aβ1-40 mimics the suppressive effect previously observed using conventional transgenic methods, further validating the somatic brain transgenic methodology. Unexpectedly, we also find that expression of wild type human BRI2 reduces cerebral Aβ deposition in an AD mouse model. Additional data indicate that the 23 amino acid peptide, Bri23, released from BRI2 by normal processing is present in human cerebrospinal fluid (CSF), inhibits Aβ aggregation in vitro, and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of Aβ deposition in vivo. PMID:18524908

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kosicek, Marko, E-mail: marko.kosicek@irb.hr; Malnar, Martina, E-mail: martina.malnar@irb.hr; Goate, Alison, E-mail: goate@icarus.wustl.edu

It has been suggested that cholesterol may modulate amyloid-{beta} (A{beta}) formation, a causative factor of Alzheimer's disease (AD), by regulating distribution of the three key proteins in the pathogenesis of AD ({beta}-amyloid precursor protein (APP), {beta}-secretase (BACE1) and/or presenilin 1 (PS1)) within lipid rafts. In this work we tested whether cholesterol accumulation upon NPC1 dysfunction, which causes Niemann Pick type C disease (NPC), causes increased partitioning of APP into lipid rafts leading to increased CTF/A{beta} formation in these cholesterol-rich membrane microdomains. To test this we used CHO NPC1{sup -/-} cells (NPC cells) and parental CHOwt cells. By sucrose density gradientmore » centrifugation we observed a shift in fl-APP/CTF compartmentalization into lipid raft fractions upon cholesterol accumulation in NPC vs. wt cells. Furthermore, {gamma}-secretase inhibitor treatment significantly increased fl-APP/CTF distribution in raft fractions in NPC vs. wt cells, suggesting that upon cholesterol accumulation in NPC1-null cells increased formation of APP-CTF and its increased processing towards A{beta} occurs in lipid rafts. Our results support that cholesterol overload, such as in NPC disease, leads to increased partitioning of APP/CTF into lipid rafts resulting in increased amyloidogenic processing of APP in these cholesterol-rich membranes. This work adds to the mechanism of the cholesterol-effect on APP processing and the pathogenesis of Alzheimer's disease and supports the role of lipid rafts in these processes.« less

Tannic Acid Is a Natural β-Secretase Inhibitor That Prevents Cognitive Impairment and Mitigates Alzheimer-like Pathology in Transgenic Mice*

PubMed Central

Mori, Takashi; Rezai-Zadeh, Kavon; Koyama, Naoki; Arendash, Gary W.; Yamaguchi, Haruyasu; Kakuda, Nobuto; Horikoshi-Sakuraba, Yuko; Tan, Jun; Town, Terrence

2012-01-01

Amyloid precursor protein (APP) proteolysis is essential for production of amyloid-β (Aβ) peptides that form β-amyloid plaques in brains of Alzheimer disease (AD) patients. Recent focus has been directed toward a group of naturally occurring anti-amyloidogenic polyphenols known as flavonoids. We orally administered the flavonoid tannic acid (TA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) and evaluated cognitive function and AD-like pathology. Consumption of TA for 6 months prevented transgene-associated behavioral impairment including hyperactivity, decreased object recognition, and defective spatial reference memory, but did not alter nontransgenic mouse behavior. Accordingly, brain parenchymal and cerebral vascular β-amyloid deposits and abundance of various Aβ species including oligomers were mitigated in TA-treated PSAPP mice. These effects occurred with decreased cleavage of the β-carboxyl-terminal APP fragment, lowered soluble APP-β production, reduced β-site APP cleaving enzyme 1 protein stability and activity, and attenuated neuroinflammation. As in vitro validation, we treated well characterized mutant human APP-overexpressing murine neuron-like cells with TA and found significantly reduced Aβ production associated with less amyloidogenic APP proteolysis. Taken together, these results raise the possibility that dietary supplementation with TA may be prophylactic for AD by inhibiting β-secretase activity and neuroinflammation and thereby mitigating AD pathology. PMID:22219198

[From physiopathology to treatment of Alzheimer's disease].

PubMed

Delacourte, A

2006-10-01

The natural and molecular history of familial or sporadic Alzheimer's disease (AD) shows that APP (amyloid protein precursor) dysfunction is a consensual central etiological factor in Alzheimer's disease (AD). This is demonstrated by 1) genetic defects involving APP gene or APP dysfunction (such as PS1 or PS2), leading to the formation of neocortical amyloid plaques in familial AD; 2) transgenic mice with these mutated genes that develop plaques; 3) both sporadic and familial AD develop plaques. But two alternatives to explain the physiopathology can be proposed: a gain of toxic function of AB peptide (reflected by the amyloid cascade hypothesis) or a loss of function of APP, a ubiquitous and well conserved protein with numerous possible neurotrophic activities. On the other hand, AD is also characterized by another inescapable degenerating process: tauopathy, an intraneuronal aggregation of tau proteins into neurofibrillary tangles. Remarkably enough, progression of tauopathy in neocortical areas fully explains the progressive clinical deficits of AD, from memory loss to aphasia, apraxia, agnosia. Also one has to bare in mind that most demented patients and most dementing neurodegenerative disorders have a tauopathy. From that, it is concluded that APP an Tau are solid therapeutic targets. But if we know that APP and Tau dysfunctions interact to boost neurodegeneration in AD, we still do no know what are the intraneuronal signaling pathways to activate or to inhibit to stop the degenerating process. There are many hypotheses and many possible approaches: the inhibition of toxicity of plaque, of AB protofibrils, or of AB oligomers inside or outside the neuron, using vaccination or ligands (Alzhemed). On the other hand, modulation of secretases that cleave APP by inhibiting those involved in the amyloidogenic pathway or by stimulating those of the non-amyloidogenic pathway, is a major route of research. Also modulation of kinases or phosphatases possibly involved in the aggregation of tau is also investigated. Because animal models are not perfectly relevant, at the end of the long and costly pathway of drug discovery, therapeutic trials are the only way to test these different hypotheses.

Memory Enhancing Effect of Black Pepper in the AlCl3 Induced Neurotoxicity Mouse Model is Mediated Through Its Active Component Chavicine.

PubMed

Iqbal, Ghazala; Iqbal, Anila; Mahboob, Aamra; Farhat, Syeda M; Ahmed, Touqeer

Black pepper (Piper nigrum Linn.) has vital pharmacological properties with profound effects on central nervous system. Neurotoxic agents like Aluminum Chloride (AlCl3) cause the oxidative stress and result in improper processing of amyloid proteins leading to accumulation of amyloid β plaques. The study aimed to explore the neuroprotective potential of black pepper (BP) extract (12.5mg/kg/day) on memory enhancement and its effect on expression of amyloid precursor protein (APP) isoforms (APP770 and APP695) in AlCl3 induced neurotoxicity (250mg/kg) mouse model. The study included the isolation and identification of pure compound from BP (chavicine) which was found pharmacologically active. Morris water maze test, elevated plus maze, fear conditioning, context and cue dependent test and social preference tests were performed to investigate the learning and memory. Gene expression (APP isoforms) and in-vitro and ex-vivo DPPH free radical scavenging activity were performed to evaluate the role of BP. BP significantly improved memory in AlCl3 induced neurotoxicity mouse model along with effectively decreasing the expression of APP770 (amyloidogenic) isoform and improved level of APP695 (non-amyloidogenic) in hippocampus, amygdala and cortex. Fear extinction learning was considerably improved in BP treated group (7.83±2.03) than AlCl3 induced neurotoxicity group (39.75±4.25). In the hippocampus, BP significantly reduced the expression of APP770 (0.37±0.05) as compared to AlCl3 induced neurotoxicity group (0.72±0.06), and effectively increased (34.80±1.39) the percentage inhibition of DPPH free radicals as compared to AlCl3 induced neurotoxicity group (14±2.68). The study revealed that BP improves memory and chavicine is a lead compound producing pharmacological effects of BP.

Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-ß production.

PubMed

Bordji, Karim; Becerril-Ortega, Javier; Nicole, Olivier; Buisson, Alain

2010-11-24

Calcium is a key mediator controlling essential neuronal functions depending on electrical activity. Altered neuronal calcium homeostasis affects metabolism of amyloid precursor protein (APP), leading to increased production of β-amyloid (Aβ), and contributing to the initiation of Alzheimer's disease (AD). A linkage between excessive glutamate receptor activation and neuronal Aβ release was established, and recent reports suggest that synaptic and extrasynaptic NMDA receptor (NMDAR) activation may have distinct consequences in plasticity, gene regulation, and neuronal death. Here, we report for the first time that prolonged activation of extrasynaptic NMDAR, but not synaptic NMDAR, dramatically increased the neuronal production of Aβ. This effect was preceded by a shift from APP695 to Kunitz protease inhibitory domain (KPI) containing APPs (KPI-APPs), isoforms exhibiting an important amyloidogenic potential. Conversely, after synaptic NMDAR activation, we failed to detect any KPI-APP expression and neuronal Aβ production was not modified. Calcium imaging data showed that intracellular calcium concentration after extrasynaptic NMDAR stimulation was lower than after synaptic activation. This suggests distinct signaling pathways for each pool of receptors. We found that modification of neuronal APP expression pattern triggered by extrasynaptic NMDAR activation was regulated at an alternative splicing level involving calcium-/calmodulin-dependent protein kinase IV, but overall APP expression remained identical. Finally, memantine dose-dependently inhibited extrasynaptic NMDAR-induced KPI-APPs expression as well as neuronal Aβ release. Altogether, these data suggest that a chronic activation of extrasynaptic NMDAR promotes amyloidogenic KPI-APP expression leading to neuronal Aβ release, representing a causal risk factor for developing AD.

Proteasome stress leads to APP axonal transport defects by promoting its amyloidogenic processing in lysosomes.

PubMed

Otero, María Gabriela; Fernandez Bessone, Ivan; Hallberg, Alan Earle; Cromberg, Lucas Eneas; De Rossi, María Cecilia; Saez, Trinidad M; Levi, Valeria; Almenar-Queralt, Angels; Falzone, Tomás Luis

2018-06-11

Alzheimer disease (AD) pathology includes the accumulation of poly-ubiquitylated (also known as poly-ubiquitinated) proteins and failures in proteasome-dependent degradation. Whereas the distribution of proteasomes and its role in synaptic function have been studied, whether proteasome activity regulates the axonal transport and metabolism of the amyloid precursor protein (APP), remains elusive. By using live imaging in primary hippocampal neurons, we showed that proteasome inhibition rapidly and severely impairs the axonal transport of APP. Fluorescence cross-correlation analyses and membrane internalization blockage experiments showed that plasma membrane APP does not contribute to transport defects. Moreover, by western blotting and double-color APP imaging, we demonstrated that proteasome inhibition precludes APP axonal transport by enhancing its endo-lysosomal delivery, where β-cleavage is induced. Taken together, we found that proteasomes control the distal transport of APP and can re-distribute Golgi-derived vesicles to the endo-lysosomal pathway. This crosstalk between proteasomes and lysosomes regulates the intracellular APP dynamics, and defects in proteasome activity can be considered a contributing factor that leads to abnormal APP metabolism in AD.This article has an associated First Person interview with the first author of the paper. © 2018. Published by The Company of Biologists Ltd.

LRP-mediated clearance of Abeta is inhibited by KPI-containing isoforms of APP.

PubMed

Moir, Robert D; Tanzi, Rudolph E

2005-04-01

The pathogenesis of Alzheimer's disease (AD) involves the abnormal accumulation and deposition of beta-amyloid in cerebral blood vessels and in the brain parenchyma. Critical in modulating beta-amyloid deposition in brain is the flux of Abeta across the blood brain barrier. The low-density lipoprotein receptor-related protein (LRP), is a large endocytic receptor that mediates the efflux of Abeta out of brain and into the periphery. The first step in the LRP-mediated clearance of Abeta involves the formation of a complex between Abeta and the LRP ligands apolipoprotein E (apoE) or alpha(2)-macroglobulin (alpha(2)M). The Abeta/chaperone complexes then bind to LRP via binding sites on apoE or alpha(2)M. The efflux of Abeta/chaperone complexes out of the neuropil and into the periphery may be attenuated by LRP-ligands that compete with apoE or alpha(2)M for LRP binding. LRP is also the cell surface receptor for Kunitz Protease Inhibitor (KPI) containing isoforms of Abeta's parent protein, the amyloid protein precursor (APP). Protein and mRNA levels of KPI-containing APP isoforms (APP-KPI) are elevated in AD brain and are associated with increased Abeta production. In this study we show that soluble non-amyloidogenic APP-KPI can also inhibit the uptake of Abeta/alpha(2)M in a cell culture model of LRP mediated Abeta clearance. Clearance of Abeta/apoE complexes was not inhibited by APP-KPI. Our findings are consistent with studies showing that apoE and alpha(2)M have discrete binding sites on LRP. Most significantly, our data suggests that the elevated levels of APP-KPI in AD brain may attenuate the clearance of Abeta, the proteins own amyloidogenic catabolic product.

Substance P and Alzheimer's Disease: Emerging Novel Roles.

PubMed

Severini, Cinzia; Petrella, Carla; Calissano, Pietro

2016-01-01

Alzheimer`s disease (AD) is an irreversible neurodegenerative disease, clinically characterized by progressive impairments of memory and cognition. The hallmarks of AD are neurofibrillary tangles, mainly constituted by altered phosphorylated and truncated portions of tau protein, and the abnormal extracellular deposition of neurotoxic beta amyloid (Aβ) peptides, derived from the proteolytic processing of amyloid precursor protein (APP). According to the amyloid hypothesis, Aβ is considered to be linked to the selective neurodegeneration seen in AD. Recent evidence points to an increase in voltage-gated potassium (Kv) channel currents in the etiology of Aβ-induced neuronal apoptosis. Substance P (SP) is an 11-aa neuropeptide, member of the tachykinin family, broadly distributed in the Central Nervous System where it acts as a neurotransmitter, neuromodulator, and neurotrophic factor. This peptide may play an important role in neurodegenerative disorders, since reduced levels of SP were found in brain areas and spinal fluid of AD patients. In addition to its neuroprotective properties, it was recently demonstrated that SP is able to stimulate non-amyloidogenic APP processing, thereby reducing the possibility of generation of toxic Aβ peptides in the brain. Recent studies, using in vitro and in vivo models, have also shown that the neuroprotective role of SP against Aβ could be related to its ability of modulate Kv channel currents. In this review, we briefly summarized the current findings on the neurotrophic and neuroprotective effects of SP, providing information about its anti-amyloidogenic and anti-Aβ toxicity role.

Novel Roles of Amyloid-Beta Protein Precursor Metabolites in Fragile X Syndrome and Autism

PubMed Central

Westmark, Cara J.; Sokol, Deborah K.; Maloney, Bryan; Lahiri, Debomoy K.

2017-01-01

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and is associated with up to 5% of autism cases. Several promising drugs are in preclinical testing for FXS; however, bench-to-bedside plans for the clinic are severely limited due to lack of validated biomarkers and outcome measures. Published work from our laboratories has demonstrated altered levels of amyloid-beta (Aβ) protein precursor (APP) and its metabolites in FXS and idiopathic autism. Westmark and colleagues have focused on β-secretase (amyloidogenic) processing and the accumulation of Aβ peptides in adult FXS models while Lahiri and Sokol have studied α-secretase (nonamyloidogenic or anabolic) processing and altered levels of sAPPα and Aβ in pediatric autism and FXS. Thus, our groups have hypothesized a pivotal role for these Alzheimer’s disease (AD)-related proteins in the neurodevelopmental disorders of FXS and autism. In this review, we discuss the contribution of APP metabolites to FXS and autism pathogenesis as well as the potential use of these metabolites as blood-based biomarkers and therapeutic targets. Our future focus is to identify key underlying mechanisms through which APP metabolites contribute to FXS and autism condition-to-disease pathology. Positive outcomes will support utilizing APP metabolites as blood-based biomarkers in clinical trials as well as testing drugs that modulate APP processing as potential disease therapeutics. Our studies to understand the role of APP metabolites in developmental conditions such as FXS and autism are a quantum leap for the neuroscience field, which has traditionally restricted any role of APP to AD and aging. PMID:27573877

Effect of Different Phospholipids on α-Secretase Activity in the Non-Amyloidogenic Pathway of Alzheimer’s Disease

PubMed Central

Grimm, Marcus O. W.; Haupenthal, Viola J.; Rothhaar, Tatjana L.; Zimmer, Valerie C.; Grösgen, Sven; Hundsdörfer, Benjamin; Lehmann, Johannes; Grimm, Heike S.; Hartmann, Tobias

2013-01-01

Alzheimer’s disease (AD) is characterized by extracellular accumulation of amyloid-β peptide (Aβ), generated by proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. Aβ generation is inhibited when the initial ectodomain shedding is caused by α-secretase, cleaving APP within the Aβ domain. Therefore, an increase in α-secretase activity is an attractive therapeutic target for AD treatment. APP and the APP-cleaving secretases are all transmembrane proteins, thus local membrane lipid composition is proposed to influence APP processing. Although several studies have focused on γ-secretase, the effect of the membrane lipid microenvironment on α-secretase is poorly understood. In the present study, we systematically investigated the effect of fatty acid (FA) acyl chain length (10:0, 12:0, 14:0, 16:0, 18:0, 20:0, 22:0, 24:0), membrane polar lipid headgroup (phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine), saturation grade and the FA double-bond position on α-secretase activity. We found that α-secretase activity is significantly elevated in the presence of FAs with short chain length and in the presence of polyunsaturated FAs, whereas variations in the phospholipid headgroups, as well as the double-bond position, have little or no effect on α-secretase activity. Overall, our study shows that local lipid membrane composition can influence α-secretase activity and might have beneficial effects for AD. PMID:23485990

Citrulline diet supplementation improves specific age-related raft changes in wild-type rodent hippocampus.

PubMed

Marquet-de Rougé, Perrine; Clamagirand, Christine; Facchinetti, Patricia; Rose, Christiane; Sargueil, Françoise; Guihenneuc-Jouyaux, Chantal; Cynober, Luc; Moinard, Christophe; Allinquant, Bernadette

2013-10-01

The levels of molecules crucial for signal transduction processing change in the brain with aging. Lipid rafts are membrane microdomains involved in cell signaling. We describe here substantial biophysical and biochemical changes occurring within the rafts in hippocampus neurons from aging wild-type rats and mice. Using continuous sucrose density gradients, we observed light-, medium-, and heavy raft subpopulations in young adult rodent hippocampus neurons containing very low levels of amyloid precursor protein (APP) and almost no caveolin-1 (CAV-1). By contrast, old rodents had a homogeneous age-specific high-density caveolar raft subpopulation containing significantly more cholesterol (CHOL), CAV-1, and APP. C99-APP-Cter fragment detection demonstrates that the first step of amyloidogenic APP processing takes place in this caveolar structure during physiological aging of the rat brain. In this age-specific caveolar raft subpopulation, levels of the C99-APP-Cter fragment are exponentially correlated with those of APP, suggesting that high APP concentrations may be associated with a risk of large increases in beta-amyloid peptide levels. Citrulline (an intermediate amino acid of the urea cycle) supplementation in the diet of aged rats for 3 months reduced these age-related hippocampus raft changes, resulting in raft patterns tightly close to those in young animals: CHOL, CAV-1, and APP concentrations were significantly lower and the C99-APP-Cter fragment was less abundant in the heavy raft subpopulation than in controls. Thus, we report substantial changes in raft structures during the aging of rodent hippocampus and describe new and promising areas of investigation concerning the possible protective effect of citrulline on brain function during aging.

Lack of tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP/PS1 mice.

PubMed

Leroy, Karelle; Ando, Kunie; Laporte, Vincent; Dedecker, Robert; Suain, Valérie; Authelet, Michèle; Héraud, Céline; Pierrot, Nathalie; Yilmaz, Zehra; Octave, Jean-Noël; Brion, Jean-Pierre

2012-12-01

Lack of tau expression has been reported to protect against excitotoxicity and to prevent memory deficits in mice expressing mutant amyloid precursor protein (APP) identified in familial Alzheimer disease. In APP mice, mutant presenilin 1 (PS1) enhances generation of Aβ42 and inhibits cell survival pathways. It is unknown whether the deficient phenotype induced by concomitant expression of mutant PS1 is rescued by absence of tau. In this study, we have analyzed the effect of tau deletion in mice expressing mutant APP and PS1. Although APP/PS1/tau(+/+) mice had a reduced survival, developed spatial memory deficits at 6 months and motor impairments at 12 months, these deficits were rescued in APP/PS1/tau(-/-) mice. Neuronal loss and synaptic loss in APP/PS1/tau(+/+) mice were rescued in the APP/PS1/tau(-/-) mice. The amyloid plaque burden was decreased by roughly 50% in the cortex and the spinal cord of the APP/PS1/tau(-/-) mice. The levels of soluble and insoluble Aβ40 and Aβ42, and the Aβ42/Aβ40 ratio were reduced in APP/PS1/tau(-/-) mice. Levels of phosphorylated APP, of β-C-terminal fragments (CTFs), and of β-secretase 1 (BACE1) were also reduced, suggesting that β-secretase cleavage of APP was reduced in APP/PS1/tau(-/-) mice. Our results indicate that tau deletion had a protective effect against amyloid induced toxicity even in the presence of mutant PS1 and reduced the production of Aβ. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway.

PubMed

Das, Utpal; Wang, Lina; Ganguly, Archan; Saikia, Junmi M; Wagner, Steven L; Koo, Edward H; Roy, Subhojit

2016-01-01

Cleavage of amyloid precursor protein (APP) by BACE-1 (β-site APP cleaving enzyme-1) is the rate-limiting step in amyloid-β (Aβ) production and a neuropathologic hallmark of Alzheimer's disease; thus, physical approximation of this substrate-enzyme pair is a crucial event with broad biological and therapeutic implications. Despite much research, neuronal locales of APP and BACE-1 convergence and APP cleavage remain unclear. Here we report an optical assay, based on fluorescence complementation, for visualizing in cellulo APP-BACE-1 interactions as a simple on/off signal. Combining this with other assays tracking the fate of internalized APP in hippocampal neurons, we found that APP and BACE-1 interacted in both biosynthetic and endocytic compartments, particularly along recycling microdomains such as dendritic spines and presynaptic boutons. In axons, APP and BACE-1 were cotransported, and they also interacted during transit. Finally, our assay revealed that the Alzheimer's disease-protective 'Icelandic' mutation greatly attenuates APP-BACE-1 interactions, suggesting a mechanistic basis for protection. Collectively, the data challenge canonical models and provide concrete insights into long-standing controversies in the field.

Opposite Dysregulation of Fragile-X Mental Retardation Protein and Heteronuclear Ribonucleoprotein C Protein Associates with Enhanced APP Translation in Alzheimer Disease.

PubMed

Borreca, Antonella; Gironi, Katia; Amadoro, Giusy; Ammassari-Teule, Martine

2016-07-01

Amyloid precursor protein (APP) is overexpressed in familiar and sporadic Alzheimer Disease (AD) patients suggesting that, in addition to abnormalities in APP cleavage, enhanced levels of APP full length might contribute to the pathology. Based on data showing that the two RNA binding proteins (RBPs), Fragile-X Mental Retardation Protein (FMRP) and heteronuclear Ribonucleoprotein C (hnRNP C), exert an opposite control on APP translation, we have analyzed whether expression and translation of these two RBPs vary in relation to changes in APP protein and mRNA levels in the AD brain at 1, 3, and 6 months of age. Here, we show that, as expected, human APP is overexpressed in hippocampal total extract from Tg2576 mice at all age points. APP overexpression, however, is not stable over time but reaches its maximal level in 1-month-old mutants in association with the stronger (i) reduction of FMRP and (ii) augmentation of hnRNP C. APP levels then decrease progressively as a function of age in close relationship with the gradual normalization of FMRP and hnRNP C levels. Consistent with the mouse data, expression of FMRP and hnRNP C are, respectively, decreased and increased in hippocampal synaptosomes from sporadic AD patients. Our findings identify two RBP targets that might be manipulated for reducing abnormally elevated levels of APP in the AD brain, with the hypothesis that acting upstream of amyloidogenic processing might contribute to attenuate the amyloid burden.

Hypoxic stress, brain vascular system, and β-amyloid: a primary cell culture study.

PubMed

Muche, Abebe; Bürger, Susanne; Arendt, Thomas; Schliebs, Reinhard

2015-01-01

This study stresses the hypothesis whether hypoxic events contribute to formation and deposition of β-amyloid (Aβ) in cerebral blood vessels by affecting the processing of endothelial amyloid precursor protein (APP). Therefore, cerebral endothelial cells (ECs) derived from transgenic Tg2576 mouse brain, were subjected to short periods of hypoxic stress, followed by assessment of formation and secretion of APP cleavage products sAPPα, sAPPβ, and Aβ as well as the expression of endothelial APP. Hypoxic stress of EC leads to enhanced secretion of sAPPβ into the culture medium as compared to normoxic controls, which is accompanied by increased APP expression, induction of vascular endothelial growth factor (VEGF) synthesis, nitric oxide production, and differential changes in endothelial p42/44 (ERK1/2) expression. The hypoxia-mediated up-regulation of p42/44 at a particular time of incubation was accompanied by a corresponding down-regulation of the phosphorylated form of p42/44. To reveal any role of hypoxia-induced VEGF in endothelial APP processing, ECs were exposed by VEGF. VEGF hardly affected the amount of sAPPβ and Aβ(1-40) secreted into the culture medium, whereas the suppression of the VEGF receptor action by SU-5416 resulted in decreased release of sAPPβ and Aβ(1-40) in comparison to control incubations, suggesting a role of VEGF in controlling the activity of γ-secretase, presumably via the VEGF receptor-associated tyrosine kinase. The data suggest that hypoxic stress represents a mayor risk factor in causing Aβ deposition in the brain vascular system by favoring the amyloidogenic route of endothelial APP processing. The hypoxic-stress-induced changes in β-secretase activity are presumably mediated by altering the phosphorylation status of p42/44, whereas the stress-induced up-regulation of VEGF appears to play a counteracting role by maintaining the balance of physiological APP processing.

Cross-linking of cell surface amyloid precursor protein leads to increased β-amyloid peptide production in hippocampal neurons: implications for Alzheimer's disease.

PubMed

Lefort, Roger; Pozueta, Julio; Shelanski, Michael

2012-08-01

The accumulation of the β-amyloid peptide (Aβ) in Alzheimer's disease (AD) is thought to play a causative role in triggering synaptic dysfunction in neurons, leading to their eventual demise through apoptosis. Aβ is produced and secreted upon sequential cleavage of the amyloid precursor protein (APP) by β-secretases and γ-secretases. However, while Aβ levels have been shown to be increased in the brains of AD patients, little is known about how the cleavage of APP and the subsequent generation of Aβ is influenced, or whether the cleavage process changes over time. It has been proposed that Aβ can bind APP and promote amyloidogenic processing of APP, further enhancing Aβ production. Proof of this idea has remained elusive because a clear mechanism has not been identified, and the promiscuous nature of Aβ binding complicates the task of demonstrating the idea. To work around these problems, we used an antibody-mediated approach to bind and cross-link cell-surface APP in cultured rat primary hippocampal neurons. Here we show that cross-linking of APP is sufficient to raise the levels of Aβ in viable neurons with a concomitant increase in the levels of the β-secretase BACE1. This appears to occur as a result of a sorting defect that stems from the caspase-3-mediated inactivation of a key sorting adaptor protein, namely GGA3, which prevents the lysosomal degradation of BACE1. Together, our data suggest the occurrence of a positive pathogenic feedback loop involving Aβ and APP in affected neurons possibly allowing Aβ to spread to nearby healthy neurons.

Visualization of APP and BACE-1 approximation in neurons: new insights into the amyloidogenic pathway

PubMed Central

Das, Utpal; Wang, Lina; Ganguly, Archan; Saikia, Junmi M.; Wagner, Steven L.; Koo, Edward H.; Roy, Subhojit

2016-01-01

Cleavage of APP (amyloid precursor protein) by BACE-1 (β-site APP cleaving enzyme-1) is the rate-limiting step in amyloid-beta (Aβ) production and a neuropathologic hallmark of Alzheimer's disease (AD); thus physical approximation of this substrate-enzyme pair is a critical event with broad biological and therapeutic implications. Despite much research, neuronal locales of APP/BACE-1 convergence and APP-cleavage remain unclear. Here we report an optical assay – based on fluorescence complementation – to visualize in-cellulo APP/BACE-1 interactions as a simple on/off signal. Combined with other assays tracking the fate of internalized APP in hippocampal neurons, we found that APP/BACE-1 interact in both biosynthetic and endocytic compartments; particularly along recycling-microdomains such as dendritic spines and presynaptic boutons. In axons, APP and BACE-1 are co-transported, and also interact during transit. Finally, our assay reveals that the AD-protective “Icelandic” mutation greatly attenuates APP/BACE-1 interactions, suggesting a mechanistic basis for protection. Collectively, the data challenge canonical models and provide concrete insights into long-standing controversies in the field. PMID:26642089

Glycines from the APP GXXXG/GXXXA Transmembrane Motifs Promote Formation of Pathogenic Aβ Oligomers in Cells

PubMed Central

Decock, Marie; Stanga, Serena; Octave, Jean-Noël; Dewachter, Ilse; Smith, Steven O.; Constantinescu, Stefan N.; Kienlen-Campard, Pascal

2016-01-01

Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by progressive cognitive decline leading to dementia. The amyloid precursor protein (APP) is a ubiquitous type I transmembrane (TM) protein sequentially processed to generate the β-amyloid peptide (Aβ), the major constituent of senile plaques that are typical AD lesions. There is a growing body of evidence that soluble Aβ oligomers correlate with clinical symptoms associated with the disease. The Aβ sequence begins in the extracellular juxtamembrane region of APP and includes roughly half of the TM domain. This region contains GXXXG and GXXXA motifs, which are critical for both TM protein interactions and fibrillogenic properties of peptides derived from TM α-helices. Glycine-to-leucine mutations of these motifs were previously shown to affect APP processing and Aβ production in cells. However, the detailed contribution of these motifs to APP dimerization, their relation to processing, and the conformational changes they can induce within Aβ species remains undefined. Here, we describe highly resistant Aβ42 oligomers that are produced in cellular membrane compartments. They are formed in cells by processing of the APP amyloidogenic C-terminal fragment (C99), or by direct expression of a peptide corresponding to Aβ42, but not to Aβ40. By a point-mutation approach, we demonstrate that glycine-to-leucine mutations in the G29XXXG33 and G38XXXA42 motifs dramatically affect the Aβ oligomerization process. G33 and G38 in these motifs are specifically involved in Aβ oligomerization; the G33L mutation strongly promotes oligomerization, while G38L blocks it with a dominant effect on G33 residue modification. Finally, we report that the secreted Aβ42 oligomers display pathological properties consistent with their suggested role in AD, but do not induce toxicity in survival assays with neuronal cells. Exposure of neurons to these Aβ42 oligomers dramatically affects neuronal differentiation and, consequently, neuronal network maturation. PMID:27242518

Iron overload accelerates neuronal amyloid-β production and cognitive impairment in transgenic mice model of Alzheimer's disease.

PubMed

Becerril-Ortega, Javier; Bordji, Karim; Fréret, Thomas; Rush, Travis; Buisson, Alain

2014-10-01

Iron dyshomeostasis is proving increasingly likely to be involved in the pathology of Alzheimer's disease (AD); yet, its mechanism is not well understood. Here, we investigated the AD-related mechanism(s) of iron-sulfate exposure in vitro and in vivo, using cultured primary cortical neurons and APP/PS1 AD-model mice, respectively. In both systems, we observed iron-induced disruptions of amyloid precursor protein (APP) processing, neuronal signaling, and cognitive behavior. Iron overload increased production of amyloidogenic KPI-APP and amyloid beta. Further, this APP misprocessing was blocked by MK-801 in vitro, suggesting the effect was N-methyl-D-aspartate receptor (NMDAR) dependent. Calcium imaging confirmed that 24 hours iron exposure led to disrupted synaptic signaling by augmenting GluN2B-containing NMDAR expression-GluN2B messenger RNA and protein levels were increased and promoting excessing extrasynaptic NMDAR signaling. The disrupted GluN2B expression was concurrent with diminished expression of the splicing factors, sc35 and hnRNPA1. In APP/PS1 mice, chronic iron treatment led to hastened progression of cognitive impairment with the novel object recognition discrimination index, revealing a deficit at the age of 4 months, concomitant with augmented GluN2B expression. Together, these data suggest iron-induced APP misprocessing and hastened cognitive decline occur through inordinate extrasynaptic NMDAR activation. Copyright © 2014 Elsevier Inc. All rights reserved.

Pharmacophore-based design and discovery of (-)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis.

PubMed

Xie, Qiong; Zheng, Zhaoxi; Shao, Biyun; Fu, Wei; Xia, Zheng; Li, Wei; Sun, Jian; Zheng, Wei; Zhang, Weiwei; Sheng, Wei; Zhang, Qihong; Chen, Hongzhuan; Wang, Hao; Qiu, Zhuibai

2017-12-01

Multifunctional carbamate-type acetylcholinesterase (AChE) inhibitors with anti-amyloidogenic properties like phenserine are potential therapeutic agents for Alzheimer's disease (AD). We reported here the design of new carbamates using pharmacophore model strategy to modulate both cholinesterase and amyloidogenesis. A five-feature pharmacophore model was generated based on 25 carbamate-type training set compounds. (-)-Meptazinol carbamates that superimposed well upon the model were designed and synthesized, which exhibited nanomolar AChE inhibitory potency and good anti-amyloidogenic properties in in vitro test. The phenylcarbamate 43 was highly potent (IC 50 31.6 nM) and slightly selective for AChE, and showed low acute toxicity. In enzyme kinetics assay, 43 exhibited uncompetitive inhibition and reacted by pseudo-irreversible mechanism. 43 also showed amyloid-β (Aβ) lowering effects (51.9% decrease of Aβ 42 ) superior to phenserine (31% decrease of total Aβ) in SH-SY5Y-APP 695 cells at 50 µM. The dual actions of 43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents.

Gold Nanoparticles and Microwave Irradiation Inhibit Beta-Amyloid Amyloidogenesis

NASA Astrophysics Data System (ADS)

Araya, Eyleen; Olmedo, Ivonne; Bastus, Neus G.; Guerrero, Simón; Puntes, Víctor F.; Giralt, Ernest; Kogan, Marcelo J.

2008-11-01

Peptide-Gold nanoparticles selectively attached to β-amyloid protein (Aβ) amyloidogenic aggregates were irradiated with microwave. This treatment produces dramatic effects on the Aβ aggregates, inhibiting both the amyloidogenesis and the restoration of the amyloidogenic potential. This novel approach offers a new strategy to inhibit, locally and remotely, the amyloidogenic process, which could have application in Alzheimer’s disease therapy. We have studied the irradiation effect on the amyloidogenic process in the presence of conjugates peptide-nanoparticle by transmission electronic microscopy observations and by Thioflavine T assays to quantify the amount of fibrils in suspension. The amyloidogenic aggregates rather than the amyloid fibrils seem to be better targets for the treatment of the disease. Our results could contribute to the development of a new therapeutic strategy to inhibit the amyloidogenic process in Alzheimer’s disease.

Alpha-Linolenic Acid from Perilla frutescens var. japonica Oil Protects Aβ-Induced Cognitive Impairment through Regulation of APP Processing and Aβ Degradation.

PubMed

Lee, Ah Young; Lee, Myoung Hee; Lee, Sanghyun; Cho, Eun Ju

2017-12-13

Alzheimer's disease (AD) is characterized by progressive cognitive and memory impairment. The major pathological hallmark of AD is the accumulation of amyloid beta (Aβ), which is produced from the amyloid precursor protein (APP) through cleavage of β- and γ-secretase. Recently, dietary plant oil containing ω-3 polyunsaturated fatty acid has become an attractive alternative source to fish oil containing eicosapentaenoic acid or docosahexaenoic acid (DHA). We investigated whether ALA isolated from perilla oil has direct effects on improvement of cognitive ability and molecular mechanisms in APP processing in comparison with DHA. In the present study, ICR mice were treated orally with ALA or DHA (100 mg/kg/day) for 14 days after i.c.v. injection of Aβ 25-35 . Administration of ALA resulted in a prevention of learning and memory deficit in Aβ 25-35 -injected mice compared with the control group, as observed in T-maze, novel object recognition, and Morris water maze tests. ALA supplementation also markedly ameliorated the Aβ 25-35 -induced oxidative stress by inhibition of lipid peroxidation and nitric oxide overproduction in the mouse brain, liver, and kidney, almost down to the levels in DHA-administered group. These effects of ALA on protective mechanisms were related to the regulation of APP processing via promoting nonamyloidogenic pathway such as up-regulation of soluble APP alpha, C-terminal fragment alpha/beta ratio, and A disintegrin and metalloprotease10 protein expressions. Furthermore, ALA inhibited the amyloidogenic pathway through the down-regulation of β-site APP-cleaving enzyme and presenilin2. ALA also enhanced Aβ degradation enzyme, insulin-degrading enzyme. In conclusion, the present study indicated a beneficial effect of ALA in improving the cognitive ability against Aβ 25-35 , and these effects were comparable to those exerted by DHA. Its neuroprotective effects are mediated, in part, by regulation of APP processing and Aβ degradation, and thus, ALA might be a potential candidate for prevention or treatment of neurodegenerative diseases such as AD.

Exposure to As-, Cd-, and Pb-mixture induces Aβ, amyloidogenic APP processing and cognitive impairments via oxidative stress-dependent neuroinflammation in young rats.

PubMed

Ashok, Anushruti; Rai, Nagendra Kumar; Tripathi, Sachin; Bandyopadhyay, Sanghamitra

2015-01-01

Environmental pollutants act as risk factors for Alzheimer's disease (AD), mainly affecting the aging population. We investigated early manifestations of AD-like pathology by a mixture of arsenic (As), cadmium (Cd), and lead (Pb), reported to impair neurodevelopment. We treated rats with As+Cd+Pb at their concentrations detected in groundwater of India, ie, 0.38, 0.098, and 0.22 ppm or 10 times of each, respectively, from gestation-05 to postnatal day-180. We identified dose-dependent increase in amyloid-beta (Aβ) in frontal cortex and hippocampus as early as post-weaning. The effect was strongly significant during early-adulthood, reaching levels comparable to an Aβ-infused AD-like rat model. The metals activated the proamyloidogenic pathway, mediated by increase in amyloid precursor protein (APP), and subsequent beta secretase (BACE) and presenilin (PS)-mediated APP-processing. Investigating the mechanism of Aβ-induction revealed an augmentation in oxidative stress-dependent neuroinflammation that stimulated APP expression through interleukin-responsive-APP-mRNA 5'-untranslated region. We then examined the effects of individual metals and binary mixtures in comparison with the tertiary. Among individual metals, Pb triggered maximum induction of Aβ, whereas individual As or Cd had a relatively non-significant effect on Aβ despite enhanced APP, owing to reduced induction of BACE and PS. Interestingly, when combined the metals demonstrated synergism, with a major contribution by As. The synergistic effect was significant and consistent in tertiary mixture, resulting in the augmentation of Aβ. Eventually, increase in Aβ culminated in cognitive impairments in the young rats. Together, our data demonstrate that exposure to As+Cd+Pb induces premature manifestation of AD-like pathology that is synergistic, and oxidative stress and inflammation dependent. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Reduced Aβ secretion by human neurons under conditions of strongly increased BACE activity.

PubMed

Scholz, Diana; Chernyshova, Yana; Ückert, Anna-Katharina; Leist, Marcel

2018-05-27

The initial step in the amyloidogenic cascade of amyloid precursor protein (APP) processing is catalyzed by beta-site APP-cleaving enzyme (BACE), and this protease has increased activities in affected areas of Alzheimer's disease brains. We hypothesized that altered APP processing, due to augmented BACE activity, would affect the actions of direct and indirect BACE inhibitors. We therefore compared postmitotic human neurons (LUHMES) with their BACE-overexpressing counterparts (BLUHMES). Although β-cleavage of APP was strongly increased in BLUHMES, they produced less full-length and truncated amyloid beta (Aβ) than LUHMES. Moreover, low concentrations of BACE inhibitors decreased cellular BACE activity as expected, but increased Aβ 1-40 levels. Several other approaches to modulate BACE activity led to a similar, apparently paradoxical, behavior. For instance, reduction of intracellular acidification by bepridil increased Aβ production in parallel with decreased BACE activity. In contrast to BLUHMES, the respective control cells (LUHMES or BLUHMES with catalytically inactive BACE) showed conventional pharmacological responses. Other non-canonical neurochemical responses (so-called 'rebound effects') are well-documented for the Aβ pathway, especially for γ-secretase: a partial block of its activity leads to an increased Aβ secretion by some cell types. We therefore compared LUHMES and BLUHMES regarding rebound effects of γ-secretase inhibitors and found an Aβ rise in LUHMES but not in BLUHMES. Thus, different cellular factors are responsible for the γ-secretase- vs. BACE-related Aβ rebound. We conclude that increased BACE activity, possibly accompanied by an altered cellular localization pattern, can dramatically influence Aβ generation in human neurons and affect pharmacological responses to secretase inhibitors. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Chronic Cladribine Administration Increases Amyloid Beta Peptide Generation and Plaque Burden in Mice

PubMed Central

Hayes, Crystal D.; Dey, Debleena; Palavicini, Juan Pablo; Wang, Hongjie; Araki, Wataru; Lakshmana, Madepalli K.

2012-01-01

Background The clinical uses of 2-chloro-2′-deoxyadenosine (2-CDA) or cladribine which was initially prescribed to patients with hematological and lymphoid cancers is now extended to treat patients with multiple sclerosis (MS). Previous data has shown that 2-CDA has high affinity to the brain and readily passes through the blood brain barrier reaching CSF concentrations 25% of that found in plasma. However, whether long-term administration of 2-CDA can lead to any adverse effects in patients or animal models is not yet clearly known. Methodology Here we show that exposure of 2-CDA to CHO cells stably expressing wild-type APP751 increased generation and secretion of amyloid β peptide (Aβ) in to the conditioned medium. Interestingly, increased Aβ levels were noticed even at non-toxic concentrations of 2-CDA. Remarkably, chronic treatment of APdE9 mice, a model of Alzheimer's disease with 2-CDA for 60 days increased amyloid plaque burden by more than 1-fold. Increased Aβ generation appears to result from increased turnover of APP as revealed by cycloheximide-chase experiments. Additionally, surface labeling of APP with biotin and immunoprecipitation of surface labeled proteins with anti-biotin antibody also indicated increased APP at the cell surface in 2-CDA treated cells compared to controls. Increased turnover of APP by 2-CDA in turn might be a consequence of decreased protein levels of PIN 1, which is known to regulate cis-trans isomerization and phosphorylation of APP. Most importantly, like many other oncology drugs, 2-CDA administration led to significant delay in acquiring a reward-based learning task in a T maze paradigm. Conclusions Taken together, these data provide compelling evidence for the first time that chronic 2-CDA administration can increase amyloidogenic processing of APP leading to robustly increased plaque burden which may be responsible for the observed deficits in learning skills. Thus chronic treatment of mice with 2-CDA can have deleterious effects in vivo. PMID:23056220

Relative increase in Alzheimer's disease of soluble forms of cerebral Abeta amyloid protein precursor containing the Kunitz protease inhibitory domain.

PubMed

Moir, R D; Lynch, T; Bush, A I; Whyte, S; Henry, A; Portbury, S; Multhaup, G; Small, D H; Tanzi, R E; Beyreuther, K; Masters, C L

1998-02-27

Although a number of studies have examined amyloid precursor protein (APP) mRNA levels in Alzheimer's disease (AD), no clear consensus has emerged as to whether the levels of transcripts for isoforms containing a Kunitz protease inhibitory (KPI)-encoded region are increased or decreased in AD. Here we compare AD and control brain for the relative amounts of APP protein containing KPI to APP protein lacking this domain. APP protein was purified from the soluble subcellular fraction and Triton X-100 membrane pellet extract of one hemisphere of AD (n = 10), normal (n = 7), and neurological control (n = 5) brains. The amount of KPI-containing APP in the purified protein samples was determined using two independent assay methods. The first assay exploited the inhibitory action of KPI-containing APP on trypsin. The second assay employed reflectance analysis of Western blots. The proportion of KPI-containing forms of APP in the soluble subcellular fraction of AD brains is significantly elevated (p < 0.01) compared with controls. Species containing a KPI domain comprise 32-41 and 76-77% of purified soluble APP from control and AD brains, respectively. For purified membrane-associated APP, 72-77 and 65-82% of control and AD samples, respectively, contain a KPI domain. Since KPI-containing species of APP may be more amyloidogenic (Ho, L., Fukuchi, K., and Yonkin, S. G. (1996) J. Biol. Chem. 271, 30929-30934), our findings support an imbalance of isoforms as one possible mechanism for amyloid deposition in sporadic AD.

Mechanisms of Melatonin in Alleviating Alzheimer’s Disease

PubMed Central

Shukla, Mayuri; Govitrapong, Piyarat; Boontem, Parichart; Reiter, Russel J.; Satayavivad, Jutamaad

2017-01-01

Alzheimer’s disease (AD) is a chronic, progressive and prevalent neurodegenerative disease characterized by the loss of higher cognitive functions and an associated loss of memory. The thus far “incurable” stigma for AD prevails because of variations in the success rates of different treatment protocols in animal and human studies. Among the classical hypotheses explaining AD pathogenesis, the amyloid hypothesis is currently being targeted for drug development. The underlying concept is to prevent the formation of these neurotoxic peptides which play a central role in AD pathology and trigger a multispectral cascade of neurodegenerative processes post-aggregation. This could possibly be achieved by pharmacological inhibition of β- or γ-secretase or stimulating the non-amyloidogenic α-secretase. Melatonin the pineal hormone is a multifunctioning indoleamine. Production of this amphiphilic molecule diminishes with advancing age and this decrease runs parallel with the progression of AD which itself explains the potential benefits of melatonin in line of development and devastating consequences of the disease progression. Our recent studies have revealed a novel mechanism by which melatonin stimulates the nonamyloidogenic processing and inhibits the amyloidogenic processing of β-amyloid precursor protein (βAPP) by stimulating α-secretases and consequently down regulating both β- and γ-secretases at the transcriptional level. In this review, we discuss and evaluate the neuroprotective functions of melatonin in AD pathogenesis, including its role in the classical hypotheses in cellular and animal models and clinical interventions in AD patients, and suggest that with early detection, melatonin treatment is qualified to be an anti-AD therapy. PMID:28294066

Genetic Ablation of Apolipoprotein A-IV Accelerates Alzheimer's Disease Pathogenesis in a Mouse Model

PubMed Central

Cui, Yujie; Huang, Mingwei; He, Yingbo; Zhang, Shuyan; Luo, Yongzhang

2011-01-01

The link between lipoprotein metabolism and Alzheimer's disease (AD) has been established. Apolipoprotein A-IV (apoA-IV), a component of lipoprotein particles similar to apolipoprotein E, has been suggested to play an important role in brain metabolism. Although there are clinical debates on the function of its polymorphism in AD, the pathologic role of apoA-IV in AD is still unknown. Here, we report that genetic ablation of apoA-IV is able to accelerate AD pathogenesis in mice. In a mouse model that overexpresses human amyloid precursor protein (APP) and presenilin 1, genetic reduction of apoA-IV augments extracellular amyloid-β peptide (Aβ) burden and aggravates neuron loss in the brain. In addition, genetic ablation of apoA-IV also accelerates spatial learning deficits and increases the mortality of mice. We have found that apoA-IV colocalizes within Aβ plaques in APP/presenilin 1 transgenic mice and binds to Aβ in vitro. Subsequent studies show that apoA-IV in this model facilitates Aβ uptake in the Aβ clearance pathway mediated by astrocytes rather than the amyloidogenic pathway of APP processing. Taken together, we conclude that apoA-IV deficiency increases Aβ deposition and results in cognitive damage in the mouse model. Enhancing levels of apoA-IV may have therapeutic potential in AD treatment. PMID:21356380

First and second generation γ-secretase modulators (GSMs) modulate amyloid-β (Aβ) peptide production through different mechanisms.

PubMed

Borgegard, Tomas; Juréus, Anders; Olsson, Fredrik; Rosqvist, Susanne; Sabirsh, Alan; Rotticci, Didier; Paulsen, Kim; Klintenberg, Rebecka; Yan, Hongmei; Waldman, Magnus; Stromberg, Kia; Nord, Johan; Johansson, Jonas; Regner, Anna; Parpal, Santiago; Malinowsky, David; Radesater, Ann-Cathrin; Li, Tingsheng; Singh, Rajeshwar; Eriksson, Hakan; Lundkvist, Johan

2012-04-06

γ-Secretase-mediated cleavage of amyloid precursor protein (APP) results in the production of Alzheimer disease-related amyloid-β (Aβ) peptides. The Aβ42 peptide in particular plays a pivotal role in Alzheimer disease pathogenesis and represents a major drug target. Several γ-secretase modulators (GSMs), such as the nonsteroidal anti-inflammatory drugs (R)-flurbiprofen and sulindac sulfide, have been suggested to modulate the Alzheimer-related Aβ production by targeting the APP. Here, we describe novel GSMs that are selective for Aβ modulation and do not impair processing of Notch, EphB2, or EphA4. The GSMs modulate Aβ both in cell and cell-free systems as well as lower amyloidogenic Aβ42 levels in the mouse brain. Both radioligand binding and cellular cross-competition experiments reveal a competitive relationship between the AstraZeneca (AZ) GSMs and the established second generation GSM, E2012, but a noncompetitive interaction between AZ GSMs and the first generation GSMs (R)-flurbiprofen and sulindac sulfide. The binding of a (3)H-labeled AZ GSM analog does not co-localize with APP but overlaps anatomically with a γ-secretase targeting inhibitor in rodent brains. Combined, these data provide compelling evidence of a growing class of in vivo active GSMs, which are selective for Aβ modulation and have a different mechanism of action compared with the original class of GSMs described.

Neprilysin and Aβ Clearance: Impact of the APP Intracellular Domain in NEP Regulation and Implications in Alzheimer’s Disease

PubMed Central

Grimm, Marcus O. W.; Mett, Janine; Stahlmann, Christoph P.; Haupenthal, Viola J.; Zimmer, Valerie C.; Hartmann, Tobias

2013-01-01

One of the characteristic hallmarks of Alzheimer’s disease (AD) is an accumulation of amyloid β (Aβ) leading to plaque formation and toxic oligomeric Aβ complexes. Besides the de novo synthesis of Aβ caused by amyloidogenic processing of the amyloid precursor protein (APP), Aβ levels are also highly dependent on Aβ degradation. Several enzymes are described to cleave Aβ. In this review we focus on one of the most prominent Aβ degrading enzymes, the zinc-metalloprotease Neprilysin (NEP). In the first part of the review we discuss beside the general role of NEP in Aβ degradation the alterations of the enzyme observed during normal aging and the progression of AD. In vivo and cell culture experiments reveal that a decreased NEP level results in an increased Aβ level and vice versa. In a pathological situation like AD, it has been reported that NEP levels and activity are decreased and it has been suggested that certain polymorphisms in the NEP gene result in an increased risk for AD. Conversely, increasing NEP activity in AD mouse models revealed an improvement in some behavioral tests. Therefore it has been suggested that increasing NEP might be an interesting potential target to treat or to be protective for AD making it indispensable to understand the regulation of NEP. Interestingly, it is discussed that the APP intracellular domain (AICD), one of the cleavage products of APP processing, which has high similarities to Notch receptor processing, might be involved in the transcriptional regulation of NEP. However, the mechanisms of NEP regulation by AICD, which might be helpful to develop new therapeutic strategies, are up to now controversially discussed and summarized in the second part of this review. In addition, we review the impact of AICD not only in the transcriptional regulation of NEP but also of further genes. PMID:24391587

Alpha-Secretase ADAM10 Regulation: Insights into Alzheimer’s Disease Treatment

PubMed Central

Peron, Rafaela; Vatanabe, Izabela Pereira; Manzine, Patricia Regina; Camins, Antoni

2018-01-01

ADAM (a disintegrin and metalloproteinase) is a family of widely expressed, transmembrane and secreted proteins of approximately 750 amino acids in length with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules. ADAM10 is the main α-secretase that cleaves APP (amyloid precursor protein) in the non-amyloidogenic pathway inhibiting the formation of β-amyloid peptide, whose accumulation and aggregation leads to neuronal degeneration in Alzheimer’s disease (AD). ADAM10 is a membrane-anchored metalloprotease that sheds, besides APP, the ectodomain of a large variety of cell-surface proteins including cytokines, adhesion molecules and notch. APP cleavage by ADAM10 results in the production of an APP-derived fragment, sAPPα, which is neuroprotective. As increased ADAM10 activity protects the brain from β-amyloid deposition in AD, this strategy has been proved to be effective in treating neurodegenerative diseases, including AD. Here, we describe the physiological mechanisms regulating ADAM10 expression at different levels, aiming to propose strategies for AD treatment. We report in this review on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or translational and post-translational levels. In addition, we describe the conditions that can change ADAM10 expression in vitro and in vivo, and discuss how this knowledge may help in AD treatment. Regulation of ADAM10 is achieved by multiple mechanisms that include transcriptional, translational and post-translational strategies, which we will summarize in this review. PMID:29382156

Selective deletion of apolipoprotein E in astrocytes ameliorates the spatial learning and memory deficits in Alzheimer's disease (APP/PS1) mice by inhibiting TGF-β/Smad2/STAT3 signaling.

PubMed

Zheng, Jin-Yu; Sun, Jian; Ji, Chun-Mei; Shen, Lin; Chen, Zhong-Jun; Xie, Peng; Sun, Yuan-Zhao; Yu, Ru-Tong

2017-06-01

Astrocytes and apolipoprotein E (apoE) play critical roles in cognitive function, not only under physiological conditions but also in some pathological situations, particularly in the pathological progression of Alzheimer's disease (AD). The regulatory mechanisms underlying the effect of apoE, derived from astrocytes, on cognitive deficits during AD pathology development are unclear. In this study, we generated amyloid precursor protein/apoE knockout (APP/apoE KO ) and APP/glial fibrillary acidic protein (GFAP)-apoE KO mice (the AD mice model used in this study was based on the APP-familial Alzheimer disease overexpression) to investigate the role of apoE, derived from astrocytes, in AD pathology and cognitive function. To explore the mechanism, we investigated the amyloidogenic process related transforming growth factor β/mothers against decapentaplegic homolog 2/signal transducer and activator of transcription 3 (TGF-β/Smad2/STAT3) signaling pathway and further confirmed by administering TGF-β-overexpression adeno-associated virus (specific to astrocytes) to APP/GFAP-apoE KO mice and TGF-β-inhibition adeno-associated virus (specific to astrocytes) to APP/WT mice. Whole body deletion of apoE significantly ameliorated the spatial learning and memory impairment, reduced amyloid β-protein production and inhibited astrogliosis in APP/apoE KO mice, as well as specific deletion apoE in astrocytes in APP/GFAP-apoE KO mice. Moreover, amyloid β-protein accumulation was increased due to promotion of amyloidogenesis of APP, and astrogliosis was upregulated by activation of TGF-β/Smad2/STAT3 signaling. Furthermore, the overexpression of TGF-β in astrocytes in APP/GFAP-apoE KO mice abrogated the effects of apoE knockout. In contrast, repression of TGF-β in astrocytes of APP/WT mice exerted a therapeutic effect similar to apoE knockout. These data suggested that apoE derived from astrocytes contributes to the risk of AD through TGF-β/Smad2/STAT3 signaling activation. These findings enhance our understanding of the role of apoE, derived from astrocytes, in AD and suggest it to be a potential biomarker and therapeutic target for AD. Copyright © 2017 Elsevier Inc. All rights reserved.

Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease.

PubMed

Pera, Marta; Larrea, Delfina; Guardia-Laguarta, Cristina; Montesinos, Jorge; Velasco, Kevin R; Agrawal, Rishi R; Xu, Yimeng; Chan, Robin B; Di Paolo, Gilbert; Mehler, Mark F; Perumal, Geoffrey S; Macaluso, Frank P; Freyberg, Zachary Z; Acin-Perez, Rebeca; Enriquez, Jose Antonio; Schon, Eric A; Area-Gomez, Estela

2017-11-15

In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β-secretase to generate a 99-aa C-terminal fragment (C99) that is then cleaved by γ-secretase to generate the β-amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ-secretase activity is enriched in mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) and that ER-mitochondrial connectivity and MAM function are upregulated in AD We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ-secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Effects of Folic Acid on Secretases Involved in Aβ Deposition in APP/PS1 Mice

PubMed Central

Tian, Tian; Bai, Dong; Li, Wen; Huang, Guo-Wei; Liu, Huan

2016-01-01

Alzheimer’s disease (AD) is the most common type of dementia. Amyloid-β protein (Aβ) is identified as the core protein of neuritic plaques. Aβ is generated by the sequential cleavage of the amyloid precursor protein (APP) via the APP cleaving enzyme (α-secretase, or β-secretase) and γ-secretase. Previous studies indicated that folate deficiency elevated Aβ deposition in APP/PS1 mice, and this rise was prevented by folic acid. In the present study, we aimed to investigate whether folic acid could influence the generation of Aβ by regulating α-, β-, and γ-secretase. Herein, we demonstrated that folic acid reduced the deposition of Aβ42 in APP/PS1 mice brain by decreasing the mRNA and protein expressions of β-secretase [beta-site APP-cleaving enzyme 1 (BACE1)] and γ-secretase complex catalytic component—presenilin 1 (PS1)—in APP/PS1 mice brain. Meanwhile, folic acid increased the levels of ADAM9 and ADAM10, which are important α-secretases in ADAM (a disintegrin and metalloprotease) family. However, folic acid has no impact on the protein expression of nicastrin (Nct), another component of γ-secretase complex. Moreover, folic acid regulated the expression of miR-126-3p and miR-339-5p, which target ADAM9 and BACE1, respectively. Taken together, the effect of folic acid on Aβ deposition may relate to making APP metabolism through non-amyloidogenic pathway by decreasing β-secretase and increasing α-secretase. MicroRNA (miRNA) may involve in the regulation mechanism of folic acid on secretase expression. PMID:27618097

Inhibition of c-Jun N-terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice.

PubMed

Zhou, Qiong; Wang, Man; Du, Ying; Zhang, Wei; Bai, Miao; Zhang, Zhuo; Li, Zhuyi; Miao, Jianting

2015-04-01

Growing evidence indicates that the activation of c-Jun N-terminal kinase (JNK) is implicated in the multiple major pathological features of Alzheimer disease (AD). However, whether specific inhibition of JNK activation could prevent disease progression in adult transgenic AD models at moderate stage remains unknown. Here we first investigated the potential disease-modifying therapeutic effect of systemic administration of SP600125, a small-molecule JNK-specific inhibitor, in middle-aged APPswe/PS1dE9 mice. Using behavioral, histological, and biochemical methods, outcomes of SP600125 treatment on neuropathology and cognitive deficits were studied in APPswe/PS1dE9 mice. Compared with vehicle-treated APPswe/PS1dE9 mice, chronic treatment of SP600125 for 12 weeks potently inhibited JNK activation, which resulted in a marked improvement of behavioral measures of cognitive deficits and a dramatic reduction in amyloid plaque burden, β-amyloid production, tau hyperphosphorylation, inflammatory responses, and synaptic loss in these transgenic animals. In particular, we found that SP600125 treatment strongly promoted nonamyloidogenic amyloid precursor protein (APP) processing and inhibited amyloidogenic APP processing via regulating APP-cleavage secretase expression (ie, ADAM10, BACE1, and PS1) in APPswe/PS1dE9 mice. Our findings demonstrate that chronic SP600125 treatment is powerfully effective in slowing down disease progression by markedly reducing multiple pathological features and ameliorating cognitive deficits associated with AD. This study highlights the concept that active JNK actually contributes to the development of the disease, and provides critical preclinical evidence that specific inhibition of JNK activation by SP600125 treatment may be a novel promising disease-modifying therapeutic strategy for the treatment of AD. © 2015 American Neurological Association.

Rescue of Hypovitaminosis A Induces Non-Amyloidogenic Amyloid Precursor Protein (APP) Processing.

PubMed

Reinhardt, Sven; Grimm, Marcus O W; Stahlmann, Christoph; Hartmann, Tobias; Shudo, Koichi; Tomita, Taisuke; Endres, Kristina

2016-01-01

Retinoic acid, the bioactive metabolite of beta-carotene or vitamin A, plays a pleiotropic, multifunctional role in vertebrate development. Studies in rodents revealed that a diet deficient in vitamin A results in a complex neonatal syndrome (the VAD syndrome), manifested in many organs. In humans, the function of retinoic acid (RA) extends into adulthood, where it has important roles in fertility, vision, and suppression of neoplastic growth. In recent years, it has also been suggested that retinoic acid might potentially act as a therapeutically relevant drug in attenuating or even preventing neurodegenerative diseases such as Alzheimer's disease (AD). Here, we report that VAD leads to an increase in A-beta peptide levels while only minor effects were observed on expression levels of the amyloid precursor protein (APP) processing proteinases in wild type mice. In line with these findings, rescue of hypovitaminosis reduced A-beta amount to baseline and induced sApp-alpha secretion in combination with an increase of alpha-secretase Adam10. By comparing retinoic acid treatment starting from a full nutrition status and a "VAD" situation in human neuroblastoma cells, we show that while intensities of differential gene expression were higher in replenished cells, a large overlap in AD-related, regulated genes was observed. Our data suggest that hypovitaminosis A can contribute to onset or progression of AD by increasing synthesis of A-beta peptides and that several AD-related genes such as ADAM10 or BDNF are regulated by retinoic acid. We suggest that dietary supplementation with retinoic acid derivatives is likely to have a beneficial effect on AD-pathology in individuals with hypovitaminosis and patients with normal vitamin A status.

Occupational exposure to aluminum and its amyloidogenic link with cognitive functions.

PubMed

Zawilla, N H; Taha, F M; Kishk, N A; Farahat, S A; Farghaly, M; Hussein, M

2014-10-01

As many other metals, aluminum is a widely recognized neurotoxicant and its link with neurodegenerative disorders has been the subject of scientific debate. One proposal focuses on amyloid β deposition (amyloidogenesis) as the key player in triggering neuronal dysfunction the so-called amyloid cascade hypothesis. We undertook this study first to investigate the cognition status of workers exposed to Al dust in an Al factory in Southern Cairo, second, to evaluate serum amyloid precursor protein (APP) and cathepsin D (CD) enzyme activity to study the possible role of Al in amyloidogenesis, and finally to explore the relation between these potential biomarkers and cognitive functions. The study was conducted on 54 exposed workers and 51 matched controls. They were subjected to questionnaire, neurological examination and a cognitive test battery, Addenbrooke's Cognitive Examination - Revised (ACE-R). Serum Al, APP and CD enzyme activity were measured. A significant increase of serum Al was found in the exposed workers with an associated increase in serum APP and decrement in CD activity. The exposed workers displayed poor performance on the ACE-R test. No significant correlation was detected between ACE-R test total score and either APP or CD activity. We concluded that occupational exposure to Al is associated with cognitive impairment. The effect of occupational Al exposure on the serum levels of APP and CD activity may be regarded as a possible mechanism of Al in amyloidogenesis. However, our findings do not support the utility of serum APP and CD activity as screening markers for early or preclinical cognitive impairment. Copyright © 2014 Elsevier Inc. All rights reserved.

Unfolded Protein Response and PERK Kinase as a New Therapeutic Target in the Pathogenesis of Alzheimer's Disease.

PubMed

Rozpedek, Wioletta; Markiewicz, Lukasz; Diehl, J Alan; Pytel, Dariusz; Majsterek, Ireneusz

2015-01-01

Recent evidence suggests that the development of Alzheimer's disease (AD) and related cognitive loss is due to mutations in the Amyloid Precursor Protein (APP) gene on chromosome 21 and increased activation of eukaryotic translation initiation factor-2α (eIF2α) phosphorylation. The high level of misfolded and unfolded proteins loading in Endoplasmic Reticulum (ER) lumen triggers ER stress and as a result Unfolded Protein Response (UPR) pathways are activated. Stress-dependent activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) leads to the significant elevation of phospho-eIF2α. That attenuates general translation and, on the other hand, promotes the preferential synthesis of Activating Transcription Factor 4 (ATF4) and secretase β (BACE1) - a pivotal enzyme responsible for the initiation of the amyloidogenic pathway resulting in the generation of the amyloid β (Aβ) variant with high ability to form toxic senile plaques in AD brains. Moreover, excessive, long-term stress conditions may contribute to inducing neuronal death by apoptosis as a result of the overactivated expression of pro-apoptotic proteins via ATF4. These findings allow to infer that dysregulated translation, increased expression of BACE1 and ATF4, as a result of eIF2α phosphorylation, may be a major contributor to structural and functional neuronal loss resulting in memory impairment. Thus, blocking PERK-dependent eIF2α phosphorylation through specific, small-molecule PERK branch inhibitors seems to be a potential treatment strategy for AD individuals. That may contribute to the restoration of global translation rates and reduction of expression of ATF4 and BACE1. Hence, the treatment strategy can block accelerated β -amyloidogenesis by reduction in APP cleaving via the BACE1-dependent amyloidogenic pathway.

Predicting Amyloidogenic Proteins in the Proteomes of Plants.

PubMed

Antonets, Kirill S; Nizhnikov, Anton A

2017-10-16

Amyloids are protein fibrils with characteristic spatial structure. Though amyloids were long perceived to be pathogens that cause dozens of incurable pathologies in humans and mammals, it is currently clear that amyloids also represent a functionally important form of protein structure implicated in a variety of biological processes in organisms ranging from archaea and bacteria to fungi and animals. Despite their social significance, plants remain the most poorly studied group of organisms in the field of amyloid biology. To date, amyloid properties have only been demonstrated in vitro or in heterologous systems for a small number of plant proteins. Here, for the first time, we performed a comprehensive analysis of the distribution of potentially amyloidogenic proteins in the proteomes of approximately 70 species of land plants using the Waltz and SARP (Sequence Analysis based on the Ranking of Probabilities) bioinformatic algorithms. We analyzed more than 2.9 million protein sequences and found that potentially amyloidogenic proteins are abundant in plant proteomes. We found that such proteins are overrepresented among membrane as well as DNA- and RNA-binding proteins of plants. Moreover, seed storage and defense proteins of most plant species are rich in amyloidogenic regions. Taken together, our data demonstrate the diversity of potentially amyloidogenic proteins in plant proteomes and suggest biological processes where formation of amyloids might be functionally important.

Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease.

PubMed

Yao, Zhiwen; Yang, Wenhao; Gao, Zhiqiang; Jia, Peng

2017-04-24

Amyloid-β (Aβ) oligomers have been accepted as major neurotoxic agents in the therapy of Alzheimer's disease (AD). It has been shown that the activity of nicotinamide adenine dinucleotide (NAD+) is related with the decline of Aβ toxicity in AD. Nicotinamide mononucleotide (NMN), the important precursor of NAD+, is produced during the reaction of nicotinamide phosphoribosyl transferase (Nampt). This study aimed to figure out the potential therapeutic effects of NMN and its underlying mechanisms in APPswe/PS1dE9 (AD-Tg) mice. We found that NMN gave rise to a substantial improvement in behavioral measures of cognitive impairments compared to control AD-Tg mice. In addition, NMN treatment significantly decreased β-amyloid production, amyloid plaque burden, synaptic loss, and inflammatory responses in transgenic animals. Mechanistically, NMN effectively controlled JNK activation. Furthermore, NMN potently progressed nonamyloidogenic amyloid precursor protein (APP) and suppressed amyloidogenic APP by mediating the expression of APP cleavage secretase in AD-Tg mice. Based on our findings, it was suggested that NMN substantially decreases multiple AD-associated pathological characteristically at least partially by the inhibition of JNK activation. Copyright © 2017 Elsevier B.V. All rights reserved.

NDM29, a RNA polymerase III-dependent non coding RNA, promotes amyloidogenic processing of APP and amyloid β secretion.

PubMed

Massone, Sara; Ciarlo, Eleonora; Vella, Serena; Nizzari, Mario; Florio, Tullio; Russo, Claudio; Cancedda, Ranieri; Pagano, Aldo

2012-07-01

Neuroblastoma Differentiation Marker 29 (NDM29) is a RNA polymerase (pol) III-transcribed non-coding (nc) RNA whose synthesis drives neuroblastoma (NB) cell differentiation to a nonmalignant neuron-like phenotype. Since in this process a complex pattern of molecular changes is associated to plasma membrane protein repertoire we hypothesized that the expression of NDM29 might influence also key players of neurodegenerative pathways. In this work we show that the NDM29-dependent cell maturation induces amyloid precursor protein (APP) synthesis, leading to the increase of amyloid β peptide (Aβ) secretion and the concomitant increment of Aβ x-42/Aβ x-40 ratio. We also demonstrate that the expression of NDM29 RNA, and the consequent increase of Aβ formation, can be promoted by inflammatory stimuli (and repressed by anti-inflammatory drugs). Moreover, NDM29 expression was detected in normal human brains although an abnormal increased synthesis of this ncRNA is induced in patients affected by neurodegenerative diseases. Therefore, the complex of events triggered by NDM29 expression induces a condition that favors the formation of Aβ peptides in the extracellular space, as it may occur in Alzheimer's Disease (AD). In addition, these data unexpectedly show that a pol III-dependent small RNA can act as key regulator of brain physiology and/or pathology suggesting that a better knowledge of this portion of the human transcriptome might provide hints for neurodegeneration studies. Copyright © 2012 Elsevier B.V. All rights reserved.

Cholesterol as a co-solvent and a ligand for membrane proteins

PubMed Central

Song, Yuanli; Kenworthy, Anne K; Sanders, Charles R

2014-01-01

As of mid 2013 a Medline search on “cholesterol” yielded over 200,000 hits, reflecting the prominence of this lipid in numerous aspects of animal cell biology and physiology under conditions of health and disease. Aberrations in cholesterol homeostasis underlie both a number of rare genetic disorders and contribute to common sporadic and complex disorders including heart disease, stroke, type II diabetes, and Alzheimer's disease. The corresponding author of this review and his lab stumbled only recently into the sprawling area of cholesterol research when they discovered that the amyloid precursor protein (APP) binds cholesterol, a topic covered by the Hans Neurath Award lecture at the 2013 Protein Society Meeting. Here, we first provide a brief overview of cholesterol-protein interactions and then offer our perspective on how and why binding of cholesterol to APP and its C99 domain (β-CTF) promotes the amyloidogenic pathway, which is closely related to the etiology of Alzheimer's disease. PMID:24155031

Anti-amyloid precursor protein antibodies inhibit amyloid-β production by steric hindrance

PubMed Central

Thomas, Rhian S.; Liddell, J. Eryl; Kidd, Emma J.

2015-01-01

Summary Cleavage of amyloid precursor protein (APP) by β- and γ-secretases results in the production of amyloid-β (Aβ) in Alzheimer’s disease (AD). We raised two monoclonal antibodies, 2B3 and 2B12, that recognise the β-secretase cleavage site on APP but not Aβ. We hypothesised that these antibodies would reduce Aβ levels via steric hindrance of β-secretase. Both antibodies decreased extracellular Aβ levels from astrocytoma cells, but 2B3 was more potent than 2B12. Levels of soluble sAPPα from the non-amyloidogenic α-secretase pathway and intracellular APP were not affected by either antibody nor were there any effects on cell viability. 2B3 exhibited a higher affinity for APP than 2B12 and its epitope appeared to span the cleavage site while 2B12 bound slightly upstream. Both of these factors probably contribute to its greater effect on Aβ levels. After 60 minutes incubation at pH 4.0, most 2B3 and 2B12 remained bound to their antigen, suggesting that the antibodies will remain bound to APP in the acidic endosomes where β-secretase cleavage probably occurs. Only 2B3 and 2B12, but not control antibodies, inhibited the cleavage of sAPPα by β-secretase in a cell-free assay where effects of antibody internalisation and intracellular degradation were excluded. 2B3 virtually abolished this cleavage. In addition, levels of C-terminal APP fragments, βCTF, generated following β-secretase cleavage, were significantly reduced in cells after incubation with 2B3. These results strongly suggest that anti-cleavage site antibodies can generically reduce Aβ levels via inhibition of β-secretase by steric hindrance and may provide a novel alternative therapy for AD. PMID:21122073

Membrane remodeling by amyloidogenic and non-amyloidogenic proteins studied by EPR

NASA Astrophysics Data System (ADS)

Varkey, Jobin; Langen, Ralf

2017-07-01

The advancement in site-directed spin labeling of proteins has enabled EPR studies to expand into newer research areas within the umbrella of protein-membrane interactions. Recently, membrane remodeling by amyloidogenic and non-amyloidogenic proteins has gained a substantial interest in relation to driving and controlling vital cellular processes such as endocytosis, exocytosis, shaping of organelles like endoplasmic reticulum, Golgi and mitochondria, intracellular vesicular trafficking, formation of filopedia and multivesicular bodies, mitochondrial fusion and fission, and synaptic vesicle fusion and recycling in neurotransmission. Misregulation in any of these processes due to an aberrant protein (mutation or misfolding) or alteration of lipid metabolism can be detrimental to the cell and cause disease. Dissection of the structural basis of membrane remodeling by proteins is thus quite necessary for an understanding of the underlying mechanisms, but it remains a formidable task due to the difficulties of various common biophysical tools in monitoring the dynamic process of membrane binding and bending by proteins. This is largely since membranes generally complicate protein structure analysis and this problem is amplified for structural analysis in the presence of different types of membrane curvatures. Recent EPR studies on membrane remodeling by proteins show that a significant structural information can be generated to delineate the role of different protein modules, domains and individual amino acids in the generation of membrane curvature. These studies also show how EPR can complement the data obtained by high resolution techniques such as X-ray and NMR. This perspective covers the application of EPR in recent studies for understanding membrane remodeling by amyloidogenic and non-amyloidogenic proteins that is useful for researchers interested in using or complimenting EPR to gain better understanding of membrane remodeling. We also discuss how a single protein can generate different type of membrane curvatures using specific conformations for specific membrane structures and how EPR is a versatile tool well-suited to analyze subtle alterations in structures under such modifying conditions which otherwise would have been difficult using other biophysical tools.

Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10.

PubMed

Seegar, Tom C M; Killingsworth, Lauren B; Saha, Nayanendu; Meyer, Peter A; Patra, Dhabaleswar; Zimmerman, Brandon; Janes, Peter W; Rubinstein, Eric; Nikolov, Dimitar B; Skiniotis, Georgios; Kruse, Andrew C; Blacklow, Stephen C

2017-12-14

Cleavage of membrane-anchored proteins by ADAM (a disintegrin and metalloproteinase) endopeptidases plays a key role in a wide variety of biological signal transduction and protein turnover processes. Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic α-secretase cleavage of the Alzheimer's precursor protein (APP). We present here the X-ray crystal structure of the ADAM10 ectodomain, which, together with biochemical and cellular studies, reveals how access to the enzyme active site is regulated. The enzyme adopts an unanticipated architecture in which the C-terminal cysteine-rich domain partially occludes the enzyme active site, preventing unfettered substrate access. Binding of a modulatory antibody to the cysteine-rich domain liberates the catalytic domain from autoinhibition, enhancing enzymatic activity toward a peptide substrate. Together, these studies reveal a mechanism for regulation of ADAM activity and offer a roadmap for its modulation. Copyright © 2017 Elsevier Inc. All rights reserved.

BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions.

PubMed

Laird, Fiona M; Cai, Huaibin; Savonenko, Alena V; Farah, Mohamed H; He, Kaiwen; Melnikova, Tatyana; Wen, Hongjin; Chiang, Hsueh-Cheng; Xu, Guilian; Koliatsos, Vassilis E; Borchelt, David R; Price, Donald L; Lee, Hey-Kyoung; Wong, Philip C

2005-12-14

A transmembrane aspartyl protease termed beta-site APP cleavage enzyme 1 (BACE1) that cleaves the amyloid-beta precursor protein (APP), which is abundant in neurons, is required for the generation of amyloid-beta (Abeta) peptides implicated in the pathogenesis of Alzheimer's disease (AD). We now demonstrate that BACE1, enriched in neurons of the CNS, is a major determinant that predisposes the brain to Abeta amyloidogenesis. The physiologically high levels of BACE1 activity coupled with low levels of BACE2 and alpha-secretase anti-amyloidogenic activities in neurons is a major contributor to the accumulation of Abeta in the CNS, whereas other organs are spared. Significantly, deletion of BACE1 in APPswe;PS1DeltaE9 mice prevents both Abeta deposition and age-associated cognitive abnormalities that occur in this model of Abeta amyloidosis. Moreover, Abeta deposits are sensitive to BACE1 dosage and can be efficiently cleared from the CNS when BACE1 is silenced. However, BACE1 null mice manifest alterations in hippocampal synaptic plasticity as well as in performance on tests of cognition and emotion. Importantly, memory deficits but not emotional alterations in BACE1(-/-) mice are prevented by coexpressing APPswe;PS1DeltaE9 transgenes, indicating that other potential substrates of BACE1 may affect neural circuits related to emotion. Our results establish BACE1 and APP processing pathways as critical for cognitive, emotional, and synaptic functions, and future studies should be alert to potential mechanism-based side effects that may occur with BACE1 inhibitors designed to ameliorate Abeta amyloidosis in AD.

BACE1, a Major Determinant of Selective Vulnerability of the Brain to Amyloid-β Amyloidogenesis, is Essential for Cognitive, Emotional, and Synaptic Functions

PubMed Central

Laird, Fiona M.; Cai, Huaibin; Savonenko, Alena V.; Farah, Mohamed H.; He, Kaiwen; Melnikova, Tatyana; Wen, Hongjin; Chiang, Hsueh-Cheng; Xu, Guilian; Koliatsos, Vassilis E.; Borchelt, David R.; Price, Donald L.; Lee, Hey-Kyoung; Wong, Philip C.

2008-01-01

A transmembrane aspartyl protease termed β-site APP cleavage enzyme 1 (BACE1) that cleaves the amyloid-β precursor protein (APP), which is abundant in neurons, is required for the generation of amyloid-β (Aβ) peptides implicated in the pathogenesis of Alzheimer’s disease (AD). We now demonstrate that BACE1, enriched in neurons of the CNS, is a major determinant that predisposes the brain to Aβ amyloidogenesis. The physiologically high levels of BACE1 activity coupled with low levels of BACE2 and α-secretase anti-amyloidogenic activities in neurons is a major contributor to the accumulation of Aβ in the CNS, whereas other organs are spared. Significantly, deletion of BACE1 in APPswe;PS1ΔE9 mice prevents both Aβ deposition and age-associated cognitive abnormalities that occur in this model of Aβ amyloidosis. Moreover, Aβ deposits are sensitive to BACE1 dosage and can be efficiently cleared from the CNS when BACE1 is silenced. However, BACE1 null mice manifest alterations in hippocampal synaptic plasticity as well as in performance on tests of cognition and emotion. Importantly, memory deficits but not emotional alterations in BACE1-/- mice are prevented by coexpressing APPswe;PS1ΔE9 transgenes, indicating that other potential substrates of BACE1 may affect neural circuits related to emotion. Our results establish BACE1 and APP processing pathways as critical for cognitive, emotional, and synaptic functions, and future studies should be alert to potential mechanism-based side effects that may occur with BACE1 inhibitors designed to ameliorate Aβ amyloidosis in AD. PMID:16354928

The amyloid interactome: Exploring protein aggregation

PubMed Central

Mastrokalou, Chara V.; Hamodrakas, Stavros J.

2017-01-01

Protein-protein interactions are the quintessence of physiological activities, but also participate in pathological conditions. Amyloid formation, an abnormal protein-protein interaction process, is a widespread phenomenon in divergent proteins and peptides, resulting in a variety of aggregation disorders. The complexity of the mechanisms underlying amyloid formation/amyloidogenicity is a matter of great scientific interest, since their revelation will provide important insight on principles governing protein misfolding, self-assembly and aggregation. The implication of more than one protein in the progression of different aggregation disorders, together with the cited synergistic occurrence between amyloidogenic proteins, highlights the necessity for a more universal approach, during the study of these proteins. In an attempt to address this pivotal need we constructed and analyzed the human amyloid interactome, a protein-protein interaction network of amyloidogenic proteins and their experimentally verified interactors. This network assembled known interconnections between well-characterized amyloidogenic proteins and proteins related to amyloid fibril formation. The consecutive extended computational analysis revealed significant topological characteristics and unraveled the functional roles of all constituent elements. This study introduces a detailed protein map of amyloidogenicity that will aid immensely towards separate intervention strategies, specifically targeting sub-networks of significant nodes, in an attempt to design possible novel therapeutics for aggregation disorders. PMID:28249044

Newly designed 11-gene panel reveals first case of hereditary amyloidosis captured by massive parallel sequencing.

PubMed

Chyra Kufova, Zuzana; Sevcikova, Tereza; Januska, Jaroslav; Vojta, Petr; Boday, Arpad; Vanickova, Pavla; Filipova, Jana; Growkova, Katerina; Jelinek, Tomas; Hajduch, Marian; Hajek, Roman

2018-02-17

Amyloidosis is caused by deposition of abnormal protein fibrils, leading to damage of organ function. Hereditary amyloidosis represents a monogenic disease caused by germline mutations in 11 amyloidogenic precursor protein genes. One of the important but non-specific symptoms of amyloidosis is hypertrophic cardiomyopathy. Diagnostics of hereditary amyloidosis is complicated and the real cause can remain overlooked. We aimed to design hereditary amyloidosis gene panel and to introduce new next-generation sequencing (NGS) approach to investigate hereditary amyloidosis in a cohort of patients with hypertrophic cardiomyopathy of unknown significance. Design of target enrichment DNA library preparation using Haloplex Custom Kit containing 11 amyloidogenic genes was followed by MiSeq Illumina sequencing and bioinformatics identification of germline variants using tool VarScan in a cohort of 40 patients. We present design of NGS panel for 11 genes ( TTR , FGA , APOA1 , APOA2 , LYZ , GSN , CST3 , PRNP , APP , B2M , ITM2B ) connected to various forms of amyloidosis. We detected one mutation, which is responsible for hereditary amyloidosis. Some other single nucleotide variants are so far undescribed or rare variants or represent common polymorphisms in European population. We report one positive case of hereditary amyloidosis in a cohort of patients with hypertrophic cardiomyopathy of unknown significance and set up first panel for NGS in hereditary amyloidosis. This work may facilitate successful implementation of the NGS method by other researchers or clinicians and may improve the diagnostic process after validation. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Membrane remodeling by amyloidogenic and non-amyloidogenic proteins studied by EPR.

PubMed

Varkey, Jobin; Langen, Ralf

2017-07-01

The advancement in site-directed spin labeling of proteins has enabled EPR studies to expand into newer research areas within the umbrella of protein-membrane interactions. Recently, membrane remodeling by amyloidogenic and non-amyloidogenic proteins has gained a substantial interest in relation to driving and controlling vital cellular processes such as endocytosis, exocytosis, shaping of organelles like endoplasmic reticulum, Golgi and mitochondria, intracellular vesicular trafficking, formation of filopedia and multivesicular bodies, mitochondrial fusion and fission, and synaptic vesicle fusion and recycling in neurotransmission. Misregulation in any of these processes due to an aberrant protein (mutation or misfolding) or alteration of lipid metabolism can be detrimental to the cell and cause disease. Dissection of the structural basis of membrane remodeling by proteins is thus quite necessary for an understanding of the underlying mechanisms, but it remains a formidable task due to the difficulties of various common biophysical tools in monitoring the dynamic process of membrane binding and bending by proteins. This is largely since membranes generally complicate protein structure analysis and this problem is amplified for structural analysis in the presence of different types of membrane curvatures. Recent EPR studies on membrane remodeling by proteins show that a significant structural information can be generated to delineate the role of different protein modules, domains and individual amino acids in the generation of membrane curvature. These studies also show how EPR can complement the data obtained by high resolution techniques such as X-ray and NMR. This perspective covers the application of EPR in recent studies for understanding membrane remodeling by amyloidogenic and non-amyloidogenic proteins that is useful for researchers interested in using or complimenting EPR to gain better understanding of membrane remodeling. We also discuss how a single protein can generate different type of membrane curvatures using specific conformations for specific membrane structures and how EPR is a versatile tool well-suited to analyze subtle alterations in structures under such modifying conditions which otherwise would have been difficult using other biophysical tools. Copyright © 2017 Elsevier Inc. All rights reserved.

Toxic β-Amyloid (Aβ) Alzheimer's Ion Channels: From Structure to Function and Design

NASA Astrophysics Data System (ADS)

Nussinov, Ruth

2012-02-01

Full-length amyloid beta peptides (Aβ1-40/42) form neuritic amyloid plaques in Alzheimer's disease (AD) patients and are implicated in AD pathology. Recent biophysical and cell biological studies suggest a direct mechanism of amyloid beta toxicity -- ion channel mediated loss of calcium homeostasis. Truncated amyloid beta fragments (Aβ11-42 and Aβ17-42), commonly termed as non-amyloidogenic are also found in amyloid plaques of Alzheimer's disease (AD) and in the preamyloid lesions of Down's syndrome (DS), a model system for early onset AD study. Very little is known about the structure and activity of these smaller peptides although they could be key AD and DS pathological agents. Using complementary techniques of explicit solvent molecular dynamics (MD) simulations, atomic force microscopy (AFM), channel conductance measurements, cell calcium uptake assays, neurite degeneration and cell death assays, we have shown that non-amyloidogenic Aβ9-42 and Aβ17-42 peptides form ion channels with loosely attached subunits and elicit single channel conductances. The subunits appear mobile suggesting insertion of small oligomers, followed by dynamic channel assembly and dissociation. These channels allow calcium uptake in APP-deficient cells and cause neurite degeneration in human cortical neurons. Channel conductance, calcium uptake and neurite degeneration are selectively inhibited by zinc, a blocker of amyloid ion channel activity. Thus truncated Aβ fragments could account for undefined roles played by full length Aβs and provide a novel mechanism of AD and DS pathology. The emerging picture from our large-scale simulations is that toxic ion channels formed by β-sheets are highly polymorphic, and spontaneously break into loosely interacting dynamic units (though still maintaining ion channel structures as imaged with AFM), that associate and dissociate leading to toxic ion flux. This sharply contrasts intact conventional gated ion channels that consist of tightly interacting α-helices that robustly prevent ion leakage, rather than hydrogen-bonded β-strands. Moreover, in comparison with β-rich antimicrobial peptide (AMP) such as a protegrin-1 (PG-1), both Aβ and PG-1 are cytotoxic, and capable of forming fibrils and dynamic channels which consist of subunits with similar dimensions. These combined properties support a functional relationship between amyloidogenic peptides and β-sheet-rich cytolytic AMPs, suggesting that PG-1 is amyloidogenic and amyloids may have an antimicrobial function.

Self-assembly of short amyloidogenic peptides at the air-water interface.

PubMed

Chaudhary, Nitin; Nagaraj, Ramakrishnan

2011-08-01

Short peptide stretches in amyloidogenic proteins can form amyloid fibrils in vitro and have served as good models for studying amyloid fibril formation. Recently, these amyloidogenic peptides have gained considerable attention, as non-amyloid ordered structures can be obtained from these peptides by carefully tuning the conditions of self-assembly, especially pH, temperature and presence of organic solvents. We have examined the effect of surface pressure on the self-assembled structures of two amyloidogenic peptides, Pβ(2)m (Ac-DWSFYLLYYTEFT-am) and AcPHF6 (Ac-VQIVYK-am) at the air-water interface when deposited from different solvents. Both the peptides are surface-active and form Thioflavin T (ThT) positive structures at the air-water interface. There is considerable hysteresis in the compression and expansion isotherms, suggesting the occurrence of structural rearrangements during compression. Preformed Pβ(2)m fibrillar structures at the air-water interface are disrupted as peptide is compressed to lower molecular areas but restored if the film is expanded, suggesting that the process is reversible. AcPHF6, on the other hand, shows largely sheet-like structures at lower molecular areas. The solvents used for dissolution of the peptides appear to influence the nature of the aggregates formed. Our results show that like hydrostatic pressure, surface pressure can also be utilized for modulating the self-assembly of the amyloidogenic and self-assembling peptides. Copyright © 2011 Elsevier Inc. All rights reserved.

Epigenetic mechanisms underlying cognitive impairment and Alzheimer disease hallmarks in 5XFAD mice.

PubMed

Griñán-Ferré, Christian; Sarroca, Sara; Ivanova, Aleksandra; Puigoriol-Illamola, Dolors; Aguado, Fernando; Camins, Antoni; Sanfeliu, Coral; Pallàs, Mercè

2016-04-01

5XFAD is an early-onset mouse transgenic model of Alzheimer disease (AD). Up to now there are no studies that focus on the epigenetic changes produced as a result of Aβ-42 accumulation and the possible involvement in the different expression of related AD-genes. Under several behavioral and cognition test, we found impairment in memory and psychoemotional changes in female 5XFAD mice in reference to wild type that worsens with age. Cognitive changes correlated with alterations on protein level analysis and gene expression of markers related with tau aberrant phosphorylation, amyloidogenic pathway (APP, BACE1), Oxidative Stress (iNOS, Aldh2) and inflammation (astrogliosis, TNF-α and IL-6); no changes were found in non-amyloidogenic pathway indicators such as ADAM10. Epigenetics changes as higher CpG methylation and transcriptional changes in DNA methyltransferases (DNMTs) family were found. Dnmt1 increases in younger 5XFAD and Dnmt3a and b high levels in the oldest transgenic mice. Similar pattern was found with histone methyltransferases such as Jarid1a andG9a. Histone deacetylase 2 (Hdac2) or Sirt6, both related with cognition and memory, presented a similar pattern. Taken together, these hallmarks presented by the 5XFAD model prompted its use in assessing different potential therapeutic interventions based on epigenetic targets after earlier amyloid deposition.

Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus.

PubMed

Torres, Manuel; Jimenez, Sebastian; Sanchez-Varo, Raquel; Navarro, Victoria; Trujillo-Estrada, Laura; Sanchez-Mejias, Elisabeth; Carmona, Irene; Davila, Jose Carlos; Vizuete, Marisa; Gutierrez, Antonia; Vitorica, Javier

2012-11-22

Axonal pathology might constitute one of the earliest manifestations of Alzheimer disease. Axonal dystrophies were observed in Alzheimer's patients and transgenic models at early ages. These axonal dystrophies could reflect the disruption of axonal transport and the accumulation of multiple vesicles at local points. It has been also proposed that dystrophies might interfere with normal intracellular proteolysis. In this work, we have investigated the progression of the hippocampal pathology and the possible implication in Abeta production in young (6 months) and aged (18 months) PS1(M146L)/APP(751sl) transgenic mice. Our data demonstrated the existence of a progressive, age-dependent, formation of axonal dystrophies, mainly located in contact with congophilic Abeta deposition, which exhibited tau and neurofilament hyperphosphorylation. This progressive pathology was paralleled with decreased expression of the motor proteins kinesin and dynein. Furthermore, we also observed an early decrease in the activity of cathepsins B and D, progressing to a deep inhibition of these lysosomal proteases at late ages. This lysosomal impairment could be responsible for the accumulation of LC3-II and ubiquitinated proteins within axonal dystrophies. We have also investigated the repercussion of these deficiencies on the APP metabolism. Our data demonstrated the existence of an increase in the amyloidogenic pathway, which was reflected by the accumulation of hAPPfl, C99 fragment, intracellular Abeta in parallel with an increase in BACE and gamma-secretase activities. In vitro experiments, using APPswe transfected N2a cells, demonstrated that any imbalance on the proteolytic systems reproduced the in vivo alterations in APP metabolism. Finally, our data also demonstrated that Abeta peptides were preferentially accumulated in isolated synaptosomes. A progressive age-dependent cytoskeletal pathology along with a reduction of lysosomal and, in minor extent, proteasomal activity could be directly implicated in the progressive accumulation of APP derived fragments (and Abeta peptides) in parallel with the increase of BACE-1 and gamma-secretase activities. This retard in the APP metabolism seemed to be directly implicated in the synaptic Abeta accumulation and, in consequence, in the pathology progression between synaptically connected regions.

Transthyretin Protects against A-Beta Peptide Toxicity by Proteolytic Cleavage of the Peptide: A Mechanism Sensitive to the Kunitz Protease Inhibitor

PubMed Central

Costa, Rita; Ferreira-da-Silva, Frederico; Saraiva, Maria J.; Cardoso, Isabel

2008-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of amyloid β-peptide (A-Beta) in the brain. Transthyretin (TTR) is a tetrameric protein of about 55 kDa mainly produced in the liver and choroid plexus of the brain. The known physiological functions of TTR are the transport of thyroid hormone T4 and retinol, through binding to the retinol binding protein. TTR has also been established as a cryptic protease able to cleave ApoA-I in vitro. It has been described that TTR is involved in preventing A-Beta fibrilization, both by inhibiting and disrupting A-Beta fibrils, with consequent abrogation of toxicity. We further characterized the nature of the TTR/A-Beta interaction and found that TTR, both recombinant or isolated from human sera, was able to proteolytically process A-Beta, cleaving the peptide after aminoacid residues 1, 2, 3, 10, 13, 14,16, 19 and 27, as determined by mass spectrometry, and reversed phase chromatography followed by N-terminal sequencing. A-Beta peptides (1–14) and (15–42) showed lower amyloidogenic potential than the full length counterpart, as assessed by thioflavin binding assay and ultrastructural analysis by transmission electron microscopy. A-Beta cleavage by TTR was inhibited in the presence of an αAPP peptide containing the Kunitz Protease Inhibitor (KPI) domain but not in the presence of the secreted αAPP derived from the APP isoform 695 without the KPI domain. TTR was also able to degrade aggregated forms of A-Beta peptide. Our results confirmed TTR as a protective molecule in AD, and prompted A-Beta proteolysis by TTR as a protective mechanism in this disease. TTR may prove to be a useful therapeutic agent for preventing or retarding the cerebral amyloid plaque formation implicated in AD pathology. PMID:18682830

SIRT3 activator Honokiol attenuates β-Amyloid by modulating amyloidogenic pathway

PubMed Central

Lynd, Tyler; Briggs, Gwyneth; Adamek, Danielle; Jones, Ellery; Heiner, Jake; Majrashi, Mohammed; Moore, Timothy; Amin, Rajesh; Suppiramaniam, Vishnu

2018-01-01

Honokiol (poly-phenolic lignan from Magnolia grandiflora) is a Sirtuin-3 (SIRT3) activator which exhibit antioxidant activity and augment mitochondrial functions in several experimental models. Modern evidence suggests the critical role of SIRT3 in the progression of several metabolic and neurodegenerative diseases. Amyloid beta (Aβ), the precursor to extracellular senile plaques, accumulates in the brains of patients with Alzheimer’s disease (AD) and is related to the development of cognitive impairment and neuronal cell death. Aβ is generated from amyloid-β precursor protein (APP) through sequential cleavages, first by β-secretase and then by γ-secretase. Drugs modulating this pathway are believed to be one of the most promising strategies for AD treatment. In the present study, we found that Honokiol significantly enhanced SIRT3 expression, reduced reactive oxygen species generation and lipid peroxidation, enhanced antioxidant activities, and mitochondrial function thereby reducing Aβ and sAPPβ levels in Chinese Hamster Ovarian (CHO) cells (carrying the amyloid precursor protein-APP and Presenilin PS1 mutation). Mechanistic studies revealed that Honokiol affects neither protein levels of APP nor α-secretase activity. In contrast, Honokiol increased the expression of AMPK, CREB, and PGC-1α, thereby inhibiting β-secretase activity leading to reduced Aβ levels. These results suggest that Honokiol is an activator of SIRT3 capable of improving antioxidant activity, mitochondrial energy regulation, while decreasing Aβ, thereby indicating it to be a lead compound for AD drug development. PMID:29324783

Sortilin-related receptor 1 interacts with amyloid precursor protein and is activated by 6-shogaol, leading to inhibition of the amyloidogenic pathway.

PubMed

Na, Ji-Young; Song, Kibbeum; Lee, Ju-Woon; Kim, Sokho; Kwon, Jungkee

2017-03-18

Sortilin-related receptor 1 (SORL1) is a neuronal sorting protein that reduces amyloid precursor protein (APP) trafficking to secretases that generate amyloid beta (Aβ). Although 6-shogaol, a constituent of ginger, has been reported to have anti-inflammatory and anti-oxidant effects on neuronal cells, research regarding the activation of SORL1 has not yet been reported. Here, we aimed to investigate whether 6-shogaol contributes to the increases in SORL1 that are related to Alzheimer's disease (AD). To clarify the effect of 6-shogaol as a possible activator of SORL1, we used SORL1 siRNA as a blockade of SORL1 in hippocampal neuronal cells (HT22). We found that SORL1 siRNA treatment naturally inhibited SORL1 and led to increases in β-secretase APP cleaving enzyme (BACE), secreted APP-β (sAPPβ) and Aβ. In contrast, 6-shogaol-mediated activation of SORL1 significantly downregulated BACE, sAPPβ, and Aβ in both in vitro HT22 cells and in vivo APPSw/PS1-dE9 Tg mice. Therefore, SORL1 activation by 6-shogaol provides neuronal cell survival through the inhibition of Aβ production. These results indicate that 6-shogaol should be regarded as an SORL1 activator and a potential preventive agent for the treatment of AD. Copyright © 2017 Elsevier Inc. All rights reserved.

Early Amyloidogenic Oligomerization Studied through Fluorescence Lifetime Correlation Spectroscopy

PubMed Central

Paredes, Jose M.; Casares, Salvador; Ruedas-Rama, Maria J.; Fernandez, Elena; Castello, Fabio; Varela, Lorena; Orte, Angel

2012-01-01

Amyloidogenic protein aggregation is a persistent biomedical problem. Despite active research in disease-related aggregation, the need for multidisciplinary approaches to the problem is evident. Recent advances in single-molecule fluorescence spectroscopy are valuable for examining heterogenic biomolecular systems. In this work, we have explored the initial stages of amyloidogenic aggregation by employing fluorescence lifetime correlation spectroscopy (FLCS), an advanced modification of conventional fluorescence correlation spectroscopy (FCS) that utilizes time-resolved information. FLCS provides size distributions and kinetics for the oligomer growth of the SH3 domain of α-spectrin, whose N47A mutant forms amyloid fibrils at pH 3.2 and 37 °C in the presence of salt. The combination of FCS with additional fluorescence lifetime information provides an exciting approach to focus on the initial aggregation stages, allowing a better understanding of the fibrillization process, by providing multidimensional information, valuable in combination with other conventional methodologies. PMID:22949804

Profiles of β-Amyloid Peptides and Key Secretases in Brain Autopsy Samples Differ with Sex and APOE ε4 Status: Impact for Risk and Progression of Alzheimer Disease.

PubMed

Nyarko, Jennifer N K; Quartey, Maa O; Pennington, Paul R; Heistad, Ryan M; Dea, Doris; Poirier, Judes; Baker, Glen B; Mousseau, Darrell D

2018-03-01

The APOE ε4 allele was originally reported to contribute to risk of Alzheimer's disease (AD) in women, yet male and female AD patient-derived data are routinely pooled. Histopathological hallmarks of AD include neurofibrillary tangles centered on hyperphosphorylated Tau and plaques composed of the β-amyloid (Aβ) peptide that is derived by sequential secretase-mediated cleavage of the Amyloid Protein Precursor (APP). We chose to examine profiles of Aβ(1-40), Aβ(1-42), and N-truncated (i.e., p3-related) fragments in the plaque-associated fraction of autopsied cortical and corresponding hippocampal samples from donors with a diagnosis of early-onset (EOAD) and late-onset (LOAD) AD. Levels of Aβ(1-40), Aβ(1-42), and the p3 fragment-enriched pool were increased in EOAD and LOAD samples, and correlated well within -but not between- regions. Counterintuitively, these increases were similar regardless of the AD donor's APOE ε4 status. Focusing on the donor's sex and APOE ε4 status as nominal variables (i.e., omitting diagnosis from the stratification) revealed that increases in Aβ peptides were specific to female carriers of the ε4 allele and correlated with the proportional expression of BACE1/β-secretase and ADAM10/α-secretase in the cortex and with nicastrin (γ-secretase) expression in the hippocampus. These data preliminarily support the possibility that AD follows distinct amyloidogenic processes in males and females, and that the APOE ε4 allele exerts a major influence on the disease process, particularly in women. This knowledge could significantly impact the (re)interpretation of unsuccessful outcomes of clinical interventions targeting either Aβ peptides directly or the secretases implicated in APP processing. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

ACE inhibition with captopril retards the development of signs of neurodegeneration in an animal model of Alzheimer's disease.

PubMed

AbdAlla, Said; Langer, Andreas; Fu, Xuebin; Quitterer, Ursula

2013-08-16

Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer's disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The angiotensin II AT1 receptor is a significant source of brain ROS, and AD patients have an increased brain angiotensin-converting enzyme (ACE) level, which could account for an excessive angiotensin-dependent AT1-induced ROS generation. Therefore, we analyzed the impact of ACE inhibition on signs of neurodegeneration of aged Tg2576 mice as a transgenic animal model of AD. Whole genome microarray gene expression profiling and biochemical analyses demonstrated that the centrally active ACE inhibitor captopril normalized the excessive hippocampal ACE activity of AD mice. Concomitantly, the development of signs of neurodegeneration was retarded by six months of captopril treatment. The neuroprotective profile triggered by captopril was accompanied by reduced amyloidogenic processing of the amyloid precursor protein (APP), and decreased hippocampal ROS, which is known to enhance Abeta generation by increased activation of beta- and gamma-secretases. Taken together, our data present strong evidence that ACE inhibition with a widely used cardiovascular drug could interfere with Abeta-dependent neurodegeneration.

ACE Inhibition with Captopril Retards the Development of Signs of Neurodegeneration in an Animal Model of Alzheimer’s Disease

PubMed Central

AbdAlla, Said; Langer, Andreas; Fu, Xuebin; Quitterer, Ursula

2013-01-01

Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer’s disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The angiotensin II AT1 receptor is a significant source of brain ROS, and AD patients have an increased brain angiotensin-converting enzyme (ACE) level, which could account for an excessive angiotensin-dependent AT1-induced ROS generation. Therefore, we analyzed the impact of ACE inhibition on signs of neurodegeneration of aged Tg2576 mice as a transgenic animal model of AD. Whole genome microarray gene expression profiling and biochemical analyses demonstrated that the centrally active ACE inhibitor captopril normalized the excessive hippocampal ACE activity of AD mice. Concomitantly, the development of signs of neurodegeneration was retarded by six months of captopril treatment. The neuroprotective profile triggered by captopril was accompanied by reduced amyloidogenic processing of the amyloid precursor protein (APP), and decreased hippocampal ROS, which is known to enhance Abeta generation by increased activation of beta- and gamma-secretases. Taken together, our data present strong evidence that ACE inhibition with a widely used cardiovascular drug could interfere with Abeta-dependent neurodegeneration. PMID:23959119

Sildenafil Decreases BACE1 and Cathepsin B Levels and Reduces APP Amyloidogenic Processing in the SAMP8 Mouse.

PubMed

Orejana, Lourdes; Barros-Miñones, Lucía; Jordan, Joaquin; Cedazo-Minguez, Angel; Tordera, Rosa M; Aguirre, Norberto; Puerta, Elena

2015-06-01

The senescence-accelerated mouse-prone 8 (SAMP8), used as a model of aging, displays many established pathological features of Alzheimer's disease. Cognitive impairments and increased levels of hyperphosphorylated tau are found in the hippocampus of SAMP8 mice along with an increased β-secretase activity and amyloid-β (Aβ) depositions that increase in number and extent with age. Based on a previous study from our laboratory showing an amelioration of cognitive impairments and tau pathology by sildenafil, in this study we tested whether this drug could also modulate the amyloid precursor protein amyloidogenic processing in this mouse model. Our results show that the protein levels of the β-secretases β-site amyloid precursor protein cleaving enzyme 1 and cathepsin B are higher in the hippocampus of 9-month-old SAMP8 mice than those of age-matched senescence-resistant-1. Sildenafil (7.5mg/kg for 4 weeks) attenuated learning and memory impairments shown by SAMP8 mice in the passive avoidance test. The increased expression of β-site amyloid precursor protein cleaving enzyme 1 was also reduced by sildenafil, an effect paralleled to decreases in the activities of two β-site amyloid precursor protein cleaving enzyme 1 modulators, calpain and cyclin-dependent kinase 5 protein. Interestingly, sildenafil enhanced both Akt and glycogen synthase kinase-3β (ser9) phosphorylation, which could be mediating the reduction in cathepsin B levels found in the hippocampus of sildenafil-treated SAMP8 mice. Sildenafil-induced reduction in β-site amyloid precursor protein cleaving enzyme 1 and cathepsin B expression in SAMP8 mice was associated with a decrease in hippocampal Aβ42 levels which, in turn, could mediate the parallel decline in glial fibrillary acidic protein expression observed in these animals. These findings highlight the therapeutic potential of sildenafil in Alzheimer's disease pathogenesis. © The Author 2014. Published by Oxford University Press on behalf of the Gerontological Society of America. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus

PubMed Central

2012-01-01

Background Axonal pathology might constitute one of the earliest manifestations of Alzheimer disease. Axonal dystrophies were observed in Alzheimer’s patients and transgenic models at early ages. These axonal dystrophies could reflect the disruption of axonal transport and the accumulation of multiple vesicles at local points. It has been also proposed that dystrophies might interfere with normal intracellular proteolysis. In this work, we have investigated the progression of the hippocampal pathology and the possible implication in Abeta production in young (6 months) and aged (18 months) PS1(M146L)/APP(751sl) transgenic mice. Results Our data demonstrated the existence of a progressive, age-dependent, formation of axonal dystrophies, mainly located in contact with congophilic Abeta deposition, which exhibited tau and neurofilament hyperphosphorylation. This progressive pathology was paralleled with decreased expression of the motor proteins kinesin and dynein. Furthermore, we also observed an early decrease in the activity of cathepsins B and D, progressing to a deep inhibition of these lysosomal proteases at late ages. This lysosomal impairment could be responsible for the accumulation of LC3-II and ubiquitinated proteins within axonal dystrophies. We have also investigated the repercussion of these deficiencies on the APP metabolism. Our data demonstrated the existence of an increase in the amyloidogenic pathway, which was reflected by the accumulation of hAPPfl, C99 fragment, intracellular Abeta in parallel with an increase in BACE and gamma-secretase activities. In vitro experiments, using APPswe transfected N2a cells, demonstrated that any imbalance on the proteolytic systems reproduced the in vivo alterations in APP metabolism. Finally, our data also demonstrated that Abeta peptides were preferentially accumulated in isolated synaptosomes. Conclusion A progressive age-dependent cytoskeletal pathology along with a reduction of lysosomal and, in minor extent, proteasomal activity could be directly implicated in the progressive accumulation of APP derived fragments (and Abeta peptides) in parallel with the increase of BACE-1 and gamma-secretase activities. This retard in the APP metabolism seemed to be directly implicated in the synaptic Abeta accumulation and, in consequence, in the pathology progression between synaptically connected regions. PMID:23173743

Synthesis, Structure-Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5-HT4 Receptor Partial Agonists.

PubMed

Nirogi, Ramakrishna; Mohammed, Abdul Rasheed; Shinde, Anil K; Gagginapally, Shankar Reddy; Kancharla, Durga Malleshwari; Middekadi, Vanaja Reddy; Bogaraju, Narsimha; Ravella, Srinivasa Rao; Singh, Pooja; Birangal, Sumit Raosaheb; Subramanian, Ramkumar; Palacharla, Raghava Choudary; Benade, Vijay; Muddana, Nageswararao; Jayarajan, Pradeep

2018-05-31

Alzheimer's disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT 4 receptor (5-HT 4 R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT 4 R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure-activity relationships, compound 4o was identified as a potent 5-HT 4 R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT 4 R antagonist, attenuated the activity of compound 4o in the novel-object-recognition-test cognition model.

Increased Secreted Amyloid Precursor Protein-α (sAPPα) in Severe Autism: Proposal of a Specific, Anabolic Pathway and Putative Biomarker

PubMed Central

Sokol, Deborah K.; Lahiri, Debomoy K.

2011-01-01

Autism is a neurodevelopmental disorder characterized by deficits in verbal communication, social interactions, and the presence of repetitive, stereotyped and compulsive behaviors. Excessive early brain growth is found commonly in some patients and may contribute to disease phenotype. Reports of increased levels of brain-derived neurotrophic factor (BDNF) and other neurotrophic-like factors in autistic neonates suggest that enhanced anabolic activity in CNS mediates this overgrowth effect. We have shown previously that in a subset of patients with severe autism and aggression, plasma levels of the secreted amyloid-β (Aβ) precursor protein-alpha form (sAPPα) were significantly elevated relative to controls and patients with mild-to-moderate autism. Here we further tested the hypothesis that levels of sAPPα and sAPPβ (proteolytic cleavage products of APP by α- and β-secretase, respectively) are deranged in autism and may contribute to an anabolic environment leading to brain overgrowth. We measured plasma levels of sAPPα, sAPPβ, Aβ peptides and BDNF by corresponding ELISA in a well characterized set of subjects. We included for analysis 18 control, 6 mild-to-moderate, and 15 severely autistic patient plasma samples. We have observed that sAPPα levels are increased and BDNF levels decreased in the plasma of patients with severe autism as compared to controls. Further, we show that Aβ1-40, Aβ1-42, and sAPPβ levels are significantly decreased in the plasma of patients with severe autism. These findings do not extend to patients with mild-to-moderate autism, providing a biochemical correlate of phenotypic severity. Taken together, this study provides evidence that sAPPα levels are generally elevated in severe autism and suggests that these patients may have aberrant non-amyloidogenic processing of APP. PMID:21731612

Functional amyloids in Streptococcus mutans, their use as targets of biofilm inhibition and initial characterization of SMU_63c

PubMed Central

Besingi, Richard N; Wenderska, Iwona B; Senadheera, Dilani B; Cvitkovitch, Dennis G; Long, Joanna R; Wen, Zezhang T

2017-01-01

Amyloids have been identified as functional components of the extracellular matrix of bacterial biofilms. Streptococcus mutans is an established aetiologic agent of dental caries and a biofilm dweller. In addition to the previously identified amyloidogenic adhesin P1 (also known as AgI/II, PAc), we show that the naturally occurring antigen A derivative of S. mutans wall-associated protein A (WapA) and the secreted protein SMU_63c can also form amyloid fibrils. P1, WapA and SMU_63c were found to significantly influence biofilm development and architecture, and all three proteins were shown by immunogold electron microscopy to reside within the fibrillar extracellular matrix of the biofilms. We also showed that SMU_63c functions as a negative regulator of biofilm cell density and genetic competence. In addition, the naturally occurring C-terminal cleavage product of P1, C123 (also known as AgII), was shown to represent the amyloidogenic moiety of this protein. Thus, P1 and WapA both represent sortase substrates that are processed to amyloidogenic truncation derivatives. Our current results suggest a novel mechanism by which certain cell surface adhesins are processed and contribute to the amyloidogenic capability of S. mutans. We further demonstrate that the polyphenolic small molecules tannic acid and epigallocatechin-3-gallate, and the benzoquinone derivative AA-861, which all inhibit amyloid fibrillization of C123 and antigen A in vitro, also inhibit S. mutans biofilm formation via P1- and WapA-dependent mechanisms, indicating that these proteins serve as therapeutic targets of anti-amyloid compounds. PMID:28141493

Mammalian amyloidogenic proteins promote prion nucleation in yeast.

PubMed

Chandramowlishwaran, Pavithra; Sun, Meng; Casey, Kristin L; Romanyuk, Andrey V; Grizel, Anastasiya V; Sopova, Julia V; Rubel, Aleksandr A; Nussbaum-Krammer, Carmen; Vorberg, Ina M; Chernoff, Yury O

2018-03-02

Fibrous cross-β aggregates (amyloids) and their transmissible forms (prions) cause diseases in mammals (including humans) and control heritable traits in yeast. Initial nucleation of a yeast prion by transiently overproduced prion-forming protein or its (typically, QN-rich) prion domain is efficient only in the presence of another aggregated (in most cases, QN-rich) protein. Here, we demonstrate that a fusion of the prion domain of yeast protein Sup35 to some non-QN-rich mammalian proteins, associated with amyloid diseases, promotes nucleation of Sup35 prions in the absence of pre-existing aggregates. In contrast, both a fusion of the Sup35 prion domain to a multimeric non-amyloidogenic protein and the expression of a mammalian amyloidogenic protein that is not fused to the Sup35 prion domain failed to promote prion nucleation, further indicating that physical linkage of a mammalian amyloidogenic protein to the prion domain of a yeast protein is required for the nucleation of a yeast prion. Biochemical and cytological approaches confirmed the nucleation of protein aggregates in the yeast cell. Sequence alterations antagonizing or enhancing amyloidogenicity of human amyloid-β (associated with Alzheimer's disease) and mouse prion protein (associated with prion diseases), respectively, antagonized or enhanced nucleation of a yeast prion by these proteins. The yeast-based prion nucleation assay, developed in our work, can be employed for mutational dissection of amyloidogenic proteins. We anticipate that it will aid in the identification of chemicals that influence initial amyloid nucleation and in searching for new amyloidogenic proteins in a variety of proteomes. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Inhibition of Wnt signaling induces amyloidogenic processing of amyloid precursor protein and the production and aggregation of Amyloid-β (Aβ)42 peptides.

PubMed

Tapia-Rojas, Cheril; Burgos, Patricia V; Inestrosa, Nibaldo C

2016-12-01

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the most frequent cause of dementia in the aged population. According to the amyloid hypothesis, the amyloid-β (Aβ) peptide plays a key role in the pathogenesis of AD. Aβ is generated from the amyloidogenic processing of amyloid precursor protein and can aggregate to form oligomers, which have been described as a major synaptotoxic agent in neurons. Dysfunction of Wnt signaling has been linked to increased Aβ formation; however, several other studies have argued against this possibility. Herein, we use multiple experimental approaches to confirm that the inhibition of Wnt signaling promoted the amyloidogenic proteolytic processing of amyloid precursor protein. We also demonstrate that inhibiting Wnt signaling increases the production of the Aβ 42 peptide, the Aβ 42 /Aβ 40 ratio, and the levels of Aβ oligomers such as trimers and tetramers. Moreover, we show that activating Wnt signaling reduces the levels of Aβ 42 and its aggregates, increases Aβ 40 levels, and reduces the Aβ 42 /Aβ 40 ratio. Finally, we show that the protective effects observed in response to activation of the Wnt pathway rely on β-catenin-dependent transcription, which is demonstrated experimentally via the expression of various 'mutant forms of β-catenin'. Together, our findings indicate that loss of the Wnt signaling pathway may contribute to the pathogenesis of AD. © 2016 International Society for Neurochemistry.

Trehalose protects from aggravation of amyloid pathology induced by isoflurane anesthesia in APP(swe) mutant mice.

PubMed

Perucho, Juan; Casarejos, Maria J; Gomez, Ana; Solano, Rosa M; de Yébenes, Justo Garcia; Mena, Maria A

2012-03-01

There is an open controversy about the role of surgery and anesthesia in the pathogenesis of Alzheimer's disease (AD). Clinical studies have shown a high prevalence of these procedures in subjects with AD but the interpretation of these studies is difficult because of the co-existence of multiple variables. Experimental studies in vitro and in vivo have shown that small molecular weight volatile anesthetics enhance amyloidogenesis in vitro and produce behavioral deficits and brain lesions similar to those found in patients with AD. We examined the effect of co-treatment with trehalose on isoflurane-induced amyloidogenesis in mice. WT and APP(swe) mice, of 11 months of age, were exposed to 1% isoflurane, 3 times, for 1.5 hours each time and sacrificed 24 hours after their last exposure to isoflurane. The right hemi-brain was used for histological analysis and the contra-lateral hemi-brain used for biochemical studies. In this study, we have shown that repetitive exposure to isoflurane in pre-symptomatic mature APP(swe) mice increases apoptosis in hippocampus and cerebral cortex, enhances astrogliosis and the expression of GFAP and that these effects are prevented by co-treatment with trehalose, a disaccharide with known effects as enhancer of autophagy. We have also confirmed that in our model the co-treatment with trehalose increases the expression of autophagic markers as well as the expression of chaperones. Cotreatment with trehalose reduces the levels of β amyloid peptide aggregates, tau plaques and levels of phospho-tau. Our study, therefore, provides new therapeutic avenues that could help to prevent the putative pro-amyloidogenic properties of small volatile anesthetics.

γ-secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aβ.

PubMed

Liu, Fei; Xue, Zhi-Qin; Deng, Si-Hao; Kun, Xiong; Luo, Xue-Gang; Patrylo, Peter R; Rose, Gregory M; Cai, Huaibin; Struble, Robert G; Cai, Yan; Yan, Xiao-Xin

2013-05-01

Deposition of β -amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Aβ peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored the possibility of Aβ production and secretion by the choroid plexus (CP). The specific binding density of [(3) H]-L-685,458, a radiolabeled high-affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post-mortem delays. The CP in post-mortem samples exhibited exceptionally high [(3) H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Aβ40 and Aβ42 into the medium. Overall, our results suggest that γ-secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non-neuronal contributor to CSF Aβ, probably at reduced levels in AD. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

γ-Secretase binding sites in aged and Alzheimer’s disease human cerebrum: The choroid plexus as a putative origin of CSF Aβ

PubMed Central

Liu, Fei; Xue, Zhi-Qin; Deng, Si-Hao; Kun, Xiong; Luo, Xue-Gang; Patrylo, Peter R.; Rose, Gregory M.; Cai, Huaibin; Struble, Robert G.; Cai, Yan; Yan, Xiao-Xin

2013-01-01

Deposition of β-amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer’s disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although less is clear about the change of the enzyme’s activity in AD brain. Cerebrospinal fluid (CSF) Aβ peptides are considered to derive from brain parenchyma, thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored a possibility of Aβ production and secretion by the choroid plexus (CP). Specific binding density of [3H]-L-685,458, a radiolabeled high affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with comparable ages and postmortem delays. The CP in postmortem samples exhibited exceptionally high [3H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins but released Aβ40 and Aβ42 into the medium. These results suggest that γ-secretase activity appears not altered in the cerebrum in AD related to aged control, nor correlated with regional amyloid plaque pathology. The choroid plexus appears to represent a novel non-neuronal source in the brain that may contribute Aβ into cerebrospinal fluid, probably at reduced levels in AD. PMID:23432732

Therapeutic approaches against common structural features of toxic oligomers shared by multiple amyloidogenic proteins.

PubMed

Guerrero-Muñoz, Marcos J; Castillo-Carranza, Diana L; Kayed, Rakez

2014-04-15

Impaired proteostasis is one of the main features of all amyloid diseases, which are associated with the formation of insoluble aggregates from amyloidogenic proteins. The aggregation process can be caused by overproduction or poor clearance of these proteins. However, numerous reports suggest that amyloid oligomers are the most toxic species, rather than insoluble fibrillar material, in Alzheimer's, Parkinson's, and Prion diseases, among others. Although the exact protein that aggregates varies between amyloid disorders, they all share common structural features that can be used as therapeutic targets. In this review, we focus on therapeutic approaches against shared features of toxic oligomeric structures and future directions. Copyright © 2014 Elsevier Inc. All rights reserved.

Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Moderate- to High-Intensity Physical Exercise in Patients with Alzheimer Disease.

PubMed

Steen Jensen, Camilla; Portelius, Erik; Siersma, Volkert; Høgh, Peter; Wermuth, Lene; Blennow, Kaj; Zetterberg, Henrik; Waldemar, Gunhild; Gregers Hasselbalch, Steen; Hviid Simonsen, Anja

2016-01-01

Physical exercise may have some effect on cognition in patients with Alzheimer disease (AD). However, the underlying biochemical effects are unclear. Animal studies have shown that amyloid beta (Aβ), one of the pathological hallmarks of AD, can be altered with high levels of physical activity. The objective of this study was to elucidate the effect of 16 weeks of moderate- to high-intensity physical exercise on the biomarkers of AD, with special emphasis on the amyloidogenic pathway. From a total of 53 patients with AD participating in the Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) study we analyzed cerebrospinal fluid samples for Aβ species, total tau (t-tau), phosphorylated tau (p-tau) and soluble amyloid precursor protein (sAPP) species. We also assessed the patients for apolipoprotein E ε4 (ApoE ε4) genotype. We found no effect of 16 weeks of physical exercise on the selected biomarkers, and no effect of ApoE ε4 genotype. Our findings suggest that the possible effect of physical exercise on cognition in patients with AD is not due to modulation of Aβ, t-tau, p-tau and sAPP species. © 2016 S. Karger AG, Basel.

Induction of CNS α-synuclein pathology by fibrillar and non-amyloidogenic recombinant α-synuclein

PubMed Central

2013-01-01

Background α-Synuclein (αS) is the major component of several types of brain inclusions including Lewy bodies, a hallmark of Parkinson’s disease. Aberrant aggregation of αS also is associated with cellular demise in multiple neurologic disorders collectively referred to as synucleinopathies. Recent studies demonstrate the induction of αS pathology by a single intracerebral injection of exogenous amyloidogenic αS in adult non-transgenic and transgenic mice expressing human αS. To further investigate the mechanism of pathology induction and evaluate an experimental paradigm with potential for higher throughput, we performed similar studies in neonatal mice injected with αS. Results In non-transgenic mice, we observed limited induction of neuronal αS inclusions predominantly 8 months after brain injection of aggregated, amyloidogenic human αS. More robust inclusion pathology was induced in transgenic mice expressing wild-type human αS (line M20), and inclusion pathology was observed at earlier time points. Injection of a non-amyloidogenic (Δ71-82) deletion protein of αS was also able to induce similar pathology in a subset of M20 transgenic mice. M20 transgenic mice injected with amyloidogenic or non-amyloidogenic αS demonstrated a delayed and robust induction of brain neuroinflammation that occurs in mice with or without αS pathological inclusions implicating this mechanism in aggregate formation. Conclusions The finding that a non-amyloidogenic Δ71-82 αS can induce pathology calls into question the simple interpretation that exogenous αS catalyzes aggregation and spread of intracellular αS pathology solely through a nucleation dependent conformational templating mechanism. These results indicate that several mechanisms may act synergistically or independently to promote the spread of αS pathology. PMID:24252149

The cleavage product of amyloid-β protein precursor sAβPPα modulates BAG3-dependent aggresome formation and enhances cellular proteasomal activity.

PubMed

Renziehausen, Jana; Hiebel, Christof; Nagel, Heike; Kundu, Arpita; Kins, Stefan; Kögel, Donat; Behl, Christian; Hajieva, Parvana

2015-01-01

Alzheimer's disease (AD) is the major age-associated form of dementia characterized by gradual cognitive decline. Aberrant cleavage of the amyloid-β protein precursor (AβPP) is thought to play an important role in the pathology of this disease. Two principal AβPP processing pathways exist: amyloidogenic cleavage of AβPP resulting in production of the soluble N-terminal fragment sAβPPβ, amyloid-β (Aβ), which accumulates in AD brain, and the AβPP intracellular domain (AICD) sAβPPα, p3 and AICD are generated in the non-amyloidogenic pathway. Prevalence of amyloidogenic versus non-amyloidogenic processing leads to depletion of sAβPPα and an increase in Aβ. Although sAβPPα is a well-accepted neurotrophic protein, molecular effects of this fragment remains unknown. Different studies reported impaired protein degradation pathways in AD brain, pointing to a role of disturbed proteasomal activity in the pathogenesis of this disease. Here we studied the possible role of sAβPPα in Bag3-mediated selective macroautophagy and proteasomal degradation. Employing human IMR90 cells, HEK 293 cells, and primary neurons, we demonstrate that sAβPPα prevents the proteotoxic stress-induced increase of Bag3 at the protein and at the mRNA level indicating a transcriptional regulation. Intriguingly, p62 and LC3, two other key players of autophagy, were not affected. Moreover, the formation and the accumulation of disease-related protein aggregates were significantly reduced by sAβPPα. Interestingly, there was a significant increase of proteasomal activity by sAβPPα as demonstrated by using various proteasome substrates. Our findings demonstrate that sAβPPα modulates Bag3 expression, aggresome formation, and proteasomal activity, thereby providing first evidence for a function of sAβPPα in the regulation of proteostasis.

Acute Effects of Muscarinic M1 Receptor Modulation on AβPP Metabolism and Amyloid-β Levels in vivo: A Microdialysis Study.

PubMed

Welt, Tobias; Kulic, Luka; Hoey, Sarah E; McAfoose, Jordan; Späni, Claudia; Chadha, Antonella Santuccione; Fisher, Abraham; Nitsch, Roger M

2015-01-01

Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely established symptomatic treatment for Alzheimer's disease (AD). Selective activation of certain muscarinic receptor subtypes has emerged as an alternative cholinergic-based amyloid-lowering strategy for AD, as selective muscarinic M1 receptor agonists can reduce amyloid-β (Aβ) production by shifting endoproteolytic amyloid-β protein precursor (AβPP) processing toward non-amyloidogenic pathways. In this study, we addressed the hypothesis that acute stimulation of muscarinic M1 receptors can inhibit Aβ production in awake and freely moving AβPP transgenic mice. By combining intracerebral microdialysis with retrodialysis, we determined hippocampal Aβ concentrations during simultaneous pharmacological modulation of brain M1 receptor function. Infusion with a M1 receptor agonist AF102B resulted in a rapid reduction of interstitial fluid (ISF) Aβ levels while treatment with the M1 antagonist dicyclomine increased ISF Aβ levels reaching significance within 120 minutes of treatment. The reduction in Aβ levels was associated with PKCα and ERK activation resulting in increased levels of the α-secretase ADAM17 and a shift in AβPP processing toward the non-amyloidogenic processing pathway. In contrast, treatment with the M1 receptor antagonist dicyclomine caused a decrease in levels of phosphorylated ERK that was independent of PKCα, and led to an elevation of β-secretase levels associated with increased amyloidogenic AβPP processing. The results of this study demonstrate rapid effects of in vivo M1 receptor modulation on the ISF pool of Aβ and suggest that intracerebral microdialysis with retrodialysis is a useful technical approach for monitoring acute treatment effects of muscarinic receptor modulators on AβPP/Aβ metabolism.

Ferret islet amyloid polypeptide (IAPP): characterization of in vitro and in vivo amyloidogenicity.

PubMed

Paulsson, Johan F; Benoit-Biancamano, Marie-Odile; Schäffer, Lauge; Dahl, Kirsten

2011-12-01

Diabetes in the domestic ferret (Mustela putorius furo) has previously been described and the purpose of this study was to evaluate if the ferret could serve as a model for the study of β-cell degeneration associated with formation of islet amyloid. The nucleotide and amino acid sequence of ferret islet amyloid polypeptide (IAPP) 1-37 was identified and the synthesized peptide was studied with regards to in vitro amyloidogenicity and potential cellular toxicity in a comparative approach to human, cat and the nonamyloidogenic rat IAPP. Ferret IAPP forms amyloid-like fibrils, but with a longer lag phase than human and cat IAPP and the aggregation process was shown to reduce cell viability of cultured β-cells, but with less potency than these two amyloidogenic counterparts. Immunohistochemistry of ferret pancreas confirmed IAPP expression in the islets of Langerhans, but no islet amyloid was found in a very limited sample size of one diabetic and five healthy ferrets. Islet amyloid has never been described in ferrets, and it is not possible to determine if it is due to lack of studies/material or to the fact that the ferret's life span is too short to present with such pathology.

Effect of Fluvoxamine on Amyloid-β Peptide Generation and Memory.

PubMed

Kim, Woojin Scott; Fu, Yuhong; Dobson-Stone, Carol; Hsiao, Jen-Hsiang T; Shang, Kani; Hallupp, Marianne; Schofield, Peter R; Garner, Brett; Karl, Tim; Kwok, John B J

2018-01-01

Alzheimer's disease is characterized by abnormal amyloid-β (Aβ) peptide accumulation beginning decades before symptom onset. An effective prophylactic treatment aimed at arresting the amyloidogenic pathway would therefore need to be initiated prior to the occurrence of Aβ pathology. The SIGMAR1 gene encodes a molecular chaperone that modulates processing of the amyloid-β protein precursor (AβPP). Fluvoxamine is a selective serotonin reuptake inhibitor and a potent SIGMAR1 agonist. We therefore hypothesized that fluvoxamine treatment would reduce Aβ production and improve cognition. We firstly investigated the impact of SIGMAR1 on AβPP processing, and found that overexpression and knockdown of SIGMAR1 significantly affected γ-secretase activity in SK-N-MC neuronal cells. We then tested the impact of fluvoxamine on Aβ production in an amyloidogenic cell model, and found that fluvoxamine significantly reduced Aβ production by inhibiting γ-secretase activity. Finally, we assessed the efficacy of long-term treatment (i.e., ∼8 months) of 10 mg/kg/day fluvoxamine in the J20 amyloidogenic mouse model; the treatment was initiated prior to the occurrence of predicted Aβ pathology. Physical examination of the animals revealed no overt pathology or change in weight. We conducted a series of behavioral tests to assess learning and memory, and found that the fluvoxamine treatment significantly improved memory function as measured by novel object recognition task. Two other tests revealed no significant change in memory function. In conclusion, fluvoxamine has a clear impact on γ-secretase activity and AβPP processing to generate Aβ, and may have a protective effect on cognition in the J20 mice.

Synthesis and physicochemical studies of amyloidogenic hexapeptides derived from human cystatin C.

PubMed

Iłowska, Emilia; Sawicka, Justyna; Szymańska, Aneta

2018-06-01

Human cystatin C (hCC) is a low molecular mass protein that belongs to the cystatin superfamily. It is an inhibitor of extracellular cysteine proteinases, present in all human body fluids. At physiological conditions, hCC is a monomer, but it has a tendency to dimerization. Naturally occurring hCC mutant, with leucine in position 68 substituted by glutamine (L68Q), is directly involved in the formation of amyloid deposits, independently of other proteins. This process is the primary cause of hereditary cerebral amyloid angiopathy, observed mainly in the Icelandic population. Oligomerization and fibrillization processes of hCC are not explained equally well, but it is proposed that domain swapping is involved in both of them. Research carried out on the fibrillization process led to new hypothesis about the existence of a steric zipper motif in amyloidogenic proteins. In the hCC sequence, there are 2 fragments which may play the role of a steric zipper: the loop L1 region and the C-terminal fragment. In this work, we focused on the first of these. Nine hexapeptides covering studied hCC fragment were synthesized, and their fibrillogenic potential was assessed using an array of biophysical methods. The obtained results showed that the studied hCC fragment has strong profibrillogenic propensities because it contains 2 fragments fulfilling the requirements for an effective steric zipper located next to each other, forming 1 super-steric zipper motif. This hCC fragment might therefore be responsible for the enhanced amyloidogenic properties of dimeric or partially unfolded hCC. Copyright © 2018 European Peptide Society and John Wiley & Sons, Ltd.

Structural features of the KPI domain control APP dimerization, trafficking, and processing.

PubMed

Ben Khalifa, Naouel; Tyteca, Donatienne; Marinangeli, Claudia; Depuydt, Mathieu; Collet, Jean-François; Courtoy, Pierre J; Renauld, Jean-Christophe; Constantinescu, Stefan; Octave, Jean-Noël; Kienlen-Campard, Pascal

2012-02-01

The two major isoforms of human APP, APP695 and APP751, differ by the presence of a Kunitz-type protease inhibitor (KPI) domain in the extracellular region. APP processing and function is thought to be regulated by homodimerization. We used bimolecular fluorescence complementation (BiFC) to study dimerization of different APP isoforms and mutants. APP751 was found to form significantly more homodimers than APP695. Mutation of dimerization motifs in the TM domain did not affect fluorescence complementation, but native folding of KPI is critical for APP751 homodimerization. APP751 and APP695 dimers were mostly localized at steady state in the Golgi region, suggesting that most of the APP751 and 695 dimers are in the secretory pathway. Mutation of the KPI led to the retention of the APP homodimers in the endoplasmic reticulum. We finally showed that APP751 is more efficiently processed through the nonamyloidogenic pathway than APP695. These findings provide new insight on the particular role of KPI domain in APP dimerization. The correlation observed between dimerization, subcellular localization, and processing suggests that dimerization acts as an efficient regulator of APP trafficking in the secretory compartments that has major consequences on its processing.

Effect of fibrillation conditions on the anti-amyloidogenic properties of polyphenols and their involved mechanisms.

PubMed

Mahdavimehr, Mohsen; Katebi, Bentolhoda; Meratan, Ali Akbar

2018-06-24

In the present study, we have investigated the effects of protein concentration and stirring on the in vitro assembly of Hen Egg White Lysozyme (HEWL), particularly with regard to the aggregate morphology and anti-amyloidogenic properties of two naturally occurring polyphenols, taxifolin and silibinin. The results obtained clearly demonstrated that applying stirring and concentration enhancement alter the amount as well as morphology of amyloid fibrils formed. Additionally, latter aggregates exhibited higher affinity for amyloid-specific dyes. The second part of the present investigation was devoted to studies involving anti-amyloidogenic properties of selected polyphenols. Importantly, we found that the potency of polyphenols to inhibit HEWL amyloid fibrillation and related toxicity is strongly dependent on the amyloidogenic conditions in which amyloid fibrils are produced. Based on obtained data, under condition where the rate of protein assembly is high (higher protein concentration and stirring), the capacity of polyphenols to inhibit HEWL fibrillogenesis and related cytotoxicity may dramatically decrease. Similar results were obtained when we used taxifolin to inhibit bovine insulin amyloid fibrillation. Additionally, amyloidogenic conditions may also affect the mechanism by which these molecules inhibit HEWL fibrillation. The possible mechanism by which selected polyphenols exert their inhibitory effects, under various experimental conditions, is also discussed. Copyright © 2018. Published by Elsevier B.V.

Pauling and Corey's alpha-pleated sheet structure may define the prefibrillar amyloidogenic intermediate in amyloid disease.

PubMed

Armen, Roger S; DeMarco, Mari L; Alonso, Darwin O V; Daggett, Valerie

2004-08-10

Transthyretin, beta(2)-microglobulin, lysozyme, and the prion protein are four of the best-characterized proteins implicated in amyloid disease. Upon partial acid denaturation, these proteins undergo conformational change into an amyloidogenic intermediate that can self-assemble into amyloid fibrils. Many experiments have shown that pH-mediated changes in structure are required for the formation of the amyloidogeneic intermediate, but it has proved impossible to characterize these conformational changes at high resolution using experimental means. To probe these conformational changes at atomic resolution, we have performed molecular dynamics simulations of these proteins at neutral and low pH. In low-pH simulations of all four proteins, we observe the formation of alpha-pleated sheet secondary structure, which was first proposed by L. Pauling and R. B. Corey [(1951) Proc. Natl. Acad. Sci. USA 37, 251-256]. In all beta-sheet proteins, transthyretin and beta(2)-microglobulin, alpha-pleated sheet structure formed over the strands that are highly protected in hydrogen-exchange experiments probing amyloidogenic conditions. In lysozyme and the prion protein, alpha-sheets formed in the specific regions of the protein implicated in the amyloidogenic conversion. We propose that the formation of alpha-pleated sheet structure may be a common conformational transition in amyloidosis.

Pauling and Corey's α-pleated sheet structure may define the prefibrillar amyloidogenic intermediate in amyloid disease

PubMed Central

Armen, Roger S.; DeMarco, Mari L.; Alonso, Darwin O. V.; Daggett, Valerie

2004-01-01

Transthyretin, β2-microglobulin, lysozyme, and the prion protein are four of the best-characterized proteins implicated in amyloid disease. Upon partial acid denaturation, these proteins undergo conformational change into an amyloidogenic intermediate that can self-assemble into amyloid fibrils. Many experiments have shown that pH-mediated changes in structure are required for the formation of the amyloidogeneic intermediate, but it has proved impossible to characterize these conformational changes at high resolution using experimental means. To probe these conformational changes at atomic resolution, we have performed molecular dynamics simulations of these proteins at neutral and low pH. In low-pH simulations of all four proteins, we observe the formation of α-pleated sheet secondary structure, which was first proposed by L. Pauling and R. B. Corey [(1951) Proc. Natl. Acad. Sci. USA 37, 251–256]. In all β-sheet proteins, transthyretin and β2-microglobulin, α-pleated sheet structure formed over the strands that are highly protected in hydrogen-exchange experiments probing amyloidogenic conditions. In lysozyme and the prion protein, α-sheets formed in the specific regions of the protein implicated in the amyloidogenic conversion. We propose that the formation of α-pleated sheet structure may be a common conformational transition in amyloidosis. PMID:15280548

Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme

PubMed Central

Bailey, Lucas J; Tan, Yong Zi; Wei, Hui; Wang, Andrew; Farcasanu, Mara; Woods, Virgil A; McCord, Lauren A; Lee, David; Shang, Weifeng; Deprez-Poulain, Rebecca; Deprez, Benoit; Liu, David R; Koide, Akiko; Koide, Shohei; Kossiakoff, Anthony A

2018-01-01

Insulin degrading enzyme (IDE) plays key roles in degrading peptides vital in type two diabetes, Alzheimer's, inflammation, and other human diseases. However, the process through which IDE recognizes peptides that tend to form amyloid fibrils remained unsolved. We used cryoEM to understand both the apo- and insulin-bound dimeric IDE states, revealing that IDE displays a large opening between the homologous ~55 kDa N- and C-terminal halves to allow selective substrate capture based on size and charge complementarity. We also used cryoEM, X-ray crystallography, SAXS, and HDX-MS to elucidate the molecular basis of how amyloidogenic peptides stabilize the disordered IDE catalytic cleft, thereby inducing selective degradation by substrate-assisted catalysis. Furthermore, our insulin-bound IDE structures explain how IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds. Together, our studies provide a mechanism for how IDE selectively degrades amyloidogenic peptides and offers structural insights for developing IDE-based therapies. PMID:29596046

Competition between crystal and fibril formation in molecular mutations of amyloidogenic peptides.

PubMed

Reynolds, Nicholas P; Adamcik, Jozef; Berryman, Joshua T; Handschin, Stephan; Zanjani, Ali Asghar Hakami; Li, Wen; Liu, Kun; Zhang, Afang; Mezzenga, Raffaele

2017-11-07

Amyloidogenic model peptides are invaluable for investigating assembly mechanisms in disease related amyloids and in protein folding. During aggregation, such peptides can undergo bifurcation leading to fibrils or crystals, however the mechanisms of fibril-to-crystal conversion are unclear. We navigate herein the energy landscape of amyloidogenic peptides by studying a homologous series of hexapeptides found in animal, human and disease related proteins. We observe fibril-to-crystal conversion occurring within single aggregates via untwisting of twisted ribbon fibrils possessing saddle-like curvature and cross-sectional aspect ratios approaching unity. Changing sequence, pH or concentration shifts the growth towards larger aspect ratio species assembling into stable helical ribbons possessing mean-curvature. By comparing atomistic calculations of desolvation energies for association of peptides we parameterise a kinetic model, providing a physical explanation of fibril-to-crystal interconversion. These results shed light on the self-assembly of amyloidogenic peptides, suggesting amyloid crystals, not fibrils, represent the ground state of the protein folding energy landscape.

Mechanisms that synergistically regulate η-secretase processing of APP and Aη-α protein levels: relevance to pathogenesis and treatment of Alzheimer's disease.

PubMed

Ward, Joseph; Wang, Haizhi; Saunders, Aleister J; Tanzi, Rudolph E; Zhang, Can

2017-02-01

The pathophysiology of Alzheimer's disease (AD) is characterized by the formation of cerebral β-amyloid plaque from a small peptide amyloid-β (Aβ). Aβ is generated from the canonical amyloid-β precursor protein (APP) proteolysis pathway through β- and γ-secretases. Decreasing Aβ levels through targeting APP processing is a very promising direction in clinical trials for AD. A novel APP processing pathway was recently identified, in which η-secretase processing of APP occurs and results in the generation of the carboxy-terminal fragment-η (CTF-η or η-CTF) (Wang et al., 2015) and Aη-α peptide (Willem et al., 2015). η-Secretase processing of APP may be up-regulated by at least two mechanisms: either through inhibition of lysosomal-cathepsin degradation pathway (Wang et al., 2015) or through inhibition of BACE1 that competes with η-secretase cleavage of APP (Willem et al., 2015). A thorough characterization of η-processing of APP is critical for a better understanding of AD pathogenesis and insights into results of clinical trials of AD. Here we further investigated η-secretase processing of APP using well-characterized cell models of AD. We found that these two mechanisms act synergistically toward increasing η-secretase processing of APP and Aη-α levels. Furthermore, we evaluated the effects of several other known secretase modulators on η-processing of APP. The results of our study should advance the understanding of pathophysiology of AD, as well as enhance the knowledge in developing effective AD treatments or interventions related to η-secretase processing of APP.

Multifaceted anti-amyloidogenic and pro-amyloidogenic effects of C-reactive protein and serum amyloid P component in vitro

PubMed Central

Ozawa, Daisaku; Nomura, Ryo; Mangione, P. Patrizia; Hasegawa, Kazuhiro; Okoshi, Tadakazu; Porcari, Riccardo; Bellotti, Vittorio; Naiki, Hironobu

2016-01-01

C-reactive protein (CRP) and serum amyloid P component (SAP), two major classical pentraxins in humans, are soluble pattern recognition molecules that regulate the innate immune system, but their chaperone activities remain poorly understood. Here, we examined their effects on the amyloid fibril formation from Alzheimer’s amyloid β (Aβ) (1-40) and on that from D76N β2-microglobulin (β2-m) which is related to hereditary systemic amyloidosis. CRP and SAP dose-dependently and substoichiometrically inhibited both Aβ(1-40) and D76N β2-m fibril formation in a Ca2+-independent manner. CRP and SAP interacted with fresh and aggregated Aβ(1-40) and D76N β2-m on the fibril-forming pathway. Interestingly, in the presence of Ca2+, SAP first inhibited, then significantly accelerated D76N β2-m fibril formation. Electron microscopically, the surface of the D76N β2-m fibril was coated with pentameric SAP. These data suggest that SAP first exhibits anti-amyloidogenic activity possibly via A face, followed by pro-amyloidogenic activity via B face, proposing a model that the pro- and anti-amyloidogenic activities of SAP are not mutually exclusive, but reflect two sides of the same coin, i.e., the B and A faces, respectively. Finally, SAP inhibits the heat-induced amorphous aggregation of human glutathione S-transferase. A possible role of pentraxins to maintain extracellular proteostasis is discussed. PMID:27380955

Using simple artificial intelligence methods for predicting amyloidogenesis in antibodies

PubMed Central

2010-01-01

Background All polypeptide backbones have the potential to form amyloid fibrils, which are associated with a number of degenerative disorders. However, the likelihood that amyloidosis would actually occur under physiological conditions depends largely on the amino acid composition of a protein. We explore using a naive Bayesian classifier and a weighted decision tree for predicting the amyloidogenicity of immunoglobulin sequences. Results The average accuracy based on leave-one-out (LOO) cross validation of a Bayesian classifier generated from 143 amyloidogenic sequences is 60.84%. This is consistent with the average accuracy of 61.15% for a holdout test set comprised of 103 AM and 28 non-amyloidogenic sequences. The LOO cross validation accuracy increases to 81.08% when the training set is augmented by the holdout test set. In comparison, the average classification accuracy for the holdout test set obtained using a decision tree is 78.64%. Non-amyloidogenic sequences are predicted with average LOO cross validation accuracies between 74.05% and 77.24% using the Bayesian classifier, depending on the training set size. The accuracy for the holdout test set was 89%. For the decision tree, the non-amyloidogenic prediction accuracy is 75.00%. Conclusions This exploratory study indicates that both classification methods may be promising in providing straightforward predictions on the amyloidogenicity of a sequence. Nevertheless, the number of available sequences that satisfy the premises of this study are limited, and are consequently smaller than the ideal training set size. Increasing the size of the training set clearly increases the accuracy, and the expansion of the training set to include not only more derivatives, but more alignments, would make the method more sound. The accuracy of the classifiers may also be improved when additional factors, such as structural and physico-chemical data, are considered. The development of this type of classifier has significant applications in evaluating engineered antibodies, and may be adapted for evaluating engineered proteins in general. PMID:20144194

Using simple artificial intelligence methods for predicting amyloidogenesis in antibodies.

PubMed

David, Maria Pamela C; Concepcion, Gisela P; Padlan, Eduardo A

2010-02-08

All polypeptide backbones have the potential to form amyloid fibrils, which are associated with a number of degenerative disorders. However, the likelihood that amyloidosis would actually occur under physiological conditions depends largely on the amino acid composition of a protein. We explore using a naive Bayesian classifier and a weighted decision tree for predicting the amyloidogenicity of immunoglobulin sequences. The average accuracy based on leave-one-out (LOO) cross validation of a Bayesian classifier generated from 143 amyloidogenic sequences is 60.84%. This is consistent with the average accuracy of 61.15% for a holdout test set comprised of 103 AM and 28 non-amyloidogenic sequences. The LOO cross validation accuracy increases to 81.08% when the training set is augmented by the holdout test set. In comparison, the average classification accuracy for the holdout test set obtained using a decision tree is 78.64%. Non-amyloidogenic sequences are predicted with average LOO cross validation accuracies between 74.05% and 77.24% using the Bayesian classifier, depending on the training set size. The accuracy for the holdout test set was 89%. For the decision tree, the non-amyloidogenic prediction accuracy is 75.00%. This exploratory study indicates that both classification methods may be promising in providing straightforward predictions on the amyloidogenicity of a sequence. Nevertheless, the number of available sequences that satisfy the premises of this study are limited, and are consequently smaller than the ideal training set size. Increasing the size of the training set clearly increases the accuracy, and the expansion of the training set to include not only more derivatives, but more alignments, would make the method more sound. The accuracy of the classifiers may also be improved when additional factors, such as structural and physico-chemical data, are considered. The development of this type of classifier has significant applications in evaluating engineered antibodies, and may be adapted for evaluating engineered proteins in general.

VRX-03011, a novel 5-HT4 agonist, enhances memory and hippocampal acetylcholine efflux.

PubMed

Mohler, Eric G; Shacham, Sharon; Noiman, Silvia; Lezoualc'h, Frank; Robert, Sylvain; Gastineau, Monique; Rutkowski, Joseph; Marantz, Yael; Dumuis, Aline; Bockaert, Joel; Gold, Paul E; Ragozzino, Michael E

2007-09-01

Recent evidence suggests that 5-hydroxytryptamine (5-HT)(4) receptor activity enhances cognition and provides neuroprotection. Here we report the effects of VRX-03011, a novel partial 5-HT(4) agonist, that is both potent (K(i) approximately 30 nM) and highly selective (K(i) > 5 microM for all other 5-HT receptors tested). In separate experiments, rats received VRX-03011 (0.1-10 mg/kg i.p.) 30 min prior to spontaneous alternation testing in a no-delay or a 30-s delay condition. VRX-03011 (1, 5 and 10 mg/kg, but not 0.1 mg/kg) significantly enhanced delayed spontaneous alternation performance while none of the doses enhanced performance in the no-delay test. VRX-03011 (1 and 5 mg/kg) concomitantly enhanced hippocampal acetylcholine output and delayed spontaneous alternation scores compared to that of vehicle controls, but had no effect on hippocampal acetylcholine release under a resting condition. Moreover, suboptimal doses of VRX-03011 and the acetylcholinesterase inhibitor galanthamine combined to enhance memory. VRX-03011 also regulated amyloid precursor protein (APP) metabolism by inducing a concentration-dependent increase in the non-amyloidogenic soluble form of APP (sAPPalpha) with an EC(50) approximately 1--10 nM. VRX-03011 had no effect on contractile properties in guinea pig ileum or colon preparations with an EC(50) > 10 microM and did not alter rat intestinal transit at doses up to 10 mg/kg. These findings suggest that VRX-03011 may represent a novel treatment for Alzheimer's disease that reduces cognitive impairments and provides neuroprotection without gastrointestinal side effects.

A Native to Amyloidogenic Transition Regulated by a Backbone Trigger

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eakin,C.; Berman, A.; Miranker, A.

2006-01-01

Many polypeptides can self-associate into linear, aggregated assemblies termed amyloid fibers. High-resolution structural insights into the mechanism of fibrillogenesis are elusive owing to the transient and mixed oligomeric nature of assembly intermediates. Here, we report the conformational changes that initiate fiber formation by beta-2-microglobulin (beta2m) in dialysis-related amyloidosis. Access of beta2m to amyloidogenic conformations is catalyzed by selective binding of divalent cations. The chemical basis of this process was determined to be backbone isomerization of a conserved proline. On the basis of this finding, we designed a beta2m variant that closely adopts this intermediate state. The variant has kinetic, thermodynamicmore » and catalytic properties consistent with its being a fibrillogenic intermediate of wild-type beta2m. Furthermore, it is stable and folded, enabling us to unambiguously determine the initiating conformational changes for amyloid assembly at atomic resolution.« less

F-box only protein 2 (Fbxo2) regulates amyloid precursor protein levels and processing.

PubMed

Atkin, Graham; Hunt, Jack; Minakawa, Eiko; Sharkey, Lisa; Tipper, Nathan; Tennant, William; Paulson, Henry L

2014-03-07

The amyloid precursor protein (APP) is an integral membrane glycoprotein whose cleavage products, particularly amyloid-β, accumulate in Alzheimer disease (AD). APP is present at synapses and is thought to play a role in both the formation and plasticity of these critical neuronal structures. Despite the central role suggested for APP in AD pathogenesis, the mechanisms regulating APP in neurons and its processing into cleavage products remain incompletely understood. F-box only protein 2 (Fbxo2), a neuron-enriched ubiquitin ligase substrate adaptor that preferentially binds high-mannose glycans on glycoproteins, was previously implicated in APP processing by facilitating the degradation of the APP-cleaving β-secretase, β-site APP-cleaving enzyme. Here, we sought to determine whether Fbxo2 plays a similar role for other glycoproteins in the amyloid processing pathway. We present in vitro and in vivo evidence that APP is itself a substrate for Fbxo2. APP levels were decreased in the presence of Fbxo2 in non-neuronal cells, and increased in both cultured hippocampal neurons and brain tissue from Fbxo2 knock-out mice. The processing of APP into its cleavage products was also increased in hippocampi and cultured hippocampal neurons lacking Fbxo2. In hippocampal slices, this increase in cleavage products was accompanied by a significant reduction in APP at the cell surface. Taken together, these results suggest that Fbxo2 regulates APP levels and processing in the brain and may play a role in modulating AD pathogenesis.

Missing the mark for patient engagement: mHealth literacy strategies and behavior change processes in smoking cessation apps.

PubMed

Paige, Samantha R; Alber, Julia M; Stellefson, Michael L; Krieger, Janice L

2018-05-01

To examine how Transtheoretical Model (TTM)'s processes of change and mHealth literacy strategies are employed in mobile smoking cessation apps. A purposive sample of 100 iTunes apps were coded to assess descriptive (price, type, developer, user-rating) and engagement metrics, including processes of change and mHealth literacy strategies (plain language, usability, interactivity). One-way ANOVAs and independent samples t-tests examined associations between descriptive and engagement metrics. Over half of the apps included 7 (78%) processes of change. Fewer included self-liberation (36%) and reinforcement management (34%). Most apps incorporated plain language, but few integrated usability and interactivity strategies. Hypnotherapy and informational apps included more behavioral processes of change than apps incorporating a combination of features, including gaming, cigarette trackers, and motivational coaching (p<0.01). Apps included behavior change processes but rarely incorporated usability and interactivity features to promote patient engagement. Engagement metrics did not vary by app user-ratings, price-to-download, or developer, including for-profit organizations or government and educational institutions. Providers should acknowledge the popularity of smoking cessation apps as potential cessation aids and communicate their benefits and drawbacks to patients. Future efforts to improve smoking cessation apps should focus on enhancing the quality of tailored and interactive content. Copyright © 2017 Elsevier B.V. All rights reserved.

Identification of a novel amyloid precursor protein processing pathway that generates secreted N-terminal fragments.

PubMed

Vella, Laura J; Cappai, Roberto

2012-07-01

Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system. The proteolytic processing of the amyloid precursor protein (APP) into the β-amyloid (Aβ) peptide is a central event in AD. While the pathway that generates Aβ is well described, many questions remain concerning general APP metabolism and its metabolites. It is becoming clear that the amino-terminal region of APP can be processed to release small N-terminal fragments (NTFs). The purpose of this study was to investigate the occurrence and generation of APP NTFs in vivo and in cell culture (SH-SY5Y) in order to delineate the cellular pathways implicated in their generation. We were able to detect 17- to 28-kDa APP NTFs in human and mouse brain tissue that are distinct from N-APP fragments previously reported. We show that the 17- to 28-kDa APP NTFs were highly expressed in mice from the age of 2 wk to adulthood. SH-SY5Y studies indicate the generation of APP NTFs involves a novel APP processing pathway, regulated by protein kinase C, but independent of α-secretase or β-secretase 1 (BACE) activity. These results identify a novel, developmentally regulated APP processing pathway that may play an important role in the physiological function of APP.

Suppression of IAPP fibrillation at anionic lipid membranes via IAPP-derived amyloid inhibitors and insulin.

PubMed

Sellin, Daniel; Yan, Li-Mei; Kapurniotu, Aphrodite; Winter, Roland

2010-08-01

Aggregation of human islet amyloid polypeptide (hIAPP) into cytotoxic beta-sheet oligomers and amyloid plaques is considered a key event in pancreatic beta-cell degeneration in type 2 diabetes (T2D). hIAPP is synthesized in the pancreatic beta-cells and it is stored, co-processed in the secretory granules, and co-secreted to the extracellular matrix together with insulin. In vivo, hIAPP aggregation may start and proceed at the water-cell membrane interface and anionic lipid membranes strongly enhance the process of hIAPP fibrillization which is causally linked to membrane disintegration and cell degeneration. In this study we explored the amyloidogenic propensity and conformational properties of hIAPP in the presence of negatively charged membrane (DOPC/DOPG phospholipid bilayers) surfaces upon addition of two recently designed potent hIAPP-derived inhibitors of hIAPP amyloidogenesis, the hexapeptide NF(N-Me)GA(N-Me)IL (NFGAIL-GI) and the 37-residue non-amyloidogenic hIAPP analog [(N-Me)G24, (N-Me)I26]-IAPP (IAPP-GI). For comparison, the effects of insulin, which is a natively occurring hIAPP aggregation inhibitor, rat IAPP (rIAPP), which is a natively non-amyloidogenic hIAPP analog, and the hIAPP amyloid core peptide hIAPP(22-27) or NFGAIL were also studied. The aim of our study was to test whether and how the above peptides which have been shown to completely block or suppress hIAPP amyloidogenesis in bulk solution in vitro would also affect these processes in the presence of lipid membranes. To this end, attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) was applied. We find that IAPP-GI, NFGAIL-GI, insulin, and rIAPP are potent inhibitors of hIAPP fibrillization. Importantly, our data also suggest that the hetero-complexes of IAPP-GI, rIAPP, and insulin with hIAPP although non-amyloidogenic per se are still able to adsorb at the lipid membrane. By contrast, in the presence of NFGAIL-GI, interaction of hIAPP with the lipid membrane is completely abolished, consistent with NFGAIL-GI mediated sequestration of hIAPP via hetero-complexation in the aqueous phase mainly accounting for the observed strong effect of NFGAIL-GI on hIAPP fibrillogenesis at the lipid membrane interface. Finally, our studies show that once hIAPP is fibrillized at the water-lipid membrane interface with fibrils being attached to the lipid membrane, it cannot be disaggregated by all above peptides.

High affinity binding of amyloid β-peptide to calmodulin: Structural and functional implications.

PubMed

Corbacho, Isaac; Berrocal, María; Török, Katalin; Mata, Ana M; Gutierrez-Merino, Carlos

2017-05-13

Amyloid β-peptides (Aβ) are a major hallmark of Alzheimer's disease (AD) and their neurotoxicity develop with cytosolic calcium dysregulation. On the other hand, calmodulin (CaM), a protein which plays a major multifunctional role in neuronal calcium signaling, has been shown to be involved in the regulation of non-amyloidogenic processing of amyloid β precursor protein (APP). Using fluorescent 6-bromoacetyl-2-dimethylaminonaphthalene derivatives of CaM, Badan-CaM, and human amyloid β(1-42) HiLyte™-Fluor555, we show in this work that Aβ binds with high affinity to CaM through the neurotoxic Aβ25-35 domain. In addition, the affinity of Aβ for calcium-saturated CaM conformation is approximately 20-fold higher than for CaM conformation in the absence of calcium (apo-CaM). Moreover, the value of K d of 0.98 ± 0.11 nM obtained for Aβ1-42 dissociation from CaM saturated by calcium points out that CaM is one of the cellular targets with highest affinity for neurotoxic Aβ peptides. A major functional consequence of Aβ-CaM interaction is that it slowdowns Aβ fibrillation. The novel and high affinity interaction between calmodulin and Aβ shown in this work opens a yet-unexplored gateway to further understand the neurotoxic effect of Aβ in different neural cells and also to address the potential of calmodulin and calmodulin-derived peptides as therapeutic agents in AD. Copyright © 2017 Elsevier Inc. All rights reserved.

In silico and in vitro characterization of anti-amyloidogenic activity of vitamin K3 analogues for Alzheimer's disease.

PubMed

Huy, Pham Dinh Quoc; Yu, Yao-Chung; Ngo, Son Tung; Thao, Tran Van; Chen, Chin-Piao; Li, Mai Suan; Chen, Yi-Cheng

2013-04-01

Aggregation of amyloid-beta (Aβ) has been proposed as the main cause of Alzheimer's disease (AD). Vitamin K deficiency has been linked to the pathogenesis of AD. Therefore, 15 synthesized vitamin K3 (VK3) analogues were studied for their anti-amyloidogenic activity. Biological and spectroscopic assays were used to characterize the effect of VK3 analogues on amyloidogenic properties of Aβ, such as aggregation, free radical formation, and cell viability. Molecular dynamics simulation was used to calculate the binding affinity and mode of VK3 analogue binding to Aβ. Both numerical and experimental results showed that several VK3 analogues, including VK3-6, VK3-8, VK3-9, VK3-10, and VK3-224 could effectively inhibit Aβ aggregation and conformational conversion. The calculated inhibition constants were in the μM range for VK3-10, VK3-6, and VK3-9 which was similar to the IC50 of curcumin. Cell viability assays indicated that VK3-9 could effectively reduce free radicals and had a protective effect on cytotoxicity induced by Aβ. The results clearly demonstrated that VK3 analogues could effectively inhibit Aβ aggregation and protect cells against Aβ induced toxicity. Modified VK3 analogues can possibly be developed as effective anti-amyloidogenic drugs for the treatment of AD. VK3 analogues effectively inhibit Aβ aggregation and are highly potent as anti-amyloidogenic drugs for therapeutic treatment of AD. Copyright © 2012 Elsevier B.V. All rights reserved.

Conformational states and recognition of amyloidogenic peptides of human insulin-degrading enzyme.

PubMed

McCord, Lauren A; Liang, Wenguang G; Dowdell, Evan; Kalas, Vasilios; Hoey, Robert J; Koide, Akiko; Koide, Shohei; Tang, Wei-Jen

2013-08-20

Insulin-degrading enzyme (IDE) selectively degrades the monomer of amyloidogenic peptides and contributes to clearance of amyloid β (Aβ). Thus, IDE retards the progression of Alzheimer's disease. IDE possesses an enclosed catalytic chamber that engulfs and degrades its peptide substrates; however, the molecular mechanism of IDE function, including substrate access to the chamber and recognition, remains elusive. Here, we captured a unique IDE conformation by using a synthetic antibody fragment as a crystallization chaperone. An unexpected displacement of a door subdomain creates an ~18-Å opening to the chamber. This swinging-door mechanism permits the entry of short peptides into the catalytic chamber and disrupts the catalytic site within IDE door subdomain. Given the propensity of amyloidogenic peptides to convert into β-strands for their polymerization into amyloid fibrils, they also use such β-strands to stabilize the disrupted catalytic site resided at IDE door subdomain for their degradation by IDE. Thus, action of the swinging door allows IDE to recognize amyloidogenicity by substrate-induced stabilization of the IDE catalytic cleft. Small angle X-ray scattering (SAXS) analysis revealed that IDE exists as a mixture of closed and open states. These open states, which are distinct from the swinging door state, permit entry of larger substrates (e.g., Aβ, insulin) to the chamber and are preferred in solution. Mutational studies confirmed the critical roles of the door subdomain and hinge loop joining the N- and C-terminal halves of IDE for catalysis. Together, our data provide insights into the conformational changes of IDE that govern the selective destruction of amyloidogenic peptides.

Role of Transbilayer Distribution of Lipid Molecules on the Structure and Protein-Lipid Interaction of an Amyloidogenic Protein on the Membrane Surface

NASA Astrophysics Data System (ADS)

Cheng, Kwan; Cheng, Sara

We used molecular dynamics simulations to examine the effects of transbilayer distribution of lipid molecules, particularly anionic lipids with negatively charged headgroups, on the structure and binding kinetics of an amyloidogenic protein on the membrane surface and subsequent protein-induced structural disruption of the membrane. Our systems consisted of a model beta-sheet rich dimeric protein absorbed on asymmetric bilayers with neutral and anionic lipids and symmetric bilayers with neutral lipids. We observed larger folding, domain aggregation, and tilt angle of the absorbed protein on the asymmetric bilayer surfaces. We also detected more focused bilayer thinning in the asymmetric bilayer due to weak lipid-protein interactions. Our results support the mechanism that the higher lipid packing in the protein-contacting lipid leaflet promotes stronger protein-protein but weaker protein-lipid interactions of an amyloidogenic protein on the membrane surface. We speculate that the observed surface-induced structural and protein-lipid interaction of our model amyloidogenic protein may play a role in the early membrane-associated amyloid cascade pathway that leads to membrane structural damage of neurons in Alzheimer's disease. NSF ACI-1531594.

Anti-Amyloidogenic Properties of Some Phenolic Compounds

PubMed Central

Porzoor, Afsaneh; Alford, Benjamin; Hügel, Helmut M.; Grando, Danilla; Caine, Joanne; Macreadie, Ian

2015-01-01

A family of 21 polyphenolic compounds consisting of those found naturally in danshen and their analogues were synthesized and subsequently screened for their anti-amyloidogenic activity against the amyloid beta peptide (Aβ42) of Alzheimer’s disease. After 24 h incubation with Aβ42, five compounds reduced thioflavin T (ThT) fluorescence, indicative of their anti-amyloidogenic propensity (p < 0.001). TEM and immunoblotting analysis also showed that selected compounds were capable of hindering fibril formation even after prolonged incubations. These compounds were also capable of rescuing the yeast cells from toxic changes induced by the chemically synthesized Aβ42. In a second assay, a Saccharomyces cerevisiae AHP1 deletant strain transformed with GFP fused to Aβ42 was treated with these compounds and analyzed by flow cytometry. There was a significant reduction in the green fluorescence intensity associated with 14 compounds. We interpret this result to mean that the compounds had an anti-amyloid-aggregation propensity in the yeast and GFP-Aβ42 was removed by proteolysis. The position and not the number of hydroxyl groups on the aromatic ring was found to be the most important determinant for the anti-amyloidogenic properties. PMID:25898401

Regulation of amyloid precursor protein processing by its KFERQ motif.

PubMed

Park, Ji-Seon; Kim, Dong-Hou; Yoon, Seung-Yong

2016-06-01

Understanding of trafficking, processing, and degradation mechanisms of amyloid precursor protein (APP) is important because APP can be processed to produce β-amyloid (Aβ), a key pathogenic molecule in Alzheimer's disease (AD). Here, we found that APP contains KFERQ motif at its C-terminus, a consensus sequence for chaperone-mediated autophagy (CMA) or microautophagy which are another types of autophagy for degradation of pathogenic molecules in neurodegenerative diseases. Deletion of KFERQ in APP increased C-terminal fragments (CTFs) and secreted N-terminal fragments of APP and kept it away from lysosomes. KFERQ deletion did not abolish the interaction of APP or its cleaved products with heat shock cognate protein 70 (Hsc70), a protein necessary for CMA or microautophagy. These findings suggest that KFERQ motif is important for normal processing and degradation of APP to preclude the accumulation of APP-CTFs although it may not be important for CMA or microautophagy. [BMB Reports 2016; 49(6): 337-342].

Developing smartphone apps for behavioural studies: The AlcoRisk app case study.

PubMed

Smith, Anthony; de Salas, Kristy; Lewis, Ian; Schüz, Benjamin

2017-08-01

Smartphone apps have emerged as valuable research tools to sample human behaviours at their time of occurrence within natural environments. Human behaviour sampling methods, such as Ecological Momentary Assessment (EMA), aim to facilitate research that is situated in ecologically valid real world environments rather than laboratory environments. Researchers have trialled a range of EMA smartphone apps to sample human behaviours such as dieting, physical activity and smoking. Software development processes for EMA smartphones apps, however, are not widely documented with little guidance provided for the integration of complex multidisciplinary behavioural and technical fields. In this paper, the AlcoRisk app for studying alcohol consumption and risk taking tendencies is presented alongside a software development process that integrates these multidisciplinary fields. The software development process consists of three stages including requirements analysis, feature and interface design followed by app implementation. Results from a preliminary feasibility study support the efficacy of the AlcoRisk app's software development process. Copyright © 2017 Elsevier Inc. All rights reserved.

Smartphones in ecology and evolution: a guide for the app-rehensive.

PubMed

Teacher, Amber G F; Griffiths, David J; Hodgson, David J; Inger, Richard

2013-12-01

Smartphones and their apps (application software) are now used by millions of people worldwide and represent a powerful combination of sensors, information transfer, and computing power that deserves better exploitation by ecological and evolutionary researchers. We outline the development process for research apps, provide contrasting case studies for two new research apps, and scan the research horizon to suggest how apps can contribute to the rapid collection, interpretation, and dissemination of data in ecology and evolutionary biology. We emphasize that the usefulness of an app relies heavily on the development process, recommend that app developers are engaged with the process at the earliest possible stage, and commend efforts to create open-source software scaffolds on which customized apps can be built by nonexperts. We conclude that smartphones and their apps could replace many traditional handheld sensors, calculators, and data storage devices in ecological and evolutionary research. We identify their potential use in the high-throughput collection, analysis, and storage of complex ecological information.

Amyloid-β Production Via Cleavage of Amyloid-β Protein Precursor is Modulated by Cell Density

PubMed Central

Zhang, Can; Browne, Andrew; DiVito, Jason R.; Stevenson, Jesse A.; Romano, Donna; Dong, Yuanlin; Xie, Zhongcong; Tanzi, Rudolph E.

2012-01-01

Mounting evidence suggests that Alzheimer disease (AD) is caused by the accumulation of the small peptide, Aβ, a proteolytic cleavage product of amyloid-β protein precursor (AβPP; or APP). Aβ is generated through a serial cleavage of APP by β- and γ-secretase. Aβ40 and Aβ42 are the two main components of amyloid plaques in AD brains, with Aβ42 being more prone to aggregation. APP can also be processed by α-secretase, which cleaves APP within the Aβ sequence, thereby preventing the generation of Aβ. Little is currently known regarding the effects of cell density on APP processing and Aβ generation. Here we assessed the effects of cell density on APP processing in neuronal and non-neuronal cell lines, as well as mouse primary cortical neurons. We found that decreased cell density significantly increases levels of Aβ40, Aβ42, total Aβ, and the ratio of Aβ42:Aβ40. These results also indicate that cell density is a significant modulator of APP processing. Overall, these findings carry profound implications for both previous and forthcoming studies aiming to assess the effects of various conditions and genetic/chemical factors, e.g. novel drugs on APP processing and Aβ generation in cell-based systems. Moreover, it is interesting to speculate whether cell density changes in vivo may also affect APP processing and Aβ levels in the AD brain. PMID:20847415

NMR-driven identification of anti-amyloidogenic compounds in green and roasted coffee extracts.

PubMed

Ciaramelli, Carlotta; Palmioli, Alessandro; De Luigi, Ada; Colombo, Laura; Sala, Gessica; Riva, Chiara; Zoia, Chiara Paola; Salmona, Mario; Airoldi, Cristina

2018-06-30

To identify food and beverages that provide the regular intake of natural compounds capable of interfering with toxic amyloidogenic aggregates, we developed an experimental protocol that combines NMR spectroscopy and atomic force microscopy, in vitro biochemical and cell assays to detect anti-Aβ molecules in natural edible matrices. We applied this approach to investigate the potential anti-amyloidogenic properties of coffee and its molecular constituents. Our data showed that green and roasted coffee extracts and their main components, 5-O-caffeoylquinic acid and melanoidins, can hinder Aβ on-pathway aggregation and toxicity in a human neuroblastoma SH-SY5Y cell line. Coffee extracts and melanoidins also counteract hydrogen peroxide- and rotenone-induced cytotoxicity and modulate some autophagic pathways in the same cell line. Copyright © 2018 Elsevier Ltd. All rights reserved.

LRP1 Modulates APP Intraneuronal Transport and Processing in Its Monomeric and Dimeric State

PubMed Central

Herr, Uta-Mareike; Strecker, Paul; Storck, Steffen E.; Thomas, Carolin; Rabiej, Verena; Junker, Anne; Schilling, Sandra; Schmidt, Nadine; Dowds, C. Marie; Eggert, Simone; Pietrzik, Claus U.; Kins, Stefan

2017-01-01

The low-density lipoprotein receptor-related protein 1, LRP1, interacts with APP and affects its processing. This is assumed to be mostly caused by the impact of LRP1 on APP endocytosis. More recently, also an interaction of APP and LRP1 early in the secretory pathway was reported whereat retention of LRP1 in the ER leads to decreased APP cell surface levels and in turn, to reduced Aβ secretion. Here, we extended the biochemical and immunocytochemical analyses by showing via live cell imaging analyses in primary neurons that LRP1 and APP are transported only partly in common (one third) but to a higher degree in distinct fast axonal transport vesicles. Interestingly, co-expression of LRP1 and APP caused a change of APP transport velocities, indicating that LRP1 recruits APP to a specific type of fast axonal transport vesicles. In contrast lowered levels of LRP1 facilitated APP transport. We further show that monomeric and dimeric APP exhibit similar transport characteristics and that both are affected by LRP1 in a similar way, by slowing down APP anterograde transport and increasing its endocytosis rate. In line with this, a knockout of LRP1 in CHO cells and in primary neurons caused an increase of monomeric and dimeric APP surface localization and in turn accelerated shedding by meprin β and ADAM10. Notably, a choroid plexus specific LRP1 knockout caused a much higher secretion of sAPP dimers into the cerebrospinal fluid compared to sAPP monomers. Together, our data show that LRP1 functions as a sorting receptor for APP, regulating its cell surface localization and thereby its processing by ADAM10 and meprin β, with the latter exhibiting a preference for APP in its dimeric state. PMID:28496400

Fluorescence fluctuation analysis of BACE1-GFP fusion protein in cultured HEK293 cells

NASA Astrophysics Data System (ADS)

Gardeen, Spencer; Johnson, Joseph L.; Heikal, Ahmed A.

2016-10-01

Beta-site APP cleaving enzyme 1 (BACE1) is a type I transmembrane aspartyl protease. In the amyloidogenic pathway, BACE1 provides β-secretase activity that cleaves the amyloid precursor protein (APP) that leads to amyloid beta (Aβ) peptides. The aggregation of these Aβ will ultimately results in amyloid plaque formation, a hallmark of Alzheimer's disease (AD). Amyloid aggregation leads to progressive memory impairment and neural loss. Recent detergent protein extraction studies suggest that the untreated BACE1 protein forms a dimer that has significantly higher catalytic activity than its monomeric counterpart. Here, we examine the dimerization hypothesis of BACE1 in cultured HEK293 cells using fluorescence correlation spectroscopy (FCS). Cells were transfected with a BACE1-EGFP fusion protein construct and imaged using confocal and DIC microscopy to monitor labeled BACE1 localization and distribution within the cell. Our one-photon fluorescence fluctuation autocorrelation of BACE1- EGFP on the plasma membrane of HEK cells is modeled using two diffusing species on the plasma membrane with estimated diffusion coefficients of 1.39 x 10-7 cm2/sec and 2.8 x 10-8 cm2/sec under resting conditions and STA-200 inhibition, respectively. Anomalous diffusion model also provided adequate description of the observed autocorrelation function of BACE1- EGFP on the plasma membrane with an estimate exponent (α) of 0.8 and 0.5 for resting and STA-200 treated cells, respectively. The corresponding hydrodynamic radius of this transmembrane fusion protein was estimated using the measured diffusion coefficients assuming both Stokes-Einstein and Saffman-Delbruck models. Our results suggest a complex diffusion pattern of BACE1-EGFP on the plasma membrane of HEK cells with the possibility for dimer formation, especially under STA-200 inhibition.

Alternative Pathways for Production of Beta-Amyloid Peptides of Alzheimer’s Disease

PubMed Central

Hook, Vivian; Schechter, Israel; Demuth, Hans-Ulrich; Hook, Gregory

2009-01-01

This highlight article describes three Alzheimer’s disease (AD) presentations made at the 5th General Meeting of the International Proteolysis Society that address enzymatic mechanisms that produce neurotoxic beta-amyloid (Aβ) peptides. One group described the poor kinetic properties of the BACE 1 β-secretase for cleaving the wild-type β-secretase site in the APP found in most AD patients. They demonstrated that cathepsin D displays BACE 1-like specificity, is 280-fold more abundant in human brain than BACE 1, and pepstatin A inhibits cleavage of β-secretase site peptides by brain extracts and cathepsin D, but not by BACE 1. Nevertheless, as BACE 1 and cathepsin D show poor activity towards the wild type β-secretase site, they suggested continuing the search for additional β-secretase candidate(s). The second group reported that cathepsin B is such an alternative β-secretase candidate possessing excellent kinetic efficiency and specificity for cleaving the wild-type β-secretase site. Significantly, they demonstrated that inhibitors of cathepsin B improved memory function with reduced amyloid plaque neuropathology and decreased brain Aβ(40/42) and β-secretase activity in AD animal models expressing APP containing the wild-type β-secretase site. The third group addressed isoaspartate and pyroglutamate (pGlu) posttranslational modifications of Aβ that are present in AD brains, with evidence that cathepsin B, but not BACE 1, efficiently cleaves the wild-type β-secretase site containing isoaspartate. They also found that cyclization of N-terminal Glu by glutaminyl cyclase generates pGluAβ(3-40/42) peptides that are highly amyloidogenic. These presentations suggested that cathepsin B and glutaminyl cyclase are potential new AD therapeutic targets. PMID:18979625

Characterization of two distinct beta2-microglobulin unfolding intermediates that may lead to amyloid fibrils of different morphology.

PubMed

Armen, Roger S; Daggett, Valerie

2005-12-13

The self-assembly of beta(2)-microglobulin into fibrils leads to dialysis-related amyloidosis. pH-mediated partial unfolding is required for the formation of the amyloidogenic intermediate that then self-assembles into amyloid fibrils. Two partially folded intermediates of beta(2)-microglobulin have been identified experimentally and linked to the formation of fibrils of distinct morphology, yet it remains difficult to characterize these partially unfolded states at high resolution using experimental approaches. Consequently, we have performed molecular dynamics simulations at neutral and low pH to determine the structures of these partially unfolded amyloidogenic intermediates. In the low-pH simulations, we observed the formation of alpha-sheet structure, which was first proposed by Pauling and Corey. Multiple simulations were performed, and two distinct intermediate state ensembles were identified that may account for the different fibril morphologies. The predominant early unfolding intermediate was nativelike in structure, in agreement with previous NMR studies. The late unfolding intermediate was significantly disordered, but it maintained an extended elongated structure, with hydrophobic clusters and residual alpha-extended chain strands in specific regions of the sequence that map to amyloidogenic peptides. We propose that the formation of alpha-sheet facilitates self-assembly into partially unfolded prefibrillar amyloidogenic intermediates.

Different disease-causing mutations in transthyretin trigger the same conformational conversion.

PubMed

Steward, Robert E; Armen, Roger S; Daggett, Valerie

2008-03-01

Transthyretin (TTR)-containing amyloid fibrils are deposited in cardiac tissue as a natural consequence of aging. A large number of inherited mutations lead to amyloid diseases by accelerating TTR deposition in other organs. Amyloid formation is preceded by a disruption of the quaternary structure of TTR and conformational changes in the monomer. To study conformational changes preceding the formation of amyloid, we performed molecular dynamics simulations of the wild-type monomer, amyloidogenic variants (V30M, L55P, V122I) and a protective variant (T119M) at neutral and low pH. At low pH, the D strand dissociated from the beta-sheet to expose the A strand, consistent with experimental studies. In amyloidogenic variants and in the wild-type at low pH, there was a conformational change in the beta-sheets into alpha-sheet via peptide bond flips that was not observed at neutral pH in the wild-type monomer. The same residues participated in conversion in each amyloidogenic variant simulation, originating in the G strand between residues 106 and 109, with accelerated conversion at low pH. The T119M protective variant changed the local conformation of the H strand and suppressed the conversion observed in amyloidogenic variants.

Membrane microdomain switching: a regulatory mechanism of amyloid precursor protein processing.

PubMed

Sakurai, Takashi; Kaneko, Kumi; Okuno, Misako; Wada, Koji; Kashiyama, Taku; Shimizu, Hideaki; Akagi, Takumi; Hashikawa, Tsutomu; Nukina, Nobuyuki

2008-10-20

Neuronal activity has an impact on beta cleavage of amyloid precursor protein (APP) by BACE1 to generate amyloid-beta peptide (Abeta). However, the molecular mechanisms underlying this effect remain to be elucidated. Cholesterol dependency of beta cleavage prompted us to analyze immunoisolated APP-containing detergent-resistant membranes from rodent brains. We found syntaxin 1 as a key molecule for activity-dependent regulation of APP processing in cholesterol-dependent microdomains. In living cells, APP associates with syntaxin 1-containing microdomains through X11-Munc18, which inhibits the APP-BACE1 interaction and beta cleavage via microdomain segregation. Phosphorylation of Munc18 by cdk5 causes a shift of APP to BACE1-containing microdomains. Neuronal hyperactivity, implicated in Abeta overproduction, promotes the switching of APP microdomain association as well as beta cleavage in a partially cdk5-dependent manner. We propose that microdomain switching is a mechanism of cholesterol- and activity-dependent regulation of APP processing in neurons.

Amyloid precursor protein controls cholesterol turnover needed for neuronal activity

PubMed Central

Pierrot, Nathalie; Tyteca, Donatienne; D'auria, Ludovic; Dewachter, Ilse; Gailly, Philippe; Hendrickx, Aurélie; Tasiaux, Bernadette; Haylani, Laetitia El; Muls, Nathalie; N'Kuli, Francisca; Laquerrière, Annie; Demoulin, Jean-Baptiste; Campion, Dominique; Brion, Jean-Pierre; Courtoy, Pierre J; Kienlen-Campard, Pascal; Octave, Jean-Noël

2013-01-01

Perturbation of lipid metabolism favours progression of Alzheimer disease, in which processing of Amyloid Precursor Protein (APP) has important implications. APP cleavage is tightly regulated by cholesterol and APP fragments regulate lipid homeostasis. Here, we investigated whether up or down regulation of full-length APP expression affected neuronal lipid metabolism. Expression of APP decreased HMG-CoA reductase (HMGCR)-mediated cholesterol biosynthesis and SREBP mRNA levels, while its down regulation had opposite effects. APP and SREBP1 co-immunoprecipitated and co-localized in the Golgi. This interaction prevented Site-2 protease-mediated processing of SREBP1, leading to inhibition of transcription of its target genes. A GXXXG motif in APP sequence was critical for regulation of HMGCR expression. In astrocytes, APP and SREBP1 did not interact nor did APP affect cholesterol biosynthesis. Neuronal expression of APP decreased both HMGCR and cholesterol 24-hydroxylase mRNA levels and consequently cholesterol turnover, leading to inhibition of neuronal activity, which was rescued by geranylgeraniol, generated in the mevalonate pathway, in both APP expressing and mevastatin treated neurons. We conclude that APP controls cholesterol turnover needed for neuronal activity. PMID:23554170

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lashuel, Hilal A.; Aljabari, Bayan; Sigurdsson, Einar M.

We demonstrate herein that human macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine expressed in the brain and not previously considered to be amyloidogenic, forms amyloid fibrils similar to those derived from the disease associated amyloidogenic proteins {beta}-amyloid and {alpha}-synuclein. Acid denaturing conditions were found to readily induce MIF to undergo amyloid fibril formation. MIF aggregates to form amyloid-like structures with a morphology that is highly dependent on pH. The mechanism of MIF amyloid formation was probed by electron microscopy, turbidity, Thioflavin T binding, circular dichroism spectroscopy, and analytical ultracentrifugation. The fibrillar structures formed by MIF bind Congo red andmore » exhibit the characteristic green birefringence under polarized light. These results are consistent with the notion that amyloid fibril formation is not an exclusive property of a select group of amyloidogenic proteins, and contribute to a better understanding of the factors which govern protein conformational changes and amyloid fibril formation in vivo.« less

RNAi-mediated knock-down of Dab and Numb attenuate Aβ levels via γ-secretase mediated APP processing.

PubMed

Xie, Zhongcong; Dong, Yuanlin; Maeda, Uta; Xia, Weiming; Tanzi, Rudolph E

2012-03-22

Amyloid-β-protein (Aβ), the key component of senile plaques in Alzheimer's disease (AD) brain, is produced from amyloid precursor protein (APP) by cleavage of β-secretase and then γ-secretase. APP adaptor proteins with phosphotyrosine-binding (PTB) domains, including Dab (gene: DAB) and Numb (gene: NUMB), can bind to and interact with the conserved YENPTY-motif in the APP C-terminus. Here we describe, for the first time, the effects of RNAi knock-down of Dab and Numb expression on APP processing and Aβ production. RNAi knock-down of Dab and Numb in H4 human neuroglioma cells stably transfected to express either FL-APP (H4-FL-APP cells) or APP-C99 (H4-APP-C99 cells) increased levels of APP-C-terminal fragments (APP-CTFs) and lowered Aβ levels in both cell lines by inhibiting γ-secretase cleavage of APP. Finally, RNAi knock-down of APP also reduced levels of Numb in H4-APP cells. These findings suggest that pharmacologically blocking interaction of APP with Dab and Numb may provide novel therapeutic strategies of AD. The notion of attenuating γ-secretase cleavage of APP via the APP adaptor proteins, Dab and Numb, is particularly attractive with regard to therapeutic potential, given that side effects of γ-secretase inhibition owing to impaired proteolysis of other γ-secretase substrates, e.g. Notch, might be avoided.

Light Chain Amyloidosis

PubMed Central

Milani, Paolo; Merlini, Giampaolo

2018-01-01

Light chain (AL) amyloidosis is caused by a usually small plasma-cell clone that is able to produce the amyloidogenic light chains. They are able to misfold and aggregate, deposit in tissues in the form of amyloid fibrils and lead to irreversible organ dysfunction and eventually death if treatment is late or ineffective. Cardiac damage is the most important prognostic determinant. The risk of dialysis is predicted by the severity of renal involvement, defined by the baseline proteinuria and glomerular filtration rate, and by the response to therapy. The specific treatment is chemotherapy targeting the underlying plasma-cell clone. It needs to be risk-adapted, according to the severity of cardiac and/or multi-organ involvement. Autologous stem cell transplant (preceded by induction and/or followed by consolidation with bortezomib-based regimens) can be considered for low-risk patients (~20%). Bortezomib combined with alkylators is used in the majority of intermediate-risk patients, and with possible dose escalation in high-risk subjects. Novel, powerful anti-plasma cell agents were investigated in the relapsed/refractory setting, and are being moved to upfront therapy in clinical trials. In addition, the use of novel approaches based on antibodies targeting the amyloid deposits or small molecules interfering with the amyloidogenic process gave promising results in preliminary studies. Some of them are under evaluation in controlled trials. These molecules will probably add powerful complements to standard chemotherapy. The understanding of the specific molecular mechanisms of cardiac damage and the characteristics of the amyloidogenic clone are unveiling novel potential treatment approaches, moving towards a cure for this dreadful disease. PMID:29531659

The intact Kunitz domain protects the amyloid precursor protein from being processed by matriptase-2.

PubMed

Beckmann, Anna-Madeleine; Glebov, Konstantin; Walter, Jochen; Merkel, Olaf; Mangold, Martin; Schmidt, Frederike; Becker-Pauly, Christoph; Gütschow, Michael; Stirnberg, Marit

2016-08-01

Proteolytic processing of the amyloid precursor protein (APP) leads to amyloid-β (Aβ) peptides. So far, the mechanism of APP processing is insufficiently characterized at the molecular level. Whereas the knowledge of Aβ generation by several proteases has been expanded, the contribution of the Kunitz-type protease inhibitor domain (KPI) present in two major APP isoforms to the complex proteolytic processing of APP is poorly understood. In this study, we have identified KPI-containing APP as a very potent, slow-binding inhibitor for the membrane-bound proteolytic regulator of iron homeostasis matriptase-2 by forming stable complexes with its target protease in HEK cells. Inhibition and complex formation depend on the intact KPI domain. By inhibiting matriptase-2, KPI-containing APP is protected from matriptase-2-mediated proteolysis within the Aβ region, thus preventing the generation of N-terminally truncated Aβ.

The Role of Oxidative Stress-Induced Epigenetic Alterations in Amyloid-β Production in Alzheimer's Disease

PubMed Central

Best, Thomas M.

2015-01-01

An increasing number of studies have proposed a strong correlation between reactive oxygen species (ROS)-induced oxidative stress (OS) and the pathogenesis of Alzheimer's disease (AD). With over five million people diagnosed in the United States alone, AD is the most common type of dementia worldwide. AD includes progressive neurodegeneration, followed by memory loss and reduced cognitive ability. Characterized by the formation of amyloid-beta (Aβ) plaques as a hallmark, the connection between ROS and AD is compelling. Analyzing the ROS response of essential proteins in the amyloidogenic pathway, such as amyloid-beta precursor protein (APP) and beta-secretase (BACE1), along with influential signaling programs of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinase (JNK), has helped visualize the path between OS and Aβ overproduction. In this review, attention will be paid to significant advances in the area of OS, epigenetics, and their influence on Aβ plaque assembly. Additionally, we aim to discuss available treatment options for AD that include antioxidant supplements, Asian traditional medicines, metal-protein-attenuating compounds, and histone modifying inhibitors. PMID:26543520

The Role of Oxidative Stress-Induced Epigenetic Alterations in Amyloid-β Production in Alzheimer's Disease.

PubMed

Zuo, Li; Hemmelgarn, Benjamin T; Chuang, Chia-Chen; Best, Thomas M

2015-01-01

An increasing number of studies have proposed a strong correlation between reactive oxygen species (ROS)-induced oxidative stress (OS) and the pathogenesis of Alzheimer's disease (AD). With over five million people diagnosed in the United States alone, AD is the most common type of dementia worldwide. AD includes progressive neurodegeneration, followed by memory loss and reduced cognitive ability. Characterized by the formation of amyloid-beta (Aβ) plaques as a hallmark, the connection between ROS and AD is compelling. Analyzing the ROS response of essential proteins in the amyloidogenic pathway, such as amyloid-beta precursor protein (APP) and beta-secretase (BACE1), along with influential signaling programs of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinase (JNK), has helped visualize the path between OS and Aβ overproduction. In this review, attention will be paid to significant advances in the area of OS, epigenetics, and their influence on Aβ plaque assembly. Additionally, we aim to discuss available treatment options for AD that include antioxidant supplements, Asian traditional medicines, metal-protein-attenuating compounds, and histone modifying inhibitors.

Contribution of Kunitz protease inhibitor and transmembrane domains to amyloid precursor protein homodimerization.

PubMed

Ben Khalifa, N; Tyteca, D; Courtoy, P J; Renauld, J C; Constantinescu, S N; Octave, J N; Kienlen-Campard, P

2012-01-01

The two major isoforms of the human amyloid precursor protein (APP) are APP695 and APP751. They differ by the insertion of a Kunitz-type protease inhibitor (KPI) sequence in the extracellular domain of APP751. APP-KPI isoforms are increased in Alzheimer's disease brains, and they could be associated with disease progression. Recent studies have shown that APP processing to Aβ is regulated by homodimerization, which involves both extracellular and juxtamembrane/transmembrane (JM/TM) regions. Our aim is to understand the mechanisms controlling APP dimerization and the contribution of the ectodomain and JM/TM regions to this process. We used bimolecular fluorescence complementation approaches coupled to fluorescence-activated cell sorting analysis to measure the dimerization level of different APP isoforms and APP C-terminal fragments (C99) mutated in their JM/TM region. APP751 was found to form significantly more homodimers than APP695. Mutation of dimerization motifs in the TM domain of APP or C99 did not significantly affect fluorescence complementation. These findings indicate that the KPI domain plays a major role in APP dimerization. They set the basis for further investigation of the relation between dimerization, metabolism and function of APP. Copyright © 2012 S. Karger AG, Basel.

The kunitz protease inhibitor form of the amyloid precursor protein (KPI/APP) inhibits the proneuropeptide processing enzyme prohormone thiol protease (PTP). Colocalization of KPI/APP and PTP in secretory vesicles.

PubMed

Hook, V Y; Sei, C; Yasothornsrikul, S; Toneff, T; Kang, Y H; Efthimiopoulos, S; Robakis, N K; Van Nostrand, W

1999-01-29

Proteolytic processing of proenkephalin and proneuropeptides is required for the production of active neurotransmitters and peptide hormones. Variations in the extent of proenkephalin processing in vivo suggest involvement of endogenous protease inhibitors. This study demonstrates that "protease nexin 2 (PN2)," the secreted form of the kunitz protease inhibitor (KPI) of the amyloid precursor protein (APP), potently inhibited the proenkephalin processing enzyme known as prohormone thiol protease (PTP), with a Ki,app of 400 nM. Moreover, PTP and PN2 formed SDS-stable complexes that are typical of kunitz protease inhibitor interactions with target proteases. In vivo, KPI/APP (120 kDa), as well as a truncated form of KPI/APP that resembles PN2 in apparent molecular mass (110 kDa), were colocalized with PTP and (Met)enkephalin in secretory vesicles of adrenal medulla (chromaffin granules). KPI/APP (110-120 kDa) was also detected in pituitary secretory vesicles that contain PTP. In chromaffin cells, calcium-dependent secretion of KPI/APP with PTP and (Met)enkephalin demonstrated the colocalization of these components in functional secretory vesicles. These results suggest a role for KPI/APP inhibition of PTP in regulated secretory vesicles. In addition, these results are the first to identify an endogenous protease target of KPI/APP, which is developmentally regulated in aging and Alzheimer's disease.

Smartphone apps and the nutrition care process: Current perspectives and future considerations.

PubMed

Chen, Juliana; Gemming, Luke; Hanning, Rhona; Allman-Farinelli, Margaret

2018-04-01

To provide dietitians with practical guidance on incorporating smartphone applications (apps) in the nutrition care process (NCP) to optimize patient education and counseling. The current evidence-base for mobile health (mHealth) apps was searched using PubMed and Google Scholar. Where and how apps could be implemented by dietitians across the four steps of the NCP is discussed. With functionality to automatically convert patient dietary records into nutrient components, nutrition assessment can be streamlined using nutrition apps, allowing more time for dietitians to deliver education and nutrition counseling. Dietitians could prescribe apps to provide patients with education on nutrition skills and in counseling for better adherence to behavior change. Improved patient-provider communication is also made possible through the opportunity for real-time monitoring and evaluation of patient progress via apps. A practical framework termed the 'Mobile Nutrition Care Process Grid' provides dietitians with best-practice guidance on how to use apps. Including apps into dietetic practice could enhance the efficiency and quality of nutrition care and counseling delivered by dietitians. Apps should be considered an adjunct to enable dietetic counseling and care, rather than to replace the expertise, social support and accountability provided by dietitians. Copyright © 2017 Elsevier B.V. All rights reserved.

β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia.

PubMed

Tamayev, Robert; Matsuda, Shuji; Arancio, Ottavio; D'Adamio, Luciano

2012-03-01

A mutation in the BRI2/ITM2b gene causes loss of BRI2 protein leading to familial Danish dementia (FDD). BRI2 deficiency of FDD provokes an increase in amyloid-β precursor protein (APP) processing since BRI2 is an inhibitor of APP proteolysis, and APP mediates the synaptic/memory deficits in FDD. APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias. We show that inhibition of APP cleavage by β-secretase rescues synaptic/memory deficits in a mouse model of FDD. β-cleavage of APP yields amino-terminal-soluble APPβ (sAPPβ) and β-carboxyl-terminal fragments (β-CTF). Processing of β-CTF by γ-secretase releases amyloid-β (Aβ), which is assumed to cause AD. However, inhibition of γ-secretase did not ameliorate synaptic/memory deficits of FDD mice. These results suggest that sAPPβ and/or β-CTF, rather than Aβ, are the toxic species causing dementia, and indicate that reducing β-cleavage of APP is an appropriate therapeutic approach to treating human dementias. Our data and the failures of anti-Aβ therapies in humans advise against targeting γ-secretase cleavage of APP and/or Aβ. Copyright © 2012 EMBO Molecular Medicine.

β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia

PubMed Central

Tamayev, Robert; Matsuda, Shuji; Arancio, Ottavio; D'Adamio, Luciano

2012-01-01

A mutation in the BRI2/ITM2b gene causes loss of BRI2 protein leading to familial Danish dementia (FDD). BRI2 deficiency of FDD provokes an increase in amyloid-β precursor protein (APP) processing since BRI2 is an inhibitor of APP proteolysis, and APP mediates the synaptic/memory deficits in FDD. APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias. We show that inhibition of APP cleavage by β-secretase rescues synaptic/memory deficits in a mouse model of FDD. β-cleavage of APP yields amino-terminal-soluble APPβ (sAPPβ) and β-carboxyl-terminal fragments (β-CTF). Processing of β-CTF by γ-secretase releases amyloid-β (Aβ), which is assumed to cause AD. However, inhibition of γ-secretase did not ameliorate synaptic/memory deficits of FDD mice. These results suggest that sAPPβ and/or β-CTF, rather than Aβ, are the toxic species causing dementia, and indicate that reducing β-cleavage of APP is an appropriate therapeutic approach to treating human dementias. Our data and the failures of anti-Aβ therapies in humans advise against targeting γ-secretase cleavage of APP and/or Aβ. PMID:22170863

DADS Analogues Ameliorated the Cognitive Impairments of Alzheimer-Like Rat Model Induced by Scopolamine.

PubMed

Manral, Apra; Meena, Poonam; Saini, Vikas; Siraj, Fouzia; Shalini, Shruti; Tiwari, Manisha

2016-10-01

The development of agents that affect two or more relevant targets has drawn considerable attention in treatment of AD. Diallyl disulfide (DADS), an active principle of garlic, has been reported to prevent APP processing by amyloidogenic pathway. Recently, we have reported a new series of DADS derivatives and our findings revealed that compound 7k and 7l could provide good templates for developing new multifunctional agents for AD treatment. Thus, the present study was constructed to investigate the neuroprotective effect of DADS analogues (7k and 7l) against Aβ-induced neurotoxicity in SH-SY5Y human neuroblastoma cells and in ameliorating the cognition deficit induced by scopolamine in rat model. The results indicated that compound 7k and 7l significantly inhibited Aβ1-42-induced neuronal cell death by inhibiting ROS generation. Moreover, they prevented apoptosis, in response to ROS, by restoring normal Bax/Bcl-2 ratio. Furthermore, it was observed that scopolamine-induced memory impairment was coupled by alterations in neurotransmitters, acetylcholinesterase activity and oxidative stress markers. Histological analysis revealed severe damaging effects of scopolamine on the structure of cerebral cortex and hippocampus. Administration of compounds 7k and 7l at 5 mg/kg significantly reversed scopolamine-induced behavioural, biochemical, neurochemical and histological changes in a manner comparable to standard donepezil. Together the present findings and previous studies indicate that compounds 7k and 7l have neuroprotective and cognition-enhancing effects, which makes them a promising multi-target candidate for addressing the complex nature of AD.

Modifications and Trafficking of APP in the Pathogenesis of Alzheimer’s Disease

PubMed Central

Wang, Xin; Zhou, Xuan; Li, Gongying; Zhang, Yun; Wu, Yili; Song, Weihong

2017-01-01

Alzheimer’s disease (AD), the most common neurodegenerative disorder, is the leading cause of dementia. Neuritic plaque, one of the major characteristics of AD neuropathology, mainly consists of amyloid β (Aβ) protein. Aβ is derived from amyloid precursor protein (APP) by sequential cleavages of β- and γ-secretase. Although APP upregulation can promote AD pathogenesis by facilitating Aβ production, growing evidence indicates that aberrant post-translational modifications and trafficking of APP play a pivotal role in AD pathogenesis by dysregulating APP processing and Aβ generation. In this report, we reviewed the current knowledge of APP modifications and trafficking as well as their role in APP processing. More importantly, we discussed the effect of aberrant APP modifications and trafficking on Aβ generation and the underlying mechanisms, which may provide novel strategies for drug development in AD. PMID:28966576

Modifications and Trafficking of APP in the Pathogenesis of Alzheimer's Disease.

PubMed

Wang, Xin; Zhou, Xuan; Li, Gongying; Zhang, Yun; Wu, Yili; Song, Weihong

2017-01-01

Alzheimer's disease (AD), the most common neurodegenerative disorder, is the leading cause of dementia. Neuritic plaque, one of the major characteristics of AD neuropathology, mainly consists of amyloid β (Aβ) protein. Aβ is derived from amyloid precursor protein (APP) by sequential cleavages of β- and γ-secretase. Although APP upregulation can promote AD pathogenesis by facilitating Aβ production, growing evidence indicates that aberrant post-translational modifications and trafficking of APP play a pivotal role in AD pathogenesis by dysregulating APP processing and Aβ generation. In this report, we reviewed the current knowledge of APP modifications and trafficking as well as their role in APP processing. More importantly, we discussed the effect of aberrant APP modifications and trafficking on Aβ generation and the underlying mechanisms, which may provide novel strategies for drug development in AD.

Optimal processing for gel electrophoresis images: Applying Monte Carlo Tree Search in GelApp.

PubMed

Nguyen, Phi-Vu; Ghezal, Ali; Hsueh, Ya-Chih; Boudier, Thomas; Gan, Samuel Ken-En; Lee, Hwee Kuan

2016-08-01

In biomedical research, gel band size estimation in electrophoresis analysis is a routine process. To facilitate and automate this process, numerous software have been released, notably the GelApp mobile app. However, the band detection accuracy is limited due to a band detection algorithm that cannot adapt to the variations in input images. To address this, we used the Monte Carlo Tree Search with Upper Confidence Bound (MCTS-UCB) method to efficiently search for optimal image processing pipelines for the band detection task, thereby improving the segmentation algorithm. Incorporating this into GelApp, we report a significant enhancement of gel band detection accuracy by 55.9 ± 2.0% for protein polyacrylamide gels, and 35.9 ± 2.5% for DNA SYBR green agarose gels. This implementation is a proof-of-concept in demonstrating MCTS-UCB as a strategy to optimize general image segmentation. The improved version of GelApp-GelApp 2.0-is freely available on both Google Play Store (for Android platform), and Apple App Store (for iOS platform). © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

RNAi-mediated knock-down of Dab and Numb attenuate Aβ levels via γ-secretase mediated APP processing

PubMed Central

2012-01-01

Amyloid-β-protein (Aβ), the key component of senile plaques in Alzheimer's disease (AD) brain, is produced from amyloid precursor protein (APP) by cleavage of β-secretase and then γ-secretase. APP adaptor proteins with phosphotyrosine-binding (PTB) domains, including Dab (gene: DAB) and Numb (gene: NUMB), can bind to and interact with the conserved YENPTY-motif in the APP C-terminus. Here we describe, for the first time, the effects of RNAi knock-down of Dab and Numb expression on APP processing and Aβ production. RNAi knock-down of Dab and Numb in H4 human neuroglioma cells stably transfected to express either FL-APP (H4-FL-APP cells) or APP-C99 (H4-APP-C99 cells) increased levels of APP-C-terminal fragments (APP-CTFs) and lowered Aβ levels in both cell lines by inhibiting γ-secretase cleavage of APP. Finally, RNAi knock-down of APP also reduced levels of Numb in H4-APP cells. These findings suggest that pharmacologically blocking interaction of APP with Dab and Numb may provide novel therapeutic strategies of AD. The notion of attenuating γ-secretase cleavage of APP via the APP adaptor proteins, Dab and Numb, is particularly attractive with regard to therapeutic potential, given that side effects of γ-secretase inhibition owing to impaired proteolysis of other γ-secretase substrates, e.g. Notch, might be avoided. PMID:23211096

Mobile Phone Apps to Improve Medication Adherence: A Systematic Stepwise Process to Identify High-Quality Apps.

PubMed

Santo, Karla; Richtering, Sarah S; Chalmers, John; Thiagalingam, Aravinda; Chow, Clara K; Redfern, Julie

2016-12-02

There are a growing number of mobile phone apps available to support people in taking their medications and to improve medication adherence. However, little is known about how these apps differ in terms of features, quality, and effectiveness. We aimed to systematically review the medication reminder apps available in the Australian iTunes store and Google Play to assess their features and their quality in order to identify high-quality apps. This review was conducted in a similar manner to a systematic review by using a stepwise approach that included (1) a search strategy; (2) eligibility assessment; (3) app selection process through an initial screening of all retrieved apps and full app review of the included apps; (4) data extraction using a predefined set of features considered important or desirable in medication reminder apps; (5) analysis by classifying the apps as basic and advanced medication reminder apps and scoring and ranking them; and (6) a quality assessment by using the Mobile App Rating Scale (MARS), a reliable tool to assess mobile health apps. We identified 272 medication reminder apps, of which 152 were found only in Google Play, 87 only in iTunes, and 33 in both app stores. Apps found in Google Play had more customer reviews, higher star ratings, and lower cost compared with apps in iTunes. Only 109 apps were available for free and 124 were recently updated in 2015 or 2016. Overall, the median number of features per app was 3.0 (interquartile range 4.0) and only 18 apps had ≥9 of the 17 desirable features. The most common features were flexible scheduling that was present in 56.3% (153/272) of the included apps, medication tracking history in 54.8% (149/272), snooze option in 34.9% (95/272), and visual aids in 32.4% (88/272). We classified 54.8% (149/272) of the included apps as advanced medication reminder apps and 45.2% (123/272) as basic medication reminder apps. The advanced apps had a higher number of features per app compared with the basic apps. Using the MARS instrument, we were able to identify high-quality apps that were rated as being very interesting and entertaining, highly interactive and customizable, intuitive, and easy to use and to navigate as well as having a high level of visual appeal and good-quality information. Many medication reminder apps are available in the app stores; however, the majority of them did not have many of the desirable features and were, therefore, considered low quality. Through a systematic stepwise process, we were able to identify high-quality apps to be tested in a future study that will provide evidence on the use of medication reminder apps to improve medication adherence. ©Karla Santo, Sarah S Richtering, John Chalmers, Aravinda Thiagalingam, Clara K Chow, Julie Redfern. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 02.12.2016.

Mobile Phone Apps to Improve Medication Adherence: A Systematic Stepwise Process to Identify High-Quality Apps

PubMed Central

Richtering, Sarah S; Chalmers, John; Thiagalingam, Aravinda; Chow, Clara K; Redfern, Julie

2016-01-01

Background There are a growing number of mobile phone apps available to support people in taking their medications and to improve medication adherence. However, little is known about how these apps differ in terms of features, quality, and effectiveness. Objective We aimed to systematically review the medication reminder apps available in the Australian iTunes store and Google Play to assess their features and their quality in order to identify high-quality apps. Methods This review was conducted in a similar manner to a systematic review by using a stepwise approach that included (1) a search strategy; (2) eligibility assessment; (3) app selection process through an initial screening of all retrieved apps and full app review of the included apps; (4) data extraction using a predefined set of features considered important or desirable in medication reminder apps; (5) analysis by classifying the apps as basic and advanced medication reminder apps and scoring and ranking them; and (6) a quality assessment by using the Mobile App Rating Scale (MARS), a reliable tool to assess mobile health apps. Results We identified 272 medication reminder apps, of which 152 were found only in Google Play, 87 only in iTunes, and 33 in both app stores. Apps found in Google Play had more customer reviews, higher star ratings, and lower cost compared with apps in iTunes. Only 109 apps were available for free and 124 were recently updated in 2015 or 2016. Overall, the median number of features per app was 3.0 (interquartile range 4.0) and only 18 apps had ≥9 of the 17 desirable features. The most common features were flexible scheduling that was present in 56.3% (153/272) of the included apps, medication tracking history in 54.8% (149/272), snooze option in 34.9% (95/272), and visual aids in 32.4% (88/272). We classified 54.8% (149/272) of the included apps as advanced medication reminder apps and 45.2% (123/272) as basic medication reminder apps. The advanced apps had a higher number of features per app compared with the basic apps. Using the MARS instrument, we were able to identify high-quality apps that were rated as being very interesting and entertaining, highly interactive and customizable, intuitive, and easy to use and to navigate as well as having a high level of visual appeal and good-quality information. Conclusions Many medication reminder apps are available in the app stores; however, the majority of them did not have many of the desirable features and were, therefore, considered low quality. Through a systematic stepwise process, we were able to identify high-quality apps to be tested in a future study that will provide evidence on the use of medication reminder apps to improve medication adherence. PMID:27913373

Guidelines and Recommendations for Developing Interactive eHealth Apps for Complex Messaging in Health Promotion.

PubMed

Heffernan, Kayla Joanne; Chang, Shanton; Maclean, Skye Tamara; Callegari, Emma Teresa; Garland, Suzanne Marie; Reavley, Nicola Jane; Varigos, George Andrew; Wark, John Dennis

2016-02-09

The now ubiquitous catchphrase, "There's an app for that," rings true owing to the growing number of mobile phone apps. In excess of 97,000 eHealth apps are available in major app stores. Yet the effectiveness of these apps varies greatly. While a minority of apps are developed grounded in theory and in conjunction with health care experts, the vast majority are not. This is concerning given the Hippocratic notion of "do no harm." There is currently no unified formal theory for developing interactive eHealth apps, and development is especially difficult when complex messaging is required, such as in health promotion and prevention. This paper aims to provide insight into the creation of interactive eHealth apps for complex messaging, by leveraging the Safe-D case study, which involved complex messaging required to guide safe but sufficient UV exposure for vitamin D synthesis in users. We aim to create recommendations for developing interactive eHealth apps for complex messages based on the lessons learned during Safe-D app development. For this case study we developed an Apple and Android app, both named Safe-D, to safely improve vitamin D status in young women through encouraging safe ultraviolet radiation exposure. The app was developed through participatory action research involving medical and human computer interaction researchers, subject matter expert clinicians, external developers, and target users. The recommendations for development were created from analysis of the development process. By working with clinicians and implementing disparate design examples from the literature, we developed the Safe-D app. From this development process, recommendations for developing interactive eHealth apps for complex messaging were created: (1) involve a multidisciplinary team in the development process, (2) manage complex messages to engage users, and (3) design for interactivity (tailor recommendations, remove barriers to use, design for simplicity). This research has provided principles for developing interactive eHealth apps for complex messaging as guidelines by aggregating existing design concepts and expanding these concepts and new learnings from our development process. A set of guidelines to develop interactive eHealth apps generally, and specifically those for complex messaging, was previously missing from the literature; this research has contributed these principles. Safe-D delivers complex messaging simply, to aid education, and explicitly, considering user safety.

Guidelines and Recommendations for Developing Interactive eHealth Apps for Complex Messaging in Health Promotion

PubMed Central

Heffernan, Kayla Joanne; Maclean, Skye Tamara; Callegari, Emma Teresa; Garland, Suzanne Marie; Reavley, Nicola Jane; Varigos, George Andrew; Wark, John Dennis

2016-01-01

Background The now ubiquitous catchphrase, “There’s an app for that,” rings true owing to the growing number of mobile phone apps. In excess of 97,000 eHealth apps are available in major app stores. Yet the effectiveness of these apps varies greatly. While a minority of apps are developed grounded in theory and in conjunction with health care experts, the vast majority are not. This is concerning given the Hippocratic notion of “do no harm.” There is currently no unified formal theory for developing interactive eHealth apps, and development is especially difficult when complex messaging is required, such as in health promotion and prevention. Objective This paper aims to provide insight into the creation of interactive eHealth apps for complex messaging, by leveraging the Safe-D case study, which involved complex messaging required to guide safe but sufficient UV exposure for vitamin D synthesis in users. We aim to create recommendations for developing interactive eHealth apps for complex messages based on the lessons learned during Safe-D app development. Methods For this case study we developed an Apple and Android app, both named Safe-D, to safely improve vitamin D status in young women through encouraging safe ultraviolet radiation exposure. The app was developed through participatory action research involving medical and human computer interaction researchers, subject matter expert clinicians, external developers, and target users. The recommendations for development were created from analysis of the development process. Results By working with clinicians and implementing disparate design examples from the literature, we developed the Safe-D app. From this development process, recommendations for developing interactive eHealth apps for complex messaging were created: (1) involve a multidisciplinary team in the development process, (2) manage complex messages to engage users, and (3) design for interactivity (tailor recommendations, remove barriers to use, design for simplicity). Conclusions This research has provided principles for developing interactive eHealth apps for complex messaging as guidelines by aggregating existing design concepts and expanding these concepts and new learnings from our development process. A set of guidelines to develop interactive eHealth apps generally, and specifically those for complex messaging, was previously missing from the literature; this research has contributed these principles. Safe-D delivers complex messaging simply, to aid education, and explicitly, considering user safety. PMID:26860623

Rivastigmine Lowers Aβ and Increases sAPPα Levels, Which Parallel Elevated Synaptic Markers and Metabolic Activity in Degenerating Primary Rat Neurons

PubMed Central

Bailey, Jason A.; Ray, Balmiki; Greig, Nigel H.; Lahiri, Debomoy K.

2011-01-01

Overproduction of amyloid-β (Aβ) protein in the brain has been hypothesized as the primary toxic insult that, via numerous mechanisms, produces cognitive deficits in Alzheimer's disease (AD). Cholinesterase inhibition is a primary strategy for treatment of AD, and specific compounds of this class have previously been demonstrated to influence Aβ precursor protein (APP) processing and Aβ production. However, little information is available on the effects of rivastigmine, a dual acetylcholinesterase and butyrylcholinesterase inhibitor, on APP processing. As this drug is currently used to treat AD, characterization of its various activities is important to optimize its clinical utility. We have previously shown that rivastigmine can preserve or enhance neuronal and synaptic terminal markers in degenerating primary embryonic cerebrocortical cultures. Given previous reports on the effects of APP and Aβ on synapses, regulation of APP processing represents a plausible mechanism for the synaptic effects of rivastigmine. To test this hypothesis, we treated degenerating primary cultures with rivastigmine and measured secreted APP (sAPP) and Aβ. Rivastigmine treatment increased metabolic activity in these cultured cells, and elevated APP secretion. Analysis of the two major forms of APP secreted by these cultures, attributed to neurons or glia based on molecular weight showed that rivastigmine treatment significantly increased neuronal relative to glial secreted APP. Furthermore, rivastigmine treatment increased α-secretase cleaved sAPPα and decreased Aβ secretion, suggesting a therapeutic mechanism wherein rivastigmine alters the relative activities of the secretase pathways. Assessment of sAPP levels in rodent CSF following once daily rivastigmine administration for 21 days confirmed that elevated levels of APP in cell culture translated in vivo. Taken together, rivastigmine treatment enhances neuronal sAPP and shifts APP processing toward the α-secretase pathway in degenerating neuronal cultures, which mirrors the trend of synaptic proteins, and metabolic activity. PMID:21799757

2-Deoxy-D-glucose treatment induces ketogenesis, sustains mitochondrial function, and reduces pathology in female mouse model of Alzheimer's disease.

PubMed

Yao, Jia; Chen, Shuhua; Mao, Zisu; Cadenas, Enrique; Brinton, Roberta Diaz

2011-01-01

Previously, we demonstrated that mitochondrial bioenergetic deficits preceded Alzheimer's disease (AD) pathology in the female triple-transgenic AD (3xTgAD) mouse model. In parallel, 3xTgAD mice exhibited elevated expression of ketogenic markers, indicating a compensatory mechanism for energy production in brain. This compensatory response to generate an alternative fuel source was temporary and diminished with disease progression. To determine whether this compensatory alternative fuel system could be sustained, we investigated the impact of 2-deoxy-D-glucose (2-DG), a compound known to induce ketogenesis, on bioenergetic function and AD pathology burden in brain. 6-month-old female 3xTgAD mice were fed either a regular diet (AIN-93G) or a diet containing 0.04% 2-DG for 7 weeks. 2-DG diet significantly increased serum ketone body level and brain expression of enzymes required for ketone body metabolism. The 2-DG-induced maintenance of mitochondrial bioenergetics was paralleled by simultaneous reduction in oxidative stress. Further, 2-DG treated mice exhibited a significant reduction of both amyloid precursor protein (APP) and amyloid beta (Aβ) oligomers, which was paralleled by significantly increased α-secretase and decreased γ-secretase expression, indicating that 2-DG induced a shift towards a non-amyloidogenic pathway. In addition, 2-DG increased expression of genes involved in Aβ clearance pathways, degradation, sequestering, and transport. Concomitant with increased bioenergetic capacity and reduced β-amyloid burden, 2-DG significantly increased expression of neurotrophic growth factors, BDNF and NGF. Results of these analyses demonstrate that dietary 2-DG treatment increased ketogenesis and ketone metabolism, enhanced mitochondrial bioenergetic capacity, reduced β-amyloid generation and increased mechanisms of β-amyloid clearance. Further, these data link bioenergetic capacity with β-amyloid generation and demonstrate that β-amyloid burden was dynamic and reversible, as 2-DG reduced activation of the amyloidogenic pathway and increased mechanisms of β-amyloid clearance. Collectively, these data provide preclinical evidence for dietary 2-DG as a disease-modifying intervention to delay progression of bioenergetic deficits in brain and associated β-amyloid burden.

APP is cleaved by Bace1 in pre-synaptic vesicles and establishes a pre-synaptic interactome, via its intracellular domain, with molecular complexes that regulate pre-synaptic vesicles functions.

PubMed

Del Prete, Dolores; Lombino, Franco; Liu, Xinran; D'Adamio, Luciano

2014-01-01

Amyloid Precursor Protein (APP) is a type I membrane protein that undergoes extensive processing by secretases, including BACE1. Although mutations in APP and genes that regulate processing of APP, such as PSENs and BRI2/ITM2B, cause dementias, the normal function of APP in synaptic transmission, synaptic plasticity and memory formation is poorly understood. To grasp the biochemical mechanisms underlying the function of APP in the central nervous system, it is important to first define the sub-cellular localization of APP in synapses and the synaptic interactome of APP. Using biochemical and electron microscopy approaches, we have found that APP is localized in pre-synaptic vesicles, where it is processed by Bace1. By means of a proteomic approach, we have characterized the synaptic interactome of the APP intracellular domain. We focused on this region of APP because in vivo data underline the central functional and pathological role of the intracellular domain of APP. Consistent with the expression of APP in pre-synaptic vesicles, the synaptic APP intracellular domain interactome is predominantly constituted by pre-synaptic, rather than post-synaptic, proteins. This pre-synaptic interactome of the APP intracellular domain includes proteins expressed on pre-synaptic vesicles such as the vesicular SNARE Vamp2/Vamp1 and the Ca2+ sensors Synaptotagmin-1/Synaptotagmin-2, and non-vesicular pre-synaptic proteins that regulate exocytosis, endocytosis and recycling of pre-synaptic vesicles, such as target-membrane-SNAREs (Syntaxin-1b, Syntaxin-1a, Snap25 and Snap47), Munc-18, Nsf, α/β/γ-Snaps and complexin. These data are consistent with a functional role for APP, via its carboxyl-terminal domain, in exocytosis, endocytosis and/or recycling of pre-synaptic vesicles.

A Comprehensive Onboarding and Orientation Plan for Neurocritical Care Advanced Practice Providers.

PubMed

Langley, Tamra M; Dority, Jeremy; Fraser, Justin F; Hatton, Kevin W

2018-06-01

As the role of advanced practice providers (APPs) expands to include increasingly complex patient care within the intensive care unit, the educational needs of these providers must also be expanded. An onboarding process was designed for APPs in the neurocritical care service line. Onboarding for new APPs revolved around 5 specific areas: candidate selection, proctor assignment, 3-phased orientation process, remediation, and mentorship. To ensure effective training for APPs, using the most time-conscious approach, the backbone of the process is a structured curriculum. This was developed and integrated within the standard orientation and onboarding process. The curriculum design incorporated measurable learning goals, objective assessments of phased goal achievements, and opportunities for remediation. The neurocritical care service implemented an onboarding process in 2014. Four APPs (3 nurse practitioners and 1 physician assistant) were employed by the department before the implementation of the orientation program. The length of employment ranged from 1 to 4 years. Lack of clinical knowledge and/or sufficient training was cited as reasons for departure from the position in 2 of the 4 APPs, as either self-expression or peer evaluation. Since implementation of this program, 12 APPs have completed the program, of which 10 remain within the division, creating an 83% retention rate. The onboarding process, including a 3-phased, structured orientation plan for neurocritical care, has increased APP retention since its implementation. The educational model, along with proctoring and mentorship, has improved clinical knowledge and increased nurse practitioner retention. A larger-scale study would help to support the validity of this onboarding process.

Membrane microdomain switching: a regulatory mechanism of amyloid precursor protein processing

PubMed Central

Sakurai, Takashi; Kaneko, Kumi; Okuno, Misako; Wada, Koji; Kashiyama, Taku; Shimizu, Hideaki; Akagi, Takumi; Hashikawa, Tsutomu; Nukina, Nobuyuki

2008-01-01

Neuronal activity has an impact on β cleavage of amyloid precursor protein (APP) by BACE1 to generate amyloid-β peptide (Aβ). However, the molecular mechanisms underlying this effect remain to be elucidated. Cholesterol dependency of β cleavage prompted us to analyze immunoisolated APP-containing detergent-resistant membranes from rodent brains. We found syntaxin 1 as a key molecule for activity-dependent regulation of APP processing in cholesterol-dependent microdomains. In living cells, APP associates with syntaxin 1–containing microdomains through X11–Munc18, which inhibits the APP–BACE1 interaction and β cleavage via microdomain segregation. Phosphorylation of Munc18 by cdk5 causes a shift of APP to BACE1-containing microdomains. Neuronal hyperactivity, implicated in Aβ overproduction, promotes the switching of APP microdomain association as well as β cleavage in a partially cdk5-dependent manner. We propose that microdomain switching is a mechanism of cholesterol- and activity-dependent regulation of APP processing in neurons. PMID:18936252

Development of a smartphone app for adolescents with lupus: a collaborative meeting-based methodology inclusive of a wide range of stakeholders.

PubMed

Herschman, Jessica; Kasenberg, Todd; Levy, Deborah; Ruth, Natasha; Taberner, Christy; Kaufman, Miriam; Regina, Andrea

2014-01-01

Traditional challenges of creating a medical app include hearing the voices of various stakeholders as a collective rather than in a consultative process that is sequential. This report describes the development of a mobile (smartphone) app for adolescents with lupus as well as the process that was used to overcome the challenge described above. The development of the smartphone app addressed optimal ways to incorporate information about 1) lupus, including the effects of both the disease and the medications used to treat it; 2) how life choices can affect lupus patients' condition; and 3) ways to increase self-management and communication. The collaborative concept-generating and requirements-gathering methodology was used during a two-day workshop with a range of stakeholders (ages 16 - 59 years) that focused on leveraging user-centered design methods to generate guidance to mobile app developers. The app development process conducted during the workshop included the following steps: 1) recruiting a goal-focused collaborative group, 2) defining app objectives, 3) evaluating potential needs of users, 4) brainstorming app features and use-case modeling, 5) reviewing existing app features and prototypes, 6) refining functionalities, 7) writing user narratives, 8) visualizing navigation and feature design, and 9) identifying content. The use of creative devices such as drawing interfaces fostered fun, engagement, and sustained energy, and the use of a brainstorming technique leveraged methods that ensured an inclusive process so that even participants who were shy, quiet, or easily intimidated by "professionals" felt confident to contribute. In addition to a name change for the app, project outcomes included the selection of the following app features: symptom tracking; appointment and medication reminders; a social media component; a medical summary; easy navigation; informational content; gamification; and personalization (options for customization).

APP processing and the APP-KPI domain involvement in the amyloid cascade.

PubMed

Menéndez-González, M; Pérez-Pinera, P; Martínez-Rivera, M; Calatayud, M T; Blázquez Menes, B

2005-01-01

Alternative APP mRNA splicing can generate isoforms of APP containing a Kunitz protease inhibitor (KPI) domain. KPI is one of the main serine protease inhibitors. Protein and mRNA KPI(+)APP levels are elevated in Alzheimer's disease (AD) brain and are associated with increased amyloid beta deposition. In the last years increasing evidence on multiple points in the amyloid cascade where KPI(+)APP is involved has been accumulated, admitting an outstanding position in the pathogenesis of AD to the KPI domain. This review focuses on the APP processing, the molecular activity of KPI and its physiological and pathological roles and the KPI involvement in the amyloid cascade through the nerve growth factor, the lipoprotein receptor-related protein, the tumor necrosis factor-alpha converting enzyme and the Notch1 protein.

''Are Chemistry Educational Apps Useful?''--A Quantitative Study with Three In-House Apps

ERIC Educational Resources Information Center

Ping, Grace Lee Yuan; Lok, Chang; Yeat, Tan Wei; Cherynn, Tan Jie Ying; Tan, Emelyn Sue Qing

2018-01-01

Three internally developed mobile apps, "3D Sym Op", "SM2 Chem" and "ARMolVis," available for free on both the Apple App Store and Google Play Store were evaluated in seven studies. Each study was a systematic process of Pre-Test, In-lecture App Demo, App Assisted Interactive Tutorials (AAITs) and/or Independent App…

η-Secretase processing of APP inhibits neuronal activity in the hippocampus.

PubMed

Willem, Michael; Tahirovic, Sabina; Busche, Marc Aurel; Ovsepian, Saak V; Chafai, Magda; Kootar, Scherazad; Hornburg, Daniel; Evans, Lewis D B; Moore, Steven; Daria, Anna; Hampel, Heike; Müller, Veronika; Giudici, Camilla; Nuscher, Brigitte; Wenninger-Weinzierl, Andrea; Kremmer, Elisabeth; Heneka, Michael T; Thal, Dietmar R; Giedraitis, Vilmantas; Lannfelt, Lars; Müller, Ulrike; Livesey, Frederick J; Meissner, Felix; Herms, Jochen; Konnerth, Arthur; Marie, Hélène; Haass, Christian

2015-10-15

Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide. Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-η, in addition to the long-known CTF-α and CTF-β fragments generated by the α- and β-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (β-site APP cleaving enzyme 1), respectively. CTF-η generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504-505 of APP695, releasing a truncated ectodomain. After shedding of this ectodomain, CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (termed Aη-α and Aη-β). CTFs produced by η-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.

Islet amyloid polypeptide (IAPP):cDNA cloning and identification of an amyloidogenic region associated with the species-specific occurrence of age-related diabetes mellitus.

PubMed

Betsholtz, C; Svensson, V; Rorsman, F; Engström, U; Westermark, G T; Wilander, E; Johnson, K; Westermark, P

1989-08-01

We have cloned and sequenced a human islet amyloid polypeptide (IAPP) cDNA. A secretory 89 amino acid IAPP protein precursor is predicted from which the 37 amino acid IAPP molecule is formed by amino- and carboxyterminal proteolytic processing. The IAPP peptide is 43-46% identical in amino acid sequence to the two members of the calcitonin gene-related peptide (CGRP) family. Evolutionary conserved proteolytic processing sites indicate that similar proteases are involved in the maturation of IAPP and CGRP and that the IAPP amyloid polypeptide is identical to the normal proteolytic product of the IAPP precursor. A synthetic peptide corresponding to a carboxyteminal fragment of human IAPP is shown to spontaneously form amyloid-like fibrils in vitro. Antibodies against this peptide cross-react with IAPP from species that develop amyloid in pancreatic islets in conjunction with age-related diabetes mellitus (human, cat, racoon), but do not cross-react with IAPP from other tested species (mouse, rat, guinea pig, dog). Thus, a species-specific structural motif in the putative amyloidogenic region of IAPP is associated with both amyloid formation and the development of age-related diabetes mellitus. This provides a new molecular clue to the pathogenesis of this disease.

Describing the Process of Adopting Nutrition and Fitness Apps: Behavior Stage Model Approach

PubMed Central

Sproesser, Gudrun; Schupp, Harald T; Renner, Britta

2018-01-01

Background Although mobile technologies such as smartphone apps are promising means for motivating people to adopt a healthier lifestyle (mHealth apps), previous studies have shown low adoption and continued use rates. Developing the means to address this issue requires further understanding of mHealth app nonusers and adoption processes. This study utilized a stage model approach based on the Precaution Adoption Process Model (PAPM), which proposes that people pass through qualitatively different motivational stages when adopting a behavior. Objective To establish a better understanding of between-stage transitions during app adoption, this study aimed to investigate the adoption process of nutrition and fitness app usage, and the sociodemographic and behavioral characteristics and decision-making style preferences of people at different adoption stages. Methods Participants (N=1236) were recruited onsite within the cohort study Konstanz Life Study. Use of mobile devices and nutrition and fitness apps, 5 behavior adoption stages of using nutrition and fitness apps, preference for intuition and deliberation in eating decision-making (E-PID), healthy eating style, sociodemographic variables, and body mass index (BMI) were assessed. Results Analysis of the 5 behavior adoption stages showed that stage 1 (“unengaged”) was the most prevalent motivational stage for both nutrition and fitness app use, with half of the participants stating that they had never thought about using a nutrition app (52.41%, 533/1017), whereas less than one-third stated they had never thought about using a fitness app (29.25%, 301/1029). “Unengaged” nonusers (stage 1) showed a higher preference for an intuitive decision-making style when making eating decisions, whereas those who were already “acting” (stage 4) showed a greater preference for a deliberative decision-making style (F4,1012=21.83, P<.001). Furthermore, participants differed widely in their readiness to adopt nutrition and fitness apps, ranging from having “decided to” but not yet begun to act (stage 2; nutrition: 6.88%, 70/1017; fitness: 9.23%, 95/1029) to being “disengaged” following previous adoption (stage 5; nutrition: 13.77%, 140/1017; fitness: 15.06%, 155/1029). Conclusions Using a behavior stage model approach to describe the process of adopting nutrition and fitness apps revealed motivational stage differences between nonusers (being “unengaged,” having “decided not to act,” having “decided to act,” and being “disengaged”), which might contribute to a better understanding of the process of adopting mHealth apps and thus inform the future development of digital interventions. This study highlights that new user groups might be better reached by apps designed to address a more intuitive decision-making style. PMID:29535078

Describing the Process of Adopting Nutrition and Fitness Apps: Behavior Stage Model Approach.

PubMed

König, Laura M; Sproesser, Gudrun; Schupp, Harald T; Renner, Britta

2018-03-13

Although mobile technologies such as smartphone apps are promising means for motivating people to adopt a healthier lifestyle (mHealth apps), previous studies have shown low adoption and continued use rates. Developing the means to address this issue requires further understanding of mHealth app nonusers and adoption processes. This study utilized a stage model approach based on the Precaution Adoption Process Model (PAPM), which proposes that people pass through qualitatively different motivational stages when adopting a behavior. To establish a better understanding of between-stage transitions during app adoption, this study aimed to investigate the adoption process of nutrition and fitness app usage, and the sociodemographic and behavioral characteristics and decision-making style preferences of people at different adoption stages. Participants (N=1236) were recruited onsite within the cohort study Konstanz Life Study. Use of mobile devices and nutrition and fitness apps, 5 behavior adoption stages of using nutrition and fitness apps, preference for intuition and deliberation in eating decision-making (E-PID), healthy eating style, sociodemographic variables, and body mass index (BMI) were assessed. Analysis of the 5 behavior adoption stages showed that stage 1 ("unengaged") was the most prevalent motivational stage for both nutrition and fitness app use, with half of the participants stating that they had never thought about using a nutrition app (52.41%, 533/1017), whereas less than one-third stated they had never thought about using a fitness app (29.25%, 301/1029). "Unengaged" nonusers (stage 1) showed a higher preference for an intuitive decision-making style when making eating decisions, whereas those who were already "acting" (stage 4) showed a greater preference for a deliberative decision-making style (F 4,1012 =21.83, P<.001). Furthermore, participants differed widely in their readiness to adopt nutrition and fitness apps, ranging from having "decided to" but not yet begun to act (stage 2; nutrition: 6.88%, 70/1017; fitness: 9.23%, 95/1029) to being "disengaged" following previous adoption (stage 5; nutrition: 13.77%, 140/1017; fitness: 15.06%, 155/1029). Using a behavior stage model approach to describe the process of adopting nutrition and fitness apps revealed motivational stage differences between nonusers (being "unengaged," having "decided not to act," having "decided to act," and being "disengaged"), which might contribute to a better understanding of the process of adopting mHealth apps and thus inform the future development of digital interventions. This study highlights that new user groups might be better reached by apps designed to address a more intuitive decision-making style. ©Laura M König, Gudrun Sproesser, Harald T Schupp, Britta Renner. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 13.03.2018.

Anatomy of an amyloidogenic intermediate: conversion of beta-sheet to alpha-sheet structure in transthyretin at acidic pH.

PubMed

Armen, Roger S; Alonso, Darwin O V; Daggett, Valerie

2004-10-01

The homotetramer of transthyretin (TTR) dissociates into a monomeric amyloidogenic intermediate that self-assembles into amyloid fibrils at low pH. We have performed molecular dynamics simulations of monomeric TTR at neutral and low pH at physiological (310 K) and very elevated temperature (498 K). In the low-pH simulations at both temperatures, one of the two beta-sheets (strands CBEF) becomes disrupted, and alpha-sheet structure forms in the other sheet (strands DAGH). alpha-sheet is formed by alternating alphaL and alphaR residues, and it was first proposed by Pauling and Corey. Overall, the simulations are in agreement with the available experimental observations, including solid-state NMR results for a TTR-peptide amyloid. In addition, they provide a unique explanation for the results of hydrogen exchange experiments of the amyloidogenic intermediate-results that are difficult to explain with beta-structure. We propose that alpha-sheet may represent a key pathological conformation during amyloidogenesis. Copyright 2004 Elsevier Ltd.

Oxidative stress and mitochondria-mediated cell death mechanisms triggered by the familial Danish dementia ADan amyloid

PubMed Central

Todd, Krysti; Ghiso, Jorge; Rostagno, Agueda

2015-01-01

Familial Danish Dementia (FDD), an early-onset non-amyloid-β (Aβ) cerebral amyloidosis, is neuropathologically characterized by widespread cerebral amyloid angiopathy, parenchymal amyloid and preamyloid deposits, as well as neurofibrillary degeneration indistinguishable to that seen in Alzheimer’s disease (AD). The main amyloid subunit composing FDD lesions, a 34-amino acid de-novo generated peptide ADan, is the direct result of a genetic defect at the 3’-end of the BRI2 gene and the physiologic action of furin-like proteolytic processing at the C-terminal region of the ADan precursor protein. We aimed to study the impact of the FDD mutation, the additional formation of the pyroglutamate (pE) posttranslational modification as well as the relevance of C-terminal truncations –all major components of the heterogeneous FDD deposits–on the structural and neurotoxic properties of the molecule. Our data indicates that whereas the mutation generated a β-sheet-rich hydrophobic ADan subunit of high oligomerization/fibrillization propensity and the pE modification further enhanced these properties, C-terminal truncations had the opposite effect mostly abolishing these features. The potentiation of pro-amyloidogenic properties correlated with the initiation of neuronal cell death mechanisms involving oxidative stress, perturbation of mitochondrial membrane potential, release of mitochondrial cytochrome c, and downstream activation of caspase-mediated apoptotic pathways. The amyloid-induced toxicity was inhibited by targeting specific components of these detrimental cellular pathways, using reactive oxygen scavengers and monoclonal antibodies recognizing the pathological amyloid subunit. Taken together, the data indicate that the FDD mutation and the pE posttranslational modification are both primary elements driving intact ADan into an amyloidogenic/neurotoxic pathway while truncations at the C-terminus eliminate the pro-amyloidogenic characteristics of the molecule, likely reflecting effect of physiologic clearance mechanisms. PMID:26459115

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baden, Elizabeth M.; Owen, Barbara A.L.; Peterson, Francis C.

Amyloidoses are devastating and currently incurable diseases in which the process of amyloid formation causes fatal cellular and organ damage. The molecular mechanisms underlying amyloidoses are not well known. In this study, we address the structural basis of immunoglobulin light chain amyloidosis, which results from deposition of light chains produced by clonal plasma cells. We compare light chain amyloidosis protein AL-09 to its wild-type counterpart, the kl O18/O8 light chain germline. Crystallographic studies indicate that both proteins form dimers. However, AL-09 has an altered dimer interface that is rotated 90 degrees from the kl O18/O8 dimer interface. The three non-conservativemore » mutations in AL-09 are located within the dimer interface, consistent with their role in the decreased stability of this amyloidogenic protein. Moreover, AL-09 forms amyloid fibrils more quickly than kl O18/O8 in vitro. These results support the notion that the increased stability of the monomer and delayed fibril formation, together with a properly formed dimer, may be protective against amyloidogenesis. This could open a new direction into rational drug design for amyloidogenic proteins.« less

What amyloidoses may tell us about normal protein folding: The Alzheimer's disease story

NASA Astrophysics Data System (ADS)

Teplow, David B.

2002-03-01

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder characterized by severe neuronal injury and death. A prominent histopathologic feature of AD is disseminated parenchymal and vascular amyloid deposition. The fibrils in these deposits are composed of the amyloid β-protein (Aβ), a peptide of 4 kDa mass. In vitro and in vivo studies of Aβ fibril formation have shown that both oligomeric and polymeric Aβ assemblies have neurotoxic activity. Understanding how these assemblies form thus could be of direct therapeutic relevance. However, the aggregation and fibril-forming propensities of Aβ have complicated structure determination. Nevertheless, careful morphologic, spectroscopic, protein chemical, and physiologic analyses of the time-dependent changes in Aβ conformation, assembly state, and biological activity which occur during fibrillogenesis have significantly advanced our understanding of this clinically important process. Here, I will discuss recent findings about the pathway(s) of Aβ folding and assembly and about key structural features of Aβ which control the associated kinetics. Interestingly, the amyloidogenic folding pathway of Aβ is in some respects the mirror image of that through which natively folded amyloidogenic proteins proceed.

Building a Mobile HIV Prevention App for Men Who Have Sex With Men: An Iterative and Community-Driven Process

PubMed Central

McDougal, Sarah J; Sullivan, Patrick S; Stekler, Joanne D; Stephenson, Rob

2015-01-01

Background Gay, bisexual, and other men who have sex with men (MSM) account for a disproportionate burden of new HIV infections in the United States. Mobile technology presents an opportunity for innovative interventions for HIV prevention. Some HIV prevention apps currently exist; however, it is challenging to encourage users to download these apps and use them regularly. An iterative research process that centers on the community’s needs and preferences may increase the uptake, adherence, and ultimate effectiveness of mobile apps for HIV prevention. Objective The aim of this paper is to provide a case study to illustrate how an iterative community approach to a mobile HIV prevention app can lead to changes in app content to appropriately address the needs and the desires of the target community. Methods In this three-phase study, we conducted focus group discussions (FGDs) with MSM and HIV testing counselors in Atlanta, Seattle, and US rural regions to learn preferences for building a mobile HIV prevention app. We used data from these groups to build a beta version of the app and theater tested it in additional FGDs. A thematic data analysis examined how this approach addressed preferences and concerns expressed by the participants. Results There was an increased willingness to use the app during theater testing than during the first phase of FGDs. Many concerns that were identified in phase one (eg, disagreements about reminders for HIV testing, concerns about app privacy) were considered in building the beta version. Participants perceived these features as strengths during theater testing. However, some disagreements were still present, especially regarding the tone and language of the app. Conclusions These findings highlight the benefits of using an interactive and community-driven process to collect data on app preferences when building a mobile HIV prevention app. Through this process, we learned how to be inclusive of the larger MSM population without marginalizing some app users. Though some issues in phase one were able to be addressed, disagreements still occurred in theater testing. If the app is going to address a large and diverse risk group, we cannot include niche functionality that may offend some of the target population. PMID:27227136

A redox-active, compact molecule for cross-linking amyloidogenic peptides into nontoxic, off-pathway aggregates: In vitro and in vivo efficacy and molecular mechanisms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Derrick, Jeffrey S.; Kerr, Richard A.; Nam, Younwoo

Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. In this paper, we report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small molecule (DMPD, N,N-dimethyl- p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addition, for the first time, biochemical, biophysical, and molecular dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small molecule (DMPD) and amyloid-β (Aβ) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generatesmore » ligand–peptide adducts via primary amine-dependent intramolecular cross-linking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathology and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer’s disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble Aβ forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Altogether our in vitro and in vivo studies of DMPD toward Aβ with the first molecular-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compounds without the structural complexity as next-generation chemical tools for amyloid management.« less

A Redox-Active, Compact Molecule for Cross-Linking Amyloidogenic Peptides into Nontoxic, Off-Pathway Aggregates: In Vitro and In Vivo Efficacy and Molecular Mechanisms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Derrick, Jeffrey S.; Kerr, Richard A.; Nam, Younwoo

Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. Herein, we report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small molecule (DMPD, N,N-dimethyl-p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addition, for the first time, biochemical, biophysical, and molecular dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small molecule (DMPD) and amyloid-β (Aβ) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generates ligand–peptide adducts viamore » primary amine-dependent intramolecular cross-linking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathology and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer’s disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble Aβ forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Overall, our in vitro and in vivo studies of DMPD toward Aβ with the first molecular-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compounds without the structural complexity as next-generation chemical tools for amyloid management.« less

Screening of plants used in the European traditional medicine to treat memory disorders for acetylcholinesterase inhibitory activity and anti amyloidogenic activity.

PubMed

Lobbens, Eva S B; Vissing, Karina J; Jorgensen, Lene; van de Weert, Marco; Jäger, Anna K

2017-03-22

Plants used in the traditional medicine of Europe to treat memory dysfunction and/or to enhance memory were investigated for activity against the underlying mechanisms of Alzheimer's disease. To investigate 35 ethanolic extracts of plants, selected using an ethnopharmacological approach, for anti-amyloidogenic activity as well as an ability to inhibit the enzymatic activity of acetylcholinesterase. The anti-amyloidogenic activity of the extracts against amyloid beta was investigated by Thioflavin T fibrillation assays and the ability to inhibit the enzymatic activity of acetylcholinesterase was evaluated monitoring the hydrolysis of acetylthiocholine RESULTS: Under the experimental conditions investigated, extracts of two plants, Carum carvi and Olea sylvestris, inhibited amyloid beta fibrillation considerably, eight plant extracts inhibited amyloid beta fibrillation to some extent, 16 plant extracts had no effect on amyloid beta fibrillation and nine extracts accelerated fibrillation of amyloid beta. Furthermore, five plant extracts from Corydalis species inhibited the enzymatic activity of acetylcholinesterase considerably, one plant extract inhibited the enzymatic activity of acetylcholinesterase to some extent and 29 plant extract had no effect on the enzymatic activity of acetylcholinesterase. An optimal extract in this study would possess acetylcholinesterase inhibitory activity as well as anti-amyloidogenic activity in order to address multiple facets of Alzheimer's disease, until the molecular origin of the disease is unraveled. Unfortunately no such extract was found. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

A redox-active, compact molecule for cross-linking amyloidogenic peptides into nontoxic, off-pathway aggregates: In vitro and in vivo efficacy and molecular mechanisms

DOE PAGES

Derrick, Jeffrey S.; Kerr, Richard A.; Nam, Younwoo; ...

2015-11-17

Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. In this paper, we report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small molecule (DMPD, N,N-dimethyl- p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addition, for the first time, biochemical, biophysical, and molecular dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small molecule (DMPD) and amyloid-β (Aβ) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generatesmore » ligand–peptide adducts via primary amine-dependent intramolecular cross-linking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathology and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer’s disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble Aβ forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Altogether our in vitro and in vivo studies of DMPD toward Aβ with the first molecular-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compounds without the structural complexity as next-generation chemical tools for amyloid management.« less

Mobile Apps for Teaching Intubation: Scoping Review and Critical Analysis in eLearning

PubMed Central

2017-01-01

Background Airway management is a core skill in anesthesia ensuring adequate oxygenation and delivery of inhalational agents for the patient. Objective The goals of this study were to critically evaluate the quality of airway management apps and target revised Bloom's Taxonomy cognitive levels. Methods An electronic search using the keywords “airway” and “airway management” was conducted in May 2015 across the App Store, Google Play, BlackBerry World, and Windows Store. Apps were included in the study if their content was related to airway management. App content and characteristics were extracted into a standard form and evaluated. Results A total of 65 apps met the inclusion criteria, and 73% (47/65) of apps were developed by companies or industry. Anesthesiology trainees were the target audience in only 20% (13/65) of apps. Bag mask ventilation and laryngeal mask airways were covered in only 20% (13/65) of apps. Only 2 apps were supported in the scientific literature. For Bloom’s Taxonomy, 37% (24/65) of apps targeted knowledge, 5% (3/65) comprehension, 22% (14/65) application, 28% (18/65) analysis, 9% (6/65) evaluation, and 0% synthesis. Multivariate analysis identified cost of apps, size of apps (MB), and apps targeting trainees and paramedics to be associated with higher levels of cognitive processing of revised Bloom’s Taxonomy. Conclusions Apps developed for teaching intubation target lower levels of cognitive processing and are largely not validated by research. Cost, app size, and targeted user are associated with higher cognitive levels. Trainees and all users should be aware of the paucity of the published evidence behind the efficacy of some of these apps. PMID:28874335

Mobile Apps for Teaching Intubation: Scoping Review and Critical Analysis in eLearning.

PubMed

Matava, Clyde; Leo, Anne-Marie; Alam, Fahad

2017-09-05

Airway management is a core skill in anesthesia ensuring adequate oxygenation and delivery of inhalational agents for the patient. The goals of this study were to critically evaluate the quality of airway management apps and target revised Bloom's Taxonomy cognitive levels. An electronic search using the keywords "airway" and "airway management" was conducted in May 2015 across the App Store, Google Play, BlackBerry World, and Windows Store. Apps were included in the study if their content was related to airway management. App content and characteristics were extracted into a standard form and evaluated. A total of 65 apps met the inclusion criteria, and 73% (47/65) of apps were developed by companies or industry. Anesthesiology trainees were the target audience in only 20% (13/65) of apps. Bag mask ventilation and laryngeal mask airways were covered in only 20% (13/65) of apps. Only 2 apps were supported in the scientific literature. For Bloom's Taxonomy, 37% (24/65) of apps targeted knowledge, 5% (3/65) comprehension, 22% (14/65) application, 28% (18/65) analysis, 9% (6/65) evaluation, and 0% synthesis. Multivariate analysis identified cost of apps, size of apps (MB), and apps targeting trainees and paramedics to be associated with higher levels of cognitive processing of revised Bloom's Taxonomy. Apps developed for teaching intubation target lower levels of cognitive processing and are largely not validated by research. Cost, app size, and targeted user are associated with higher cognitive levels. Trainees and all users should be aware of the paucity of the published evidence behind the efficacy of some of these apps. ©Clyde Matava, Anne-Marie Leo, Fahad Alam. Originally published in JMIR Medical Education (http://mededu.jmir.org), 05.09.2017.

Epic Allies: Development of a Gaming App to Improve Antiretroviral Therapy Adherence Among Young HIV-Positive Men Who Have Sex With Men.

PubMed

LeGrand, Sara; Muessig, Kathryn Elizabeth; McNulty, Tobias; Soni, Karina; Knudtson, Kelly; Lemann, Alex; Nwoko, Nkechinyere; Hightow-Weidman, Lisa B

2016-05-13

In the United States, the human immunodeficiency virus (HIV) disproportionately affects young men who have sex with men (YMSM). For HIV-positive individuals, adherence to antiretroviral therapy (ART) is critical for achieving optimal health outcomes and reducing secondary transmission of HIV. However, YMSM often struggle with ART adherence. Novel mobile phone apps that incorporate game-based mechanics and social networking elements represent a promising intervention approach for improving ART adherence among YMSM. This study used a multiphase, iterative development process to create an ART adherence app for YMSM. The three-phase development process included: (1) theory-based concept development jointly by public health researchers and the technology team, (2) assessment of the target population's ART adherence needs and app preferences and development and testing of a clickable app prototype, and (3) development and usability testing of the final app prototype. The initial theory-based app concept developed in Phase One included medication reminders, daily ART adherence tracking and visualization, ART educational modules, limited virtual interactions with other app users, and gamification elements. In Phase Two, adherence needs, including those related to information, motivation, and behavioral skills, were identified. Participants expressed preferences for an ART adherence app that was informational, interactive, social, and customizable. Based on the findings from Phase Two, additional gaming features were added in Phase Three, including an interactive battle, superhero app theme, and app storyline. Other features were modified to increase interactivity and customization options and integrate the game theme. During usability testing of the final prototype, participants were able to understand and navigate the app successfully and rated the app favorably. An iterative development process was critical for the development of an ART adherence game app that was viewed as highly acceptable, relevant, and useful by YMSM.

Epic Allies: Development of a Gaming App to Improve Antiretroviral Therapy Adherence Among Young HIV-Positive Men Who Have Sex With Men

PubMed Central

Muessig, Kathryn Elizabeth; McNulty, Tobias; Soni, Karina; Knudtson, Kelly; Lemann, Alex; Nwoko, Nkechinyere; Hightow-Weidman, Lisa B

2016-01-01

Background In the United States, the human immunodeficiency virus (HIV) disproportionately affects young men who have sex with men (YMSM). For HIV-positive individuals, adherence to antiretroviral therapy (ART) is critical for achieving optimal health outcomes and reducing secondary transmission of HIV. However, YMSM often struggle with ART adherence. Novel mobile phone apps that incorporate game-based mechanics and social networking elements represent a promising intervention approach for improving ART adherence among YMSM. Objective This study used a multiphase, iterative development process to create an ART adherence app for YMSM. Methods The three-phase development process included: (1) theory-based concept development jointly by public health researchers and the technology team, (2) assessment of the target population’s ART adherence needs and app preferences and development and testing of a clickable app prototype, and (3) development and usability testing of the final app prototype. Results The initial theory-based app concept developed in Phase One included medication reminders, daily ART adherence tracking and visualization, ART educational modules, limited virtual interactions with other app users, and gamification elements. In Phase Two, adherence needs, including those related to information, motivation, and behavioral skills, were identified. Participants expressed preferences for an ART adherence app that was informational, interactive, social, and customizable. Based on the findings from Phase Two, additional gaming features were added in Phase Three, including an interactive battle, superhero app theme, and app storyline. Other features were modified to increase interactivity and customization options and integrate the game theme. During usability testing of the final prototype, participants were able to understand and navigate the app successfully and rated the app favorably. Conclusions An iterative development process was critical for the development of an ART adherence game app that was viewed as highly acceptable, relevant, and useful by YMSM. PMID:27178752

3,4-Methylenedioxymethamphetamine (MDMA), but not morphine, alters APP processing in the rat brain.

PubMed

Kálmán, János; Bjelik, Annamária; Hugyecz, Marietta; Tímár, Júlia; Gyarmati, Zsuzsanna; Zana, Marianna; Fürst, Zsuzsanna; Janka, Zoltán; Rakonczay, Zoltán; Horváth, Zoltán; Pákáski, Magdolna

2007-04-01

The abuse of drugs such as opioids and 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') can have detrimental effects on the cognitive functions, but the exact molecular mechanism whereby these drugs promote neurodegeneration remains to be elucidated. The major purpose of the present pilot study was to determine whether the chronic in-vivo administration of morphine (10 mg/kg) or MDMA (1 mg/kg) to rats can alter the expression and processing of amyloid precursor protein (APP), the central molecule in the proposed pathomechanism of Alzheimer's disease. MDMA treatment significantly decreased the production of APP in the cytosolic fraction of the brain cortex. A concomitant 25% increase was found both in the beta-secretase (BACE) and APP mRNA levels (108%). In contrast, in the applied single dosage chronic morphine treatment did not influence either the APP and BACE protein levels or the APP mRNA production. These results indicate that the chronic use of 'ecstasy', but not morphine, may be harmful via a novel mode of action, i.e. by altering the APP expression and processing in the brain.

Content Analysis of Diet-Related Mobile Apps: A Self-Regulation Perspective.

PubMed

Zahry, Nagwan R; Cheng, Ying; Peng, Wei

2016-10-01

Diet-related mobile apps hold promise in helping individuals self-regulate their eating behaviors. Nevertheless, little is known about the extent to which diet-related mobile apps incorporate the established behavior change theories and evidence-based practices that promote dietary self-regulation. Guided by the self-regulation aspect of Bandura's social cognitive theory and the Dietary Guidelines for Americans 2010 of the U.S. Department of Agriculture, this study conducts a content analysis of diet-related mobile apps for iPhone (N = 400). In terms of the adherence to the self-regulation aspect of the social cognitive theory, results show that although 72.5% of the apps incorporate at least one theoretical construct, few apps tap all three processes of self-regulation (i.e., self-observation/monitoring, judgment process, and self-reaction). Additionally, outcome expectation is manifested in a majority of the diet-related apps. In terms of the Dietary Guidelines for Americans 2010, while the diet-related apps equally emphasize setting goals for calorie intake or nutrient consumption, more apps feature nutrient tracking than calorie tracking. Implications and limitations are discussed.

APP heterozygosity averts memory deficit in knockin mice expressing the Danish dementia BRI2 mutant.

PubMed

Tamayev, Robert; Matsuda, Shuji; Giliberto, Luca; Arancio, Ottavio; D'Adamio, Luciano

2011-05-17

An autosomal dominant mutation in the BRI2/ITM2B gene causes familial Danish dementia (FDD). Analysis of FDD(KI) mice, a mouse model of FDD genetically congruous to the human disease since they carry one mutant and one wild-type Bri2/Itm2b allele, has shown that the Danish mutation causes loss of Bri2 protein, synaptic plasticity and memory impairments. BRI2 is a physiological interactor of Aβ-precursor protein (APP), a gene associated with Alzheimer disease, which inhibits processing of APP. Here, we show that APP/Bri2 complexes are reduced in synaptic membranes of FDD(KI) mice. Consequently, APP metabolites derived from processing of APP by β-, α- and γ-secretases are increased in Danish dementia mice. APP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for APP metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that APP and BRI2 functionally interact, and that the neurological effects of the Danish form of BRI2 only occur when sufficient levels of APP are supplied by two alleles. This evidence establishes a pathogenic sameness between familial Danish and Alzheimer's dementias.

APP heterozygosity averts memory deficit in knockin mice expressing the Danish dementia BRI2 mutant

PubMed Central

Tamayev, Robert; Matsuda, Shuji; Giliberto, Luca; Arancio, Ottavio; D'Adamio, Luciano

2011-01-01

An autosomal dominant mutation in the BRI2/ITM2B gene causes familial Danish dementia (FDD). Analysis of FDDKI mice, a mouse model of FDD genetically congruous to the human disease since they carry one mutant and one wild-type Bri2/Itm2b allele, has shown that the Danish mutation causes loss of Bri2 protein, synaptic plasticity and memory impairments. BRI2 is a physiological interactor of Aβ-precursor protein (APP), a gene associated with Alzheimer disease, which inhibits processing of APP. Here, we show that APP/Bri2 complexes are reduced in synaptic membranes of FDDKI mice. Consequently, APP metabolites derived from processing of APP by β-, α- and γ-secretases are increased in Danish dementia mice. APP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for APP metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that APP and BRI2 functionally interact, and that the neurological effects of the Danish form of BRI2 only occur when sufficient levels of APP are supplied by two alleles. This evidence establishes a pathogenic sameness between familial Danish and Alzheimer's dementias. PMID:21587206

Apps in therapy: occupational therapists' use and opinions.

PubMed

Seifert, Anna M; Stotz, Nicole; Metz, Alexia E

2017-11-01

To gather information on occupational therapy practitioners' use and opinions of apps, an online survey was distributed to occupational therapy practitioners licensed in the state of Ohio. The survey sought information regarding clinical populations and skill areas for which apps are used, potential barriers to use of apps and preferred apps/app features. OTs working in medical and education-based settings and with clients of all ages responded to the survey. Over half (53%) reported not using apps in therapy, with "not having access to the technology at work" being the leading reason endorsed. Of practitioners who did report using apps, the majority used them with ≤25% of their case load and primarily used tablets to do so. Clinicians indicated that they use apps for a wide variety of reasons, including to promote skill building and to support the therapeutic process. Preferred features included the ability to grade difficulty up/down, multiple uses and accurate feedback. Recommendations from peers were the most commonly reported way respondents found new apps. The results suggest that occupational therapy practitioners employ clinical reasoning when implementing apps in therapy. Possible ways to improve access to apps for therapists who would like to implement them are discussed. Implications for Rehabilitation Many occupational therapy practitioners are using apps with at least a portion of their caseloads. Therapists select apps based on peer recommendations, most commonly selecting those which promote skill building and support the therapeutic process. More therapists might make use of apps if potential barriers were reduced or eliminated, including availability of technology in the clinical practice setting, therapist training and education, therapist input into app development and an enhanced evidence base.

Car App's Persuasive Design Principles and Behavior Change

ERIC Educational Resources Information Center

Zhang, Chao; Wan, Lili; Min, Daihwan

2016-01-01

The emphasis of this study lies in behavior change after using car apps that assist users in using their vehicles and establishing a process for examining the interrelationship between car app's persuasive characteristics and behavior change. A categorizing method was developed and 697 car apps were investigated and classified into eight…

The Amyloid Precursor Protein is rapidly transported from the Golgi apparatus to the lysosome and where it is processed into beta-amyloid

PubMed Central

2014-01-01

Background Alzheimer’s disease (AD) is characterized by cerebral deposition of β-amyloid peptide (Aβ). Aβ is produced by sequential cleavage of the Amyloid Precursor Protein (APP) by β- and γ-secretases. Many studies have demonstrated that the internalization of APP from the cell surface can regulate Aβ production, although the exact organelle in which Aβ is produced remains contentious. A number of recent studies suggest that intracellular trafficking also plays a role in regulating Aβ production, but these pathways are relatively under-studied. The goal of this study was to elucidate the intracellular trafficking of APP, and to examine the site of intracellular APP processing. Results We have tagged APP on its C-terminal cytoplasmic tail with photoactivatable Green Fluorescent Protein (paGFP). By photoactivating APP-paGFP in the Golgi, using the Golgi marker Galactosyltranferase fused to Cyan Fluorescent Protein (GalT-CFP) as a target, we are able to follow a population of nascent APP molecules from the Golgi to downstream compartments identified with compartment markers tagged with red fluorescent protein (mRFP or mCherry); including rab5 (early endosomes) rab9 (late endosomes) and LAMP1 (lysosomes). Because γ-cleavage of APP releases the cytoplasmic tail of APP including the photoactivated GFP, resulting in loss of fluorescence, we are able to visualize the cleavage of APP in these compartments. Using APP-paGFP, we show that APP is rapidly trafficked from the Golgi apparatus to the lysosome; where it is rapidly cleared. Chloroquine and the highly selective γ-secretase inhibitor, L685, 458, cause the accumulation of APP in lysosomes implying that APP is being cleaved by secretases in the lysosome. The Swedish mutation dramatically increases the rate of lysosomal APP processing, which is also inhibited by chloroquine and L685, 458. By knocking down adaptor protein 3 (AP-3; a heterotetrameric protein complex required for trafficking many proteins to the lysosome) using siRNA, we are able to reduce this lysosomal transport. Blocking lysosomal transport of APP reduces Aβ production by more than a third. Conclusion These data suggests that AP-3 mediates rapid delivery of APP to lysosomes, and that the lysosome is a likely site of Aβ production. PMID:25085554

The Totality App — General Lessons and Future Eclipses

NASA Astrophysics Data System (ADS)

Bennett, Jeffrey

2018-06-01

With the excitement around the 2017 eclipse, I worked with an app development company to create the Totality app, which featured eclipse predictions from the code of Xavier Jubier. We have since updated the app for future eclipses, including a Spanish version given the upcoming eclipses in Chile/Argentina. I will briefly discuss the current app, the process through which we developed it, and relevant lessons learned along the way that may be useful to others interested in developing apps for astronomy education.

Finding Quality Geometry Apps: Not as Simple as a[superscript 2] + b[superscript 2] = c[superscript 2

ERIC Educational Resources Information Center

Larkin, Kevin

2016-01-01

Trying to find quality apps for use in mathematics classes can be time consuming and bewildering. This article outlines a process for evaluating apps and provides teachers with access to comprehensive qualitative evaluations of 53 geometrical apps based on pedagogical, mathematical and cognitive fidelities.

The Metalloprotease Meprin β Generates Amino Terminal-truncated Amyloid β Peptide Species*

PubMed Central

Bien, Jessica; Jefferson, Tamara; Čaušević, Mirsada; Jumpertz, Thorsten; Munter, Lisa; Multhaup, Gerd; Weggen, Sascha; Becker-Pauly, Christoph; Pietrzik, Claus U.

2012-01-01

The amyloid β (Aβ) peptide, which is abundantly found in the brains of patients suffering from Alzheimer disease, is central in the pathogenesis of this disease. Therefore, to understand the processing of the amyloid precursor protein (APP) is of critical importance. Recently, we demonstrated that the metalloprotease meprin β cleaves APP and liberates soluble N-terminal APP (N-APP) fragments. In this work, we present evidence that meprin β can also process APP in a manner reminiscent of β-secretase. We identified cleavage sites of meprin β in the amyloid β sequence of the wild type and Swedish mutant of APP at positions p1 and p2, thereby generating Aβ variants starting at the first or second amino acid residue. We observed even higher kinetic values for meprin β than BACE1 for both the wild type and the Swedish mutant APP form. This enzymatic activity of meprin β on APP and Aβ generation was also observed in the absence of BACE1/2 activity using a β-secretase inhibitor and BACE knock-out cells, indicating that meprin β acts independently of β-secretase. PMID:22879596

Design, synthesis of allosteric peptide activator for human SIRT1 and its biological evaluation in cellular model of Alzheimer's disease.

PubMed

Kumar, Rahul; Nigam, Lokesh; Singh, Amrendra Pratap; Singh, Kusum; Subbarao, Naidu; Dey, Sharmistha

2017-02-15

Sirtuin 1 (SIRT1) is one of the member of the mammalian proteins of the Sirtuin family of NAD + dependent deacetylases, has recently been shown to attenuate amyloidogenic processing of amyloid protein precursor (APP) in in-vitro cell culture studies and transgenic mouse models of Alzheimer's disease (AD). SIRT1 has been shown to have a protective role against (AD). It has been reported earlier that increasing SIRT1 activity can prevent AD in mice model. Tripeptide as an activator of SIRT1 were screened on the basis of structural information by molecular docking and synthesized by solid phase method. The enhancement of biochemical activity of pure recombinant SIRT1 as well as SIRT1 in serum of AD patients in presence of tripeptide was done by Fluorescent Activity Assay. The activity of SIRT1 by peptide was assessed in IMR-32 cell line by measuring acetylated p53 level. Further the protective effect of SIRT1 activator in cellular model of AD was analyzed by MTT assay. We find CWR tripeptide as a SIRT1 activator by molecular docking, enhanced the activity of SIRT1 protein by lowering the Michaelis constant, Km by allosteric mechanism. The activity of serum SIRT1 of AD was also increases by CWR. It also decreased the acetylation of p53 in IMR32 neuroblastoma cells and protected the cell death caused by Aβ amyloid fragments in cell line model of AD. Thus, it can be concluded that CWR may serve as platform to elucidate further small molecule activator as a therapeutic agent for AD targeting SIRT1. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Worsening of memory deficit induced by energy-dense diet in a rat model of early-Alzheimer's disease is associated to neurotoxic Aβ species and independent of neuroinflammation.

PubMed

Martino Adami, Pamela V; Galeano, Pablo; Wallinger, Marina L; Quijano, Celia; Rabossi, Alejandro; Pagano, Eleonora S; Olivar, Natividad; Reyes Toso, Carlos; Cardinali, Daniel; Brusco, Luis I; Do Carmo, Sonia; Radi, Rafael; Gevorkian, Goar; Castaño, Eduardo M; Cuello, A Claudio; Morelli, Laura

2017-03-01

Diet is a modifiable risk factor for Alzheimer's disease (AD), but the mechanisms linking alterations in peripheral metabolism and cognition remain unclear. Since it is especially difficult to study long-term effects of high-energy diet in individuals at risk for AD, we addressed this question by using the McGill-R-Thy1-APP transgenic rat model (Tg(+/-)) that mimics presymptomatic AD. Wild-type and Tg(+/-) rats were exposed during 6months to a standard diet or a Western diet (WD), high in saturated fat and sugar. Results from peripheral and hippocampal biochemical analysis and in situ respirometry showed that WD induced a metabolic syndrome and decreased presynaptic bioenergetic parameters without alterations in hippocampal insulin signaling or lipid composition. Cognitive tests, ELISA multiplex, Western blot, immunohistochemistry and RT-qPCR indicated that WD worsened cognition in Tg(+/-) rats, increased hippocampal levels of monomeric Aβ isoforms and oligomeric species, promoted deposits of N-Terminal pyroglutamate-Aβ (AβN3(pE)) in CA1 pyramidal neurons and interneurons, decreased transcript levels of genes involved in neuroprotective pathways such as Sirtuin-1 and increased nitrated proteins. Our results support the concept that in the presence of early Aβ pathology, diet-induced metabolic dysfunctions may contribute as a "second hit" to impair cognition. Noteworthy, such effect is not mediated by higher microglia activation or disruption of blood brain barrier. However, it may be attributed to increased amyloidogenic processing of amyloid precursor protein, generation of AβN3(pE) and dysregulation of pathways governed by Sirtuin-1. This evidence reinforces the implementation of prophylactic interventions in individuals at risk for AD. Copyright © 2016 Elsevier B.V. All rights reserved.

Inhibition of amyloidogenesis by non-steroidal anti-inflammatory drugs and their hybrid nitrates

PubMed Central

Schiefer, Isaac T.; Abdul-Hay, Samer; Wang, Huali; Vanni, Michael; Qin, Zhihui; Thatcher, Gregory R. J.

2011-01-01

Poor blood-brain barrier penetration of non-steroidal anti-inflammatory drugs (NSAIDs) has been blamed for the failure of the selective amyloid lowering agent (SALA) R-flurbiprofen in phase 3 clinical trials for Alzheimer’s disease (AD). NO-donor NSAIDs (NO-NSAIDs) provide an alternative, gastric-sparing approach to NSAID SALAs, which may improve bioavailability. NSAID analogs were studied for anti-inflammatory activity and for SALA activity in N2a neuronal cells transfected with human amyloid precursor protein (APP). Flurbiprofen (1) analogs were obtained with enhanced anti-inflammatory and anti-amyloidogenic properties compared to 1, however, esterification led to elevated Aβ1–42 levels. Hybrid nitrate prodrugs possessed superior anti-inflammatory activity and reduced toxicity relative to the parent NSAIDs, including clinical candidate, CHF5074. Although hybrid nitrates elevated Aβ1–42 at higher concentration, SALA activity was observed at low concentrations (≤ 1 µM): both Aβ1–42 and the ratio of Aβ1–42/Aβ1–40 were lowered. This biphasic SALA activity was attributed to the intact nitrate drug. For several compounds the selective modulation of amyloidogenesis was tested using an immunoprecipitation MALDI-TOF approach. These data support the development of NO-NSAIDs as an alternative approach towards a clinically useful SALA. PMID:21405086

Implementing Project SIED: Special Education Teachers' Perceptions of a Simplified Technology Decision-Making Process for App Identification and Evaluation

ERIC Educational Resources Information Center

Schmidt, Matthew M.; Lin, Meng-Fen Grace; Paek, Seungoh; MacSuga-Gage, Ashley; Gage, Nicholas A.

2017-01-01

The worldwide explosion in popularity of mobile devices has created a dramatic increase in mobile software (apps) that are quick and easy to find and install, cheap, disposable, and usually single purpose. Hence, teachers need an equally streamlined and simplified decision-making process to help them identify educational apps--an approach that…

Detection and Characterization of Aggregates, Prefibrillar Amyloidogenic Oligomers, and Protofibrils Using Fluorescence Spectroscopy

PubMed Central

Lindgren, Mikael; Sörgjerd, Karin; Hammarström, Per

2005-01-01

Transthyretin (TTR) is a protein linked to a number of different amyloid diseases including senile systemic amyloidosis and familial amyloidotic polyneuropathy. The transient nature of oligomeric intermediates of misfolded TTR that later mature into fibrillar aggregates makes them hard to study, and methods to study these species are sparse. In this work we explore a novel pathway for generation of prefibrillar aggregates of TTR, which provides important insight into TTR misfolding. Prefibrillar amyloidogenic oligomers and protofibrils of misfolded TTR were generated in vitro through induction of the molten globule type A-state from acid unfolded TTR through the addition of NaCl. The aggregation process produced fairly monodisperse oligomers (300–500 kD) within 2 h that matured after 20 h into larger spherical clusters (30–50 nm in diameter) and protofibrils as shown by transmission electron microscopy. Further maturation of the aggregates showed shrinkage of the spheres as the fibrils grew in length, suggesting a conformational change of the spheres into more rigid structures. The structural and physicochemical characteristics of the aggregates were investigated using fluorescence, circular dichroism, chemical cross-linking, and transmission electron microscopy. The fluorescent dyes 1-anilinonaphthalene-8-sulfonate (ANS), 4-4-bis-1-phenylamino-8-naphthalene sulfonate (Bis-ANS), 4-(dicyanovinyl)-julolidine (DCVJ), and thioflavin T (ThT) were employed in both static and kinetic assays to characterize these oligomeric and protofibrillar states using both steady-state and time-resolved fluorescence techniques. DCVJ, a molecular rotor, was employed for the first time for studies of an amyloidogenic process and is shown useful for detection of the early steps of the oligomerization process. DCVJ bound to the early prefibrillar oligomers (300–500 kD) with an apparent dissociation constant of 1.6 μM, which was slightly better than for ThT (6.8 μM). Time-resolved fluorescence anisotropy decay of ANS was shown to be a useful tool for giving further structural and kinetic information of the oligomeric aggregates. ThT dramatically increases its fluorescence quantum yield when bound to amyloid fibrils; however, the mechanism behind this property is unknown. Data from this work suggest that unbound ThT is also intrinsically quenched and functions similarly to a molecular rotor, which in combination with its environmental dependence provides a blue shift to the characteristic 482 nm wavelength when bound to amyloid fibrils. PMID:15764666

Distinct amyloid precursor protein processing machineries of the olfactory system.

PubMed

Kim, Jae Yeon; Rasheed, Ameer; Yoo, Seung-Jun; Kim, So Yeun; Cho, Bongki; Son, Gowoon; Yu, Seong-Woon; Chang, Keun-A; Suh, Yoo-Hun; Moon, Cheil

2018-01-01

Processing of amyloid precursor protein (APP) occurs through sequential cleavages first by β-secretase and then by the γ-secretase complex. However, abnormal processing of APP leads to excessive production of β-amyloid (Aβ) in the central nervous system (CNS), an event which is regarded as a primary cause of Alzheimer's disease (AD). In particular, gene mutations of the γ-secretase complex-which contains presenilin 1 or 2 as the catalytic core-could trigger marked Aβ accumulation. Olfactory dysfunction usually occurs before the onset of typical AD-related symptoms (eg, memory loss or muscle retardation), suggesting that the olfactory system may be one of the most vulnerable regions to AD. To date however, little is known about why the olfactory system is affected so early by AD prior to other regions. Thus, we examined the distribution of secretases and levels of APP processing in the olfactory system under either healthy or pathological conditions. Here, we show that the olfactory system has distinct APP processing machineries. In particular, we identified higher expressions levels and activity of γ-secretase in the olfactory epithelium (OE) than other regions of the brain. Moreover, APP c-terminal fragments (CTF) are markedly detected. During AD progression, we note increased expression of presenilin2 of γ-secretases in the OE, not in the OB, and show that neurotoxic Aβ*56 accumulates more quickly in the OE. Taken together, these results suggest that the olfactory system has distinct APP processing machineries under healthy and pathological conditions. This finding may provide a crucial understanding of the unique APP-processing mechanisms in the olfactory system, and further highlights the correlation between olfactory deficits and AD symptoms. Copyright © 2017 Elsevier Inc. All rights reserved.

Mitosis-specific phosphorylation of amyloid precursor protein at Threonine 668 leads to its altered processing and association with centrosomes

PubMed Central

2011-01-01

Background Atypical expression of cell cycle regulatory proteins has been implicated in Alzheimer's disease (AD), but the molecular mechanisms by which they induce neurodegeneration are not well understood. We examined transgenic mice expressing human amyloid precursor protein (APP) and presenilin 1 (PS1) for changes in cell cycle regulatory proteins to determine whether there is a correlation between cell cycle activation and pathology development in AD. Results Our studies in the AD transgenic mice show significantly higher levels of cyclin E, cyclin D1, E2F1, and P-cdc2 in the cells in the vicinity of the plaques where maximum levels of Threonine 668 (Thr668)-phosphorylated APP accumulation was observed. This suggests that the cell cycle regulatory proteins might be influencing plaque pathology by affecting APP phosphorylation. Using neuroglioma cells overexpressing APP we demonstrate that phosphorylation of APP at Thr668 is mitosis-specific. Cells undergoing mitosis show altered cellular distribution and localization of P-APP at the centrosomes. Also, Thr668 phosphorylation in mitosis correlates with increased processing of APP to generate Aβ and the C-terminal fragment of APP, which is prevented by pharmacological inhibitors of the G1/S transition. Conclusions The data presented here suggests that cell cycle-dependent phosphorylation of APP may affect its normal cellular function. For example, association of P-APP with the centrosome may affect spindle assembly and cell cycle progression, further contributing to the development of pathology in AD. The experiments with G1/S inhibitors suggest that cell cycle inhibition may impede the development of Alzheimer's pathology by suppressing modification of βAPP, and thus may represent a novel approach to AD treatment. Finally, the cell cycle regulated phosphorylation and processing of APP into Aβ and the C-terminal fragment suggest that these proteins may have a normal function during mitosis. PMID:22112898

Trehalose and Magnesium Chloride Exert a Common Anti-amyloidogenic Effect Towards Hen Egg White Lysozyme.

PubMed

Chatterjee, Rupsa; Kolli, Vidyalatha; Sarkar, Nandini

2017-04-01

Many degenerative disorder such as Parkinsons, Alzheimers, Huntingtons disease, etc are caused due to the deposition of amyloid fibrils, formed due to the ordered aggregation of misfolded/unfolded proteins. Misfolded or unfolded proteins aggregate mostly through hydrophobic interactions which are unexposed in native state, but become exposed upon unfolding. To counteract amyloid related diseases, inhibition of the protein self assembly into fibril is a potential therapeutic strategy. The study aims at investigating the effect of selected compounds, namely trehalose and magnesium chloride hexahydrate towards inhibition and disaggregation of amyloid fibrils using Hen Egg White Lysozyme as a model. We further attempted to understand the mechanism of action with the help of various biophysical, microscopic as well as computational studies. A common mechanism of action was identified where the selected compounds exert their anti-amyloidogenic effects by altering HEWL conformations characterized by reduction in the beta sheet content and decrease in exposed hydrophobic surfaces. The altered conformation seems to have lesser amyloidogenic propensity leading to inhibition as well as disaggregation of amyloids.

Cryptic Amyloidogenic Elements in the 3′ UTRs of Neurofilament Genes Trigger Axonal Neuropathy

PubMed Central

Rebelo, Adriana P.; Abrams, Alexander J.; Cottenie, Ellen; Horga, Alejandro; Gonzalez, Michael; Bis, Dana M.; Sanchez-Mejias, Avencia; Pinto, Milena; Buglo, Elena; Markel, Kasey; Prince, Jeffrey; Laura, Matilde; Houlden, Henry; Blake, Julian; Woodward, Cathy; Sweeney, Mary G.; Holton, Janice L.; Hanna, Michael; Dallman, Julia E.; Auer-Grumbach, Michaela; Reilly, Mary M.; Zuchner, Stephan

2016-01-01

Abnormal protein aggregation is observed in an expanding number of neurodegenerative diseases. Here, we describe a mechanism for intracellular toxic protein aggregation induced by an unusual mutation event in families affected by axonal neuropathy. These families carry distinct frameshift variants in NEFH (neurofilament heavy), leading to a loss of the terminating codon and translation of the 3′ UTR into an extra 40 amino acids. In silico aggregation prediction suggested the terminal 20 residues of the altered NEFH to be amyloidogenic, which we confirmed experimentally by serial deletion analysis. The presence of this amyloidogenic motif fused to NEFH caused prominent and toxic protein aggregates in transfected cells and disrupted motor neurons in zebrafish. We identified a similar aggregation-inducing mechanism in NEFL (neurofilament light) and FUS (fused in sarcoma), in which mutations are known to cause aggregation in Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis, respectively. In summary, we present a protein-aggregation-triggering mechanism that should be taken into consideration during the evaluation of stop-loss variants. PMID:27040688

Digital health technology and trauma: development of an app to standardize care.

PubMed

Hsu, Jeremy M

2015-04-01

Standardized practice results in less variation, therefore reducing errors and improving outcome. Optimal trauma care is achieved through standardization, as is evidenced by the widespread adoption of the Advanced Trauma Life Support approach. The challenge for an individual institution is how does one educate and promulgate these standardized processes widely and efficiently? In today's world, digital health technology must be considered in the process. The aim of this study was to describe the process of developing an app, which includes standardized trauma algorithms. The objective of the app was to allow easy, real-time access to trauma algorithms, and therefore reduce omissions/errors. A set of trauma algorithms, relevant to the local setting, was derived from the best available evidence. After obtaining grant funding, a collaborative endeavour was undertaken with an external specialist app developing company. The process required 6 months to translate the existing trauma algorithms into an app. The app contains 32 separate trauma algorithms, formatted as a single-page flow diagram. It utilizes specific smartphone features such as 'pinch to zoom', jump-words and pop-ups to allow rapid access to the desired information. Improvements in trauma care outcomes result from reducing variation. By incorporating digital health technology, a trauma app has been developed, allowing easy and intuitive access to evidenced-based algorithms. © 2015 Royal Australasian College of Surgeons.

Using redescription mining to relate clinical and biological characteristics of cognitively impaired and Alzheimer's disease patients.

PubMed

Mihelčić, Matej; Šimić, Goran; Babić Leko, Mirjana; Lavrač, Nada; Džeroski, Sašo; Šmuc, Tomislav

2017-01-01

Based on a set of subjects and a collection of attributes obtained from the Alzheimer's Disease Neuroimaging Initiative database, we used redescription mining to find interpretable rules revealing associations between those determinants that provide insights about the Alzheimer's disease (AD). We extended the CLUS-RM redescription mining algorithm to a constraint-based redescription mining (CBRM) setting, which enables several modes of targeted exploration of specific, user-constrained associations. Redescription mining enabled finding specific constructs of clinical and biological attributes that describe many groups of subjects of different size, homogeneity and levels of cognitive impairment. We confirmed some previously known findings. However, in some instances, as with the attributes: testosterone, ciliary neurotrophic factor, brain natriuretic peptide, Fas ligand, the imaging attribute Spatial Pattern of Abnormalities for Recognition of Early AD, as well as the levels of leptin and angiopoietin-2 in plasma, we corroborated previously debatable findings or provided additional information about these variables and their association with AD pathogenesis. Moreover, applying redescription mining on ADNI data resulted with the discovery of one largely unknown attribute: the Pregnancy-Associated Protein-A (PAPP-A), which we found highly associated with cognitive impairment in AD. Statistically significant correlations (p ≤ 0.01) were found between PAPP-A and clinical tests: Alzheimer's Disease Assessment Scale, Clinical Dementia Rating Sum of Boxes, Mini Mental State Examination, etc. The high importance of this finding lies in the fact that PAPP-A is a metalloproteinase, known to cleave insulin-like growth factor binding proteins. Since it also shares similar substrates with A Disintegrin and the Metalloproteinase family of enzymes that act as α-secretase to physiologically cleave amyloid precursor protein (APP) in the non-amyloidogenic pathway, it could be directly involved in the metabolism of APP very early during the disease course. Therefore, further studies should investigate the role of PAPP-A in the development of AD more thoroughly.

First demonstration of cerebrospinal fluid and plasma A beta lowering with oral administration of a beta-site amyloid precursor protein-cleaving enzyme 1 inhibitor in nonhuman primates.

PubMed

Sankaranarayanan, Sethu; Holahan, Marie A; Colussi, Dennis; Crouthamel, Ming-Chih; Devanarayan, Viswanath; Ellis, Joan; Espeseth, Amy; Gates, Adam T; Graham, Samuel L; Gregro, Allison R; Hazuda, Daria; Hochman, Jerome H; Holloway, Katharine; Jin, Lixia; Kahana, Jason; Lai, Ming-tain; Lineberger, Janet; McGaughey, Georgia; Moore, Keith P; Nantermet, Philippe; Pietrak, Beth; Price, Eric A; Rajapakse, Hemaka; Stauffer, Shaun; Steinbeiser, Melissa A; Seabrook, Guy; Selnick, Harold G; Shi, Xiao-Ping; Stanton, Matthew G; Swestock, John; Tugusheva, Katherine; Tyler, Keala X; Vacca, Joseph P; Wong, Jacky; Wu, Guoxin; Xu, Min; Cook, Jacquelynn J; Simon, Adam J

2009-01-01

beta-Site amyloid precursor protein (APP)-cleaving enzyme (BACE) 1 cleavage of amyloid precursor protein is an essential step in the generation of the potentially neurotoxic and amyloidogenic A beta 42 peptides in Alzheimer's disease. Although previous mouse studies have shown brain A beta lowering after BACE1 inhibition, extension of such studies to nonhuman primates or man was precluded by poor potency, brain penetration, and pharmacokinetics of available inhibitors. In this study, a novel tertiary carbinamine BACE1 inhibitor, tertiary carbinamine (TC)-1, was assessed in a unique cisterna magna ported rhesus monkey model, where the temporal dynamics of A beta in cerebrospinal fluid (CSF) and plasma could be evaluated. TC-1, a potent inhibitor (IC(50) approximately 0.4 nM), has excellent passive membrane permeability, low susceptibility to P-glycoprotein transport, and lowered brain A beta levels in a mouse model. Intravenous infusion of TC-1 led to a significant but transient lowering of CSF and plasma A beta levels in conscious rhesus monkeys because it underwent CYP3A4-mediated metabolism. Oral codosing of TC-1 with ritonavir, a potent CYP3A4 inhibitor, twice daily over 3.5 days in rhesus monkeys led to sustained plasma TC-1 exposure and a significant and sustained reduction in CSF sAPP beta, A beta 40, A beta 42, and plasma A beta 40 levels. CSF A beta 42 lowering showed an EC(50) of approximately 20 nM with respect to the CSF [TC-1] levels, demonstrating excellent concordance with its potency in a cell-based assay. These results demonstrate the first in vivo proof of concept of CSF A beta lowering after oral administration of a BACE1 inhibitor in a nonhuman primate.

Using redescription mining to relate clinical and biological characteristics of cognitively impaired and Alzheimer’s disease patients

PubMed Central

Mihelčić, Matej; Šimić, Goran; Babić Leko, Mirjana; Lavrač, Nada; Džeroski, Sašo; Šmuc, Tomislav

2017-01-01

Based on a set of subjects and a collection of attributes obtained from the Alzheimer’s Disease Neuroimaging Initiative database, we used redescription mining to find interpretable rules revealing associations between those determinants that provide insights about the Alzheimer’s disease (AD). We extended the CLUS-RM redescription mining algorithm to a constraint-based redescription mining (CBRM) setting, which enables several modes of targeted exploration of specific, user-constrained associations. Redescription mining enabled finding specific constructs of clinical and biological attributes that describe many groups of subjects of different size, homogeneity and levels of cognitive impairment. We confirmed some previously known findings. However, in some instances, as with the attributes: testosterone, ciliary neurotrophic factor, brain natriuretic peptide, Fas ligand, the imaging attribute Spatial Pattern of Abnormalities for Recognition of Early AD, as well as the levels of leptin and angiopoietin-2 in plasma, we corroborated previously debatable findings or provided additional information about these variables and their association with AD pathogenesis. Moreover, applying redescription mining on ADNI data resulted with the discovery of one largely unknown attribute: the Pregnancy-Associated Protein-A (PAPP-A), which we found highly associated with cognitive impairment in AD. Statistically significant correlations (p ≤ 0.01) were found between PAPP-A and clinical tests: Alzheimer’s Disease Assessment Scale, Clinical Dementia Rating Sum of Boxes, Mini Mental State Examination, etc. The high importance of this finding lies in the fact that PAPP-A is a metalloproteinase, known to cleave insulin-like growth factor binding proteins. Since it also shares similar substrates with A Disintegrin and the Metalloproteinase family of enzymes that act as α-secretase to physiologically cleave amyloid precursor protein (APP) in the non-amyloidogenic pathway, it could be directly involved in the metabolism of APP very early during the disease course. Therefore, further studies should investigate the role of PAPP-A in the development of AD more thoroughly. PMID:29088293

Notch signaling proteins HES-1 and Hey-1 bind to insulin degrading enzyme (IDE) proximal promoter and repress its transcription and activity: Implications for cellular Aβ metabolism

PubMed Central

Leal, María C.; Surace, Ezequiel I.; Holgado, María P.; Ferrari, Carina C.; Tarelli, Rodolfo; Pitossi, Fernando; Wisniewski, Thomas; Castaño, Eduardo M.; Morelli, Laura

2012-01-01

Cerebral amyloid β (Aβ) accumulation is pathogenically associated with sporadic Alzheimer’s disease (SAD). BACE-1 is involved in Aβ generation while insulin-degrading enzyme (IDE) partakes in Aβ proteolytic clearance. Vulnerable regions in AD brains show increased BACE-1 protein levels and enzymatic activity while the opposite occurs with IDE. Another common feature in SAD brains is Notch1 overexpression. Here we demonstrate an increase in mRNA levels of Hey-1, a Notch target gene, and a decrease of IDE transcripts in the hippocampus of SAD brains as compared to controls. Transient transfection of Notch intracellular domain (NICD) in N2aSW cells, mouse neuroblastoma cells (N2a) stably expressing human amyloid precursor protein (APP) Swedish mutation, reduce IDE mRNA levels, promoting extracellular Aβ accumulation. Also, NICD, HES-1 and Hey-1 overexpression result in decreased IDE proximal promoter activity. This effect was mediated by 2 functional sites located at −379/−372 and −310 −303 from the first translation start site in the −575/−19 (556 bp) fragment of IDE proximal promoter. By site-directed mutagenesis of the IDE promoter region we reverted the inhibitory effect mediated by NICD transfection suggesting that these sites are indeed responsible for the Notch-mediated inhibition of the IDE gene expression. Intracranial injection of the Notch ligand JAG-1 in Tg2576 mice, expressing the Swedish mutation in human APP, induced overexpression of HES-1 and Hey-1 and reduction of IDE mRNA levels, respectively. Our results support our theory that a Notch-dependent IDE transcriptional modulation may impact on Aβ metabolism providing a functional link between Notch signaling and the amyloidogenic pathway in SAD. PMID:22036964

How the formation of amyloid plaques and neurofibrillary tangles may be related: a mathematical modelling study

NASA Astrophysics Data System (ADS)

Kuznetsov, I. A.; Kuznetsov, A. V.

2018-02-01

We develop a mathematical model that enables us to investigate possible mechanisms by which two primary markers of Alzheimer's disease (AD), extracellular amyloid plaques and intracellular tangles, may be related. Our model investigates the possibility that the decay of anterograde axonal transport of amyloid precursor protein (APP), caused by toxic tau aggregates, leads to decreased APP transport towards the synapse and APP accumulation in the soma. The developed model thus couples three processes: (i) slow axonal transport of tau, (ii) tau misfolding and agglomeration, which we simulated by using the Finke-Watzky model and (iii) fast axonal transport of APP. Because the timescale for tau agglomeration is much larger than that for tau transport, we suggest using the quasi-steady-state approximation for formulating and solving the governing equations for these three processes. Our results suggest that misfolded tau most likely accumulates in the beginning of the axon. The analysis of APP transport suggests that APP will also likely accumulate in the beginning of the axon, causing an increased APP concentration in this region, which could be interpreted as a `traffic jam'. The APP flux towards the synapse is significantly reduced by tau misfolding, but not due to the APP traffic jam, which can be viewed as a symptom, but rather due to the reduced affinity of kinesin-1 motors to APP-transporting vesicles.

High-speed atomic force microscopy reveals structural dynamics of amyloid β1–42 aggregates

PubMed Central

Watanabe-Nakayama, Takahiro; Ono, Kenjiro; Itami, Masahiro; Takahashi, Ryoichi; Teplow, David B.; Yamada, Masahito

2016-01-01

Aggregation of amyloidogenic proteins into insoluble amyloid fibrils is implicated in various neurodegenerative diseases. This process involves protein assembly into oligomeric intermediates and fibrils with highly polymorphic molecular structures. These structural differences may be responsible for different disease presentations. For this reason, elucidation of the structural features and assembly kinetics of amyloidogenic proteins has been an area of intense study. We report here the results of high-speed atomic force microscopy (HS-AFM) studies of fibril formation and elongation by the 42-residue form of the amyloid β-protein (Aβ1–42), a key pathogenetic agent of Alzheimer's disease. Our data demonstrate two different growth modes of Aβ1–42, one producing straight fibrils and the other producing spiral fibrils. Each mode depends on initial fibril nucleus structure, but switching from one growth mode to another was occasionally observed, suggesting that fibril end structure fluctuated between the two growth modes. This switching phenomenon was affected by buffer salt composition. Our findings indicate that polymorphism in fibril structure can occur after fibril nucleation and is affected by relatively modest changes in environmental conditions. PMID:27162352

Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster

PubMed Central

Kumita, Janet R.; Helmfors, Linda; Williams, Jocy; Luheshi, Leila M.; Menzer, Linda; Dumoulin, Mireille; Lomas, David A.; Crowther, Damian C.; Dobson, Christopher M.; Brorsson, Ann-Christin

2012-01-01

We have created a Drosophila model of lysozyme amyloidosis to investigate the in vivo behavior of disease-associated variants. To achieve this objective, wild-type (WT) protein and the amyloidogenic variants F57I and D67H were expressed in Drosophila melanogaster using the UAS-gal4 system and both the ubiquitous and retinal expression drivers Act5C-gal4 and gmr-gal4. The nontransgenic w1118 Drosophila line was used as a control throughout. We utilized ELISA experiments to probe lysozyme protein levels, scanning electron microscopy for eye phenotype classification, and immunohistochemistry to detect the unfolded protein response (UPR) activation. We observed that expressing the destabilized F57I and D67H lysozymes triggers UPR activation, resulting in degradation of these variants, whereas the WT lysozyme is secreted into the fly hemolymph. Indeed, the level of WT was up to 17 times more abundant than the variant proteins. In addition, the F57I variant gave rise to a significant disruption of the eye development, and this correlated to pronounced UPR activation. These results support the concept that the onset of familial amyloid disease is linked to an inability of the UPR to degrade completely the amyloidogenic lysozymes prior to secretion, resulting in secretion of these destabilized variants, thereby leading to deposition and associated organ damage.—Kumita, J. R., Helmfors, L., Williams, J., Luheshi, L. M., Menzer, L., Dumoulin, M., Lomas, D. A., Crowther, D. C., Dobson, C. M., Brorsson, A.-C. Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster. PMID:21965601

Switch-peptides: design and characterization of controllable super-amyloid-forming host-guest peptides as tools for identifying anti-amyloid agents.

PubMed

Camus, Marie-Stéphanie; Dos Santos, Sonia; Chandravarkar, Arunan; Mandal, Bhubaneswar; Schmid, Adrian W; Tuchscherer, Gabriele; Mutter, Manfred; Lashuel, Hilal A

2008-09-01

Several amyloid-forming proteins are characterized by the presence of hydrophobic and highly amyloidogenic core sequences that play critical roles in the initiation and progression of amyloid fibril formation. Therefore targeting these sequences represents a viable strategy for identifying candidate molecules that could interfere with amyloid formation and toxicity of the parent proteins. However, the highly amyloidogenic and insoluble nature of these sequences has hampered efforts to develop high-throughput fibrillization assays. Here we describe the design and characterization of host-guest switch peptides that can be used for in vitro mechanistic and screening studies that are aimed at discovering aggregation inhibitors that target highly amyloidogenic sequences. These model systems are based on a host-guest system where the amyloidogenic sequence (guest peptide) is flanked by two beta-sheet-promoting (Leu-Ser)(n) oligomers as host sequences. Two host-guest peptides were prepared by using the hydrophobic core of Abeta comprising residues 14-24 (HQKLVFFAEDV) as the guest peptide with switch elements inserted within (peptide 1) or at the N and C termini of the guest peptide (peptide 2). Both model peptides can be triggered to undergo rapid self-assembly and amyloid formation in a highly controllable manner and their fibrillization kinetics is tuneable by manipulating solution conditions (for example, peptide concentration and pH). The fibrillization of both peptides reproduces many features of the full-length Abeta peptides and can be inhibited by known inhibitors of Abeta fibril formation. Our results suggest that this approach can be extended to other amyloid proteins and should facilitate the discovery of small-molecule aggregation inhibitors and the development of more efficacious anti-amyloid agents to treat and/or reverse the pathogenesis of neurodegenerative and systemic amyloid diseases.

The development of Drink Less: an alcohol reduction smartphone app for excessive drinkers.

PubMed

Garnett, Claire; Crane, David; West, Robert; Brown, Jamie; Michie, Susan

2018-05-04

Excessive alcohol consumption poses a serious problem for public health. Digital behavior change interventions have the potential to help users reduce their drinking. In accordance with Open Science principles, this paper describes the development of a smartphone app to help individuals who drink excessively to reduce their alcohol consumption. Following the UK Medical Research Council's guidance and the Multiphase Optimization Strategy, development consisted of two phases: (i) selection of intervention components and (ii) design and development work to implement the chosen components into modules to be evaluated further for inclusion in the app. Phase 1 involved a scoping literature review, expert consensus study and content analysis of existing alcohol apps. Findings were integrated within a broad model of behavior change (Capability, Opportunity, Motivation-Behavior). Phase 2 involved a highly iterative process and used the "Person-Based" approach to promote engagement. From Phase 1, five intervention components were selected: (i) Normative Feedback, (ii) Cognitive Bias Re-training, (iii) Self-monitoring and Feedback, (iv) Action Planning, and (v) Identity Change. Phase 2 indicated that each of these components presented different challenges for implementation as app modules; all required multiple iterations and design changes to arrive at versions that would be suitable for inclusion in a subsequent evaluation study. The development of the Drink Less app involved a thorough process of component identification with a scoping literature review, expert consensus, and review of other apps. Translation of the components into app modules required a highly iterative process involving user testing and design modification.

Modulation of beta-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family.

PubMed

Cam, Judy A; Bu, Guojun

2006-08-18

Amyloid-beta peptide (Abeta) accumulation in the brain is an early, toxic event in the pathogenesis of Alzheimer's disease (AD). Abeta is produced by proteolytic processing of a transmembrane protein, beta-amyloid precursor protein (APP), by beta- and gamma-secretases. Mounting evidence has demonstrated that alterations in APP cellular trafficking and localization directly impact its processing to Abeta. Recent studies have shown that members of the low-density lipoprotein receptor family, including LRP, LRP1B, SorLA/LR11, and apolipoprotein E (apoE) receptor 2, interact with APP and regulate its endocytic trafficking. Another common feature of these receptors is their ability to bind apoE, which exists in three isoforms in humans and the presence of the epsilon4 allele represents a genetic risk factor for AD. In this review, we summarize the current understanding of the function of these apoE receptors with a focus on their role in APP trafficking and processing. Knowledge of the interactions between these distinct low-density lipoprotein receptor family members and APP may ultimately influence future therapies for AD.

The Long Way From Government Open Data to Mobile Health Apps: Overcoming Institutional Barriers in the US Federal Government

PubMed Central

2014-01-01

Background Government agencies in the United States are creating mobile health (mHealth) apps as part of recent policy changes initiated by the White House’s Digital Government Strategy. Objective The objective of the study was to understand the institutional and managerial barriers for the implementation of mHealth, as well as the resulting adoption pathways of mHealth. Methods This article is based on insights derived from qualitative interview data with 35 public managers in charge of promoting the reuse of open data through Challenge.gov, the platform created to run prizes, challenges, and the vetting and implementation of the winning and vendor-created apps. Results The process of designing apps follows three different pathways: (1) entrepreneurs start to see opportunities for mobile apps, and develop either in-house or contract out to already vetted Web design vendors; (2) a top-down policy mandates agencies to adopt at least two customer-facing mobile apps; and (3) the federal government uses a policy instrument called “Prizes and Challenges”, encouraging civic hackers to design health-related mobile apps using open government data from HealthData.gov, in combination with citizen needs. All pathways of the development process incur a set of major obstacles that have to be actively managed before agencies can promote mobile apps on their websites and app stores. Conclusions Beyond the cultural paradigm shift to design interactive apps and to open health-related data to the public, the managerial challenges include accessibility, interoperability, security, privacy, and legal concerns using interactive apps tracking citizen. PMID:25537314

The Long Way From Government Open Data to Mobile Health Apps: Overcoming Institutional Barriers in the US Federal Government.

PubMed

Mergel, Ines

2014-12-23

Government agencies in the United States are creating mobile health (mHealth) apps as part of recent policy changes initiated by the White House's Digital Government Strategy. The objective of the study was to understand the institutional and managerial barriers for the implementation of mHealth, as well as the resulting adoption pathways of mHealth. This article is based on insights derived from qualitative interview data with 35 public managers in charge of promoting the reuse of open data through Challenge.gov, the platform created to run prizes, challenges, and the vetting and implementation of the winning and vendor-created apps. The process of designing apps follows three different pathways: (1) entrepreneurs start to see opportunities for mobile apps, and develop either in-house or contract out to already vetted Web design vendors; (2) a top-down policy mandates agencies to adopt at least two customer-facing mobile apps; and (3) the federal government uses a policy instrument called "Prizes and Challenges", encouraging civic hackers to design health-related mobile apps using open government data from HealthData.gov, in combination with citizen needs. All pathways of the development process incur a set of major obstacles that have to be actively managed before agencies can promote mobile apps on their websites and app stores. Beyond the cultural paradigm shift to design interactive apps and to open health-related data to the public, the managerial challenges include accessibility, interoperability, security, privacy, and legal concerns using interactive apps tracking citizen.

Privacy as Part of the App Decision-Making Process

DTIC Science & Technology

2013-02-06

concerns they may not actively consider privacy while downloading apps from smartphone application marketplaces. Currently Android users have only the... Android permissions display which appears after they have selected an app to download to help them understand how applications access their information...marketplaces. Currently, Android users have only the Android permissions display, which appears after they have selected an app to download, to help

The Fate of Nascent APP in Hippocampal Neurons: A Live Cell Imaging Study.

PubMed

DelBove, Claire E; Deng, Xian-Zhen; Zhang, Qi

2018-06-21

Amyloid precursor protein (APP) is closely associated with Alzheimer's disease (AD) because its proteolytic products form amyloid plaques and its mutations are linked to familial AD patients. As a membrane protein, APP is involved in neuronal development and plasticity. However, it remains unclear how nascent APP is distributed and transported to designated membrane compartments to execute its diverse functions. Here, we employed a dual-tagged APP fusion protein in combination with a synaptic vesicle marker to study the surface trafficking and cleavage of APP in hippocampal neurons immediately after its synthesis. Using long-term time-lapse imaging, we found that a considerable amount of nascent APP was directly transported to the somatodendritic surface, from which it propagates to distal neurites. Some APP in the plasma membrane was endocytosed and some was cleaved by α-secretase. Hence, we conclude that surface transportation of APP is a major step preceding its proteolytic processing and neuritic distribution.

BeWell24: development and process evaluation of a smartphone "app" to improve sleep, sedentary, and active behaviors in US Veterans with increased metabolic risk.

PubMed

Buman, Matthew P; Epstein, Dana R; Gutierrez, Monica; Herb, Christine; Hollingshead, Kevin; Huberty, Jennifer L; Hekler, Eric B; Vega-López, Sonia; Ohri-Vachaspati, Punam; Hekler, Andrea C; Baldwin, Carol M

2016-09-01

Lifestyle behaviors across the 24-h spectrum (i.e., sleep, sedentary, and active behaviors) drive metabolic risk. We describe the development and process evaluation of BeWell24, a multicomponent smartphone application (or "app") that targets behavior change in these interdependent behaviors. A community-embedded iterative design framework was used to develop the app. An 8-week multiphase optimization strategy design study was used to test the initial efficacy of the sleep, sedentary, and exercise components of the app. Process evaluation outcomes included objectively measured app usage statistics (e.g., minutes of usage, self-monitoring patterns), user experience interviews, and satisfaction ratings. Participants (N = 26) logged approximately 60 % of their sleep, sedentary, and exercise behaviors, which took 3-4 min/day to complete. Usage of the sleep and sedentary components peaked at week 2 and remained high throughout the intervention. Exercise component use was low. User experiences were mixed, and overall satisfaction was modest.

The Development of the Recovery Assessments by Phone Points (RAPP): A Mobile Phone App for Postoperative Recovery Monitoring and Assessment.

PubMed

Jaensson, Maria; Dahlberg, Karuna; Eriksson, Mats; Grönlund, Åke; Nilsson, Ulrica

2015-09-11

In Sweden, day surgery is performed in almost 2 million patients per year. Patient satisfaction is closely related to potential adverse events during the recovery process. A way to empower patients and give them the opportunity to affect care delivery is to let them evaluate their recovery process. The most common evaluation method is a follow-up telephone call by a nurse one or two days after surgery. In recent years, mHealth apps have been used to evaluate the nurse-patient relationship for self-management in chronic diseases or to evaluate pain after surgery. To the best of our knowledge, no previous research has explored the recovery process after day surgery via mobile phone in a Swedish cohort. The objective of the study is to describe the process of developing a mobile phone app using a Swedish Web-based Quality of Recovery (SwQoR) questionnaire to evaluate postoperative recovery after day surgery. The development process included five steps: (1) setting up an interdisciplinary task force, (2) evaluating the potential needs of app users, (3) developing the Swedish Web version of a QoR questionnaire, (4) constructing a mobile phone app, and (5) evaluating the interface and design by staff working in a day-surgery department and patients undergoing day surgery. A task force including specialists in information and communication technology, eHealth, and nursing care worked closely together to develop a Web-based app. Modifications to the QoR questionnaire were inspired by instruments used in the field of recovery for both children and adults. The Web-based app, Recovery Assessment by Phone Points (RAPP) consists of two parts: (1) a mobile app installed on the patient's private mobile phone, and (2) an administrator interface for the researchers. The final version of the SwQoR questionnaire, which includes 31 items, was successfully installed in RAPP. The interface and the design were evaluated by asking for user opinions about the design and usefulness of the app with 10 day surgery patients. Some minor adjustments were made concerning text size and screen color. Taking advantage of joint expertise, a useable Web-based app adaptable to different technical platforms was constructed. In addition, the SwQoR was successfully transferred into digital format for use on mobile phones.

Hydrophobic and superhydrophobic surfaces fabricated using atmospheric pressure cold plasma technology: A review.

PubMed

Dimitrakellis, Panagiotis; Gogolides, Evangelos

2018-04-01

Hydrophobic surfaces are often used to reduce wetting of surfaces by water. In particular, superhydrophobic surfaces are highly desired for several applications due to their exceptional properties such as self-cleaning, anti-icing, anti-friction and others. Such surfaces can be prepared via numerous methods including plasma technology, a dry technique with low environmental impact. Atmospheric pressure plasma (APP) has recently attracted significant attention as lower-cost alternative to low-pressure plasmas, and as a candidate for continuous rather than batch processing. Although there are many reviews on water-repellent surfaces, and a few reviews on APP technology, there are hardly any review works on APP processing for hydrophobic and superhydrohobic surface fabrication, a topic of high importance in nanotechnology and interface science. Herein, we critically review the advances on hydrophobic and superhydrophobic surface fabrication using APP technology, trying also to give some perspectives in the field. After a short introduction to superhydrophobicity of nanostructured surfaces and to APPs we focus this review on three different aspects: (1) The atmospheric plasma reactor technology used for fabrication of (super)hydrophobic surfaces. (2) The APP process for hydrophobic surface preparation. The hydrophobic surface preparation processes are categorized methodologically as: a) activation, b) grafting, c) polymerization, d) roughening and hydrophobization. Each category includes subcategories related to different precursors used. (3) One of the most important sections of this review concerns superhydrophobic surfaces fabricated using APP. These are methodologically characterized as follows: a) single step processes where micro-nano textured topography and low surface energy coating are created at the same time, or b) multiple step processes, where these steps occur sequentially in or out of the plasma. We end the review with some perspectives in the field. We aspire to address scientists, who will get involved in the fields of (super)hydrophobicity and/or in atmospheric pressure plasma processing. Copyright © 2018 Elsevier B.V. All rights reserved.

Moving Phones Tick Slower: Creating an Android App to Demonstrate Time Dilation

NASA Astrophysics Data System (ADS)

Underwood, Bret; Zhai, Yunxiao

2016-05-01

Smartphones and tablets are packed with sensors that allow us to take experimental data, essentially making them mobile physics labs. Apps exist that make it easy to capture and analyze data from these sensors, allowing users to study diverse phenomena such as free fall acceleration, the speed of sound, radioactivity, and many others. Commonly, the use of apps in the physics classroom focuses on existing apps rather than on the creation of apps themselves. This is for a good reason-writing an app usually requires advanced knowledge of programming languages and experience with app design. These skills are generally regarded as beyond the typical physics student. However, there are app development environments, such as MIT App Inventor 2 for Android, which make the process of creating an app and utilizing the sensors much more accessible to students. Putting the ability to create and configure apps within the reach of students can also help integrate computation into the curriculum. In this article, we discuss our creation of an Android app, Time Dilation Calculator, done as part of a senior undergraduate capstone project, which uses App Inventor and a mobile device's global positioning system (GPS) receiver to calculate the time dilation effect of special relativity.

Oxidative stress and mitochondria-mediated cell death mechanisms triggered by the familial Danish dementia ADan amyloid.

PubMed

Todd, Krysti; Ghiso, Jorge; Rostagno, Agueda

2016-01-01

Familial Danish Dementia (FDD), an early-onset non-amyloid-β (Aβ) cerebral amyloidosis, is neuropathologically characterized by widespread cerebral amyloid angiopathy, parenchymal amyloid and preamyloid deposits, as well as neurofibrillary degeneration indistinguishable to that seen in Alzheimer's disease (AD). The main amyloid subunit composing FDD lesions, a 34-amino acid de-novo generated peptide ADan, is the direct result of a genetic defect at the 3'-end of the BRI2 gene and the physiologic action of furin-like proteolytic processing at the C-terminal region of the ADan precursor protein. We aimed to study the impact of the FDD mutation, the additional formation of the pyroglutamate (pE) posttranslational modification as well as the relevance of C-terminal truncations -all major components of the heterogeneous FDD deposits- on the structural and neurotoxic properties of the molecule. Our data indicates that whereas the mutation generated a β-sheet-rich hydrophobic ADan subunit of high oligomerization/fibrillization propensity and the pE modification further enhanced these properties, C-terminal truncations had the opposite effect mostly abolishing these features. The potentiation of pro-amyloidogenic properties correlated with the initiation of neuronal cell death mechanisms involving oxidative stress, perturbation of mitochondrial membrane potential, release of mitochondrial cytochrome c, and downstream activation of caspase-mediated apoptotic pathways. The amyloid-induced toxicity was inhibited by targeting specific components of these detrimental cellular pathways, using reactive oxygen scavengers and monoclonal antibodies recognizing the pathological amyloid subunit. Taken together, the data indicate that the FDD mutation and the pE posttranslational modification are both primary elements driving intact ADan into an amyloidogenic/neurotoxic pathway while truncations at the C-terminus eliminate the pro-amyloidogenic characteristics of the molecule, likely reflecting effect of physiologic clearance mechanisms. Copyright © 2015 Elsevier Inc. All rights reserved.

The use of Facebook and WhatsApp application in learning process of physics to train students’ critical thinking skills

NASA Astrophysics Data System (ADS)

Kustijono, R.; Zuhri, F.

2018-01-01

The purpose of this research is to describe the learning process by using Facebook and WhatsApp to train students’ critical thinking skills. The research steps are: 1) analysis; 2) design; 3) development; 4) implementation; 5) evaluation. The research subjects are 40 students of Physics Department of Universitas Negeri Surabaya. This research used descriptive qualitative approach. The study The validation point, practicality, effectiveness, and critical thinking skills of students assessment use Likert scale. Learning process criteria are eligible if ≥ 60% is rated good or excellent. The results are: 1) the use of Facebook and WhatsApp can be implemented in the learning process, and the existing constraints can be overcome; 2) the assessment of students’ critical thinking skills is categorized as good and excellent. These results suggest that learning by using Facebook and WhatsApp can be used to train students’ critical thinking skills.

Bone marrow amyloid spherulites in a case of AL amyloidosis.

PubMed

Bommannan B K, Karthik; Sonai, Mukinkumar; Sachdeva, Man Updesh Singh

2016-05-01

Parallel arrangement of β-pleated sheets by amyloidogenic proteins is a well known phenomenon. Rarely, amyloid fibrils undergo radial orientation to form globular structures called spherulites. These amyloid spherulites show Maltese cross pattern under polarized microscopy. The clinical significance of amyloid spherulites is undetermined. Amyloidogenic proteins like insulin and β-lactoglobulin form spherulites in vitro. The senile plaques of Alzheimer's disease rarely form in vivo spherulites. Amyloid spherulites have been described in the liver and small intestine. For the first time, we document amyloid spherulite formation in the bone marrow biopsy of an AL amyloidosis patient. Copyright © 2016 Elsevier Inc. All rights reserved.

Atomic structures of corkscrew-forming segments of SOD1 reveal varied oligomer conformations.

PubMed

Sangwan, Smriti; Sawaya, Michael R; Murray, Kevin A; Hughes, Michael P; Eisenberg, David S

2018-02-17

The aggregation cascade of disease-related amyloidogenic proteins, terminating in insoluble amyloid fibrils, involves intermediate oligomeric states. The structural and biochemical details of these oligomers have been largely unknown. Here we report crystal structures of variants of the cytotoxic oligomer-forming segment residues 28-38 of the ALS-linked protein, SOD1. The crystal structures reveal three different architectures: corkscrew oligomeric structure, nontwisting curved sheet structure and a steric zipper proto-filament structure. Our work highlights the polymorphism of the segment 28-38 of SOD1 and identifies the molecular features of amyloidogenic entities. © 2018 The Protein Society.

Cations as Switches of Amyloid-Mediated Membrane Disruption Mechanisms: Calcium and IAPP

PubMed Central

Sciacca, Michele F.M.; Milardi, Danilo; Messina, Grazia M.L.; Marletta, Giovanni; Brender, Jeffrey R.; Ramamoorthy, Ayyalusamy; La Rosa, Carmelo

2013-01-01

Disruption of the integrity of the plasma membrane by amyloidogenic proteins is linked to the pathogenesis of a number of common age-related diseases. Although accumulating evidence suggests that adverse environmental stressors such as unbalanced levels of metal ions may trigger amyloid-mediated membrane damage, many features of the molecular mechanisms underlying these events are unknown. Using human islet amyloid polypeptide (hIAPP, aka amylin), an amyloidogenic peptide associated with β-cell death in type 2 diabetes, we demonstrate that the presence of Ca2+ ions inhibits membrane damage occurring immediately after the interaction of freshly dissolved hIAPP with the membrane, but significantly enhances fiber-dependent membrane disruption. In particular, dye leakage, quartz crystal microbalance, atomic force microscopy, and NMR experiments show that Ca2+ ions promote a shallow membrane insertion of hIAPP, which leads to the removal of lipids from the bilayer through a detergent-like mechanism triggered by fiber growth. Because both types of membrane-damage mechanisms are common to amyloid toxicity by most amyloidogenic proteins, it is likely that unregulated ion homeostasis, amyloid aggregation, and membrane disruption are all parts of a self-perpetuating cycle that fuels amyloid cytotoxicity. PMID:23332070

Systematic and Iterative Development of a Smartphone App to Promote Sun-Protection Among Holidaymakers: Design of a Prototype and Results of Usability and Acceptability Testing

PubMed Central

Sniehotta, Falko F; Birch-Machin, Mark A; Olivier, Patrick; Araújo-Soares, Vera

2017-01-01

Background Sunburn and intermittent exposure to ultraviolet rays are risk factors for melanoma. Sunburn is a common experience during holidays, making tourism settings of particular interest for skin cancer prevention. Holidaymakers are a volatile populations found at different locations, which may make them difficult to reach. Given the widespread use of smartphones, evidence suggests that this might be a novel, convenient, scalable, and feasible way of reaching the target population. Objective The main objective of this study was to describe and appraise the process of systematically developing a smartphone intervention (mISkin app) to promote sun-protection during holidays. Methods The iterative development process of the mISkin app was conducted over four sequential stages: (1) identify evidence on the most effective behavior change techniques (BCTs) used (active ingredients) as well as theoretical predictors and theories, (2) evidence-based intervention design, (3) co-design with users of the mISkin app prototype, and (4) refinement of the app. Each stage provided key findings that were subsequently used to inform the design of the mISkin app. Results The sequential approach to development integrates different strands of evidence to inform the design of an evidence-based intervention. A systematic review on previously tested interventions to promote sun-protection provided cues and constraints for the design of this intervention. The development and design of the mISkin app also incorporated other sources of information, such as other literature reviews and experts’ consultations. The developed prototype of the mISkin app was evaluated by engaging potential holidaymakers in the refinement and further development of the mISkin app through usability (ease-of-use) and acceptability testing of the intervention prototype. All 17 participants were satisfied with the mISkin prototype and expressed willingness to use it. Feedback on the app was integrated in the optimization process of the mISkin app. Conclusions The mISkin app was designed to promote sun-protection among holidaymakers and was based on current evidence, experts’ knowledge and experience, and user involvement. Based on user feedback, the app has been refined and a fully functional version is ready for formal testing in a feasibility pilot study. PMID:28606892

Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoform-dependent manner: implications for Alzheimer disease pathogenesis.

PubMed

Kyriazis, George A; Wei, Zelan; Vandermey, Miriam; Jo, Dong-Gyu; Xin, Ouyang; Mattson, Mark P; Chan, Sic L

2008-09-12

Central to the pathogenesis of Alzheimer disease is the aberrant processing of the amyloid precursor protein (APP) to generate amyloid beta-peptide (Abeta), the principle component of amyloid plaques. The cell fate determinant Numb is a phosphotyrosine binding domain (PTB)-containing endocytic adapter protein that interacts with the carboxyl-terminal domain of APP. The physiological relevance of this interaction is unknown. Mammals produce four alternatively spliced variants of Numb that differ in the length of their PTB and proline-rich region. In the current study, we determined the influence of the four human Numb isoforms on the intracellular trafficking and processing of APP. Stable expression of Numb isoforms that differ in the PTB but not in the proline-rich region results in marked differences in the sorting of APP to the recycling and degradative pathways. Neural cells expressing Numb isoforms that lack the insert in the PTB (short PTB (SPTB)) exhibited marked accumulation of APP in Rab5A-labeled early endosomal and recycling compartments, whereas those expressing isoforms with the insertion in the PTB (long PTB (LPTB)) exhibited reduced amounts of cellular APP and its proteolytic derivatives relative to parental control cells. Neither the activities of the beta- and gamma-secretases nor the expression of APP mRNA were significantly different in the stably transfected cells, suggesting that the differential effects of the Numb proteins on APP metabolism is likely to be secondary to altered APP trafficking. In addition, the expression of SPTB-Numb increases at the expense of LPTB-Numb in neuronal cultures subjected to stress, suggesting a role for Numb in stress-induced Abeta production. Taken together, these results suggest distinct roles for the human Numb isoforms in APP metabolism and may provide a novel potential link between altered Numb isoform expression and increased Abeta generation.

Human apoB overexpression and a high-cholesterol diet differently modify the brain APP metabolism in the transgenic mouse model of atherosclerosis.

PubMed

Bjelik, Annamária; Bereczki, Erika; Gonda, Szilvia; Juhász, Anna; Rimanóczy, Agnes; Zana, Marianna; Csont, Tamás; Pákáski, Magdolna; Boda, Krisztina; Ferdinandy, Péter; Dux, László; Janka, Zoltán; Sántha, Miklós; Kálmán, János

2006-09-01

Epidemiological and biochemical data suggest a link between the cholesterol metabolism, the amyloid precursor protein (APP) processing and the increased cerebral beta-amyloid (Abeta) deposition in Alzheimer's disease (AD). The individual and combined effects of a high-cholesterol (HC) diet and the overexpression of the human apoB-100 gene were therefore examined on the cerebral expression and processing of APP in homozygous apoB-100 transgenic mice [Tg (apoB(+/+))], a validated model of atherosclerosis. When fed with 2% cholesterol for 17 weeks, only the wild-type mice exhibited significantly increased APP695 (123%) and APP770 (138%) mRNA levels in the cortex. The HC diet-induced hypercholesterolemia significantly increased the APP isoform levels in the membrane-bound fraction, not only in the wild-type animals (114%), but also in the Tg apoB(+/+) group (171%). The overexpression of human apoB-100 gene by the liver alone reduced the brain APP isoform levels in the membrane-bound fraction (78%), whereas the levels were increased by the combined effect of HC and the overexpression of the human apoB-100 gene (134%). The protein kinase C and beta-secretase protein levels were not altered by the individual or combined effects of these two factors. Our data indicate that the two atherogenic factors, the HC diet and the overexpression of the human apoB-100 gene by the liver, could exert different effects on the processing and expression of APP in the mice brain.

Regulation of Synaptic Amyloid-β Generation through BACE1 Retrograde Transport in a Mouse Model of Alzheimer's Disease

PubMed Central

Ye, Xuan; Chang, Qing; Jeong, Yu Young; Cai, Huaibin; Kusnecov, Alexander

2017-01-01

Amyloid-β (Aβ) peptides play a key role in synaptic damage and memory deficits in the early pathogenesis of Alzheimer's disease (AD). Abnormal accumulation of Aβ at nerve terminals leads to synaptic pathology and ultimately to neurodegeneration. β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major neuronal β-secretase for Aβ generation. However, the mechanisms regulating BACE1 distribution in axons and β cleavage of APP at synapses remain largely unknown. Here, we reveal that dynein–Snapin-mediated retrograde transport regulates BACE1 trafficking in axons and APP processing at presynaptic terminals. BACE1 is predominantly accumulated within late endosomes at the synapses of AD-related mutant human APP (hAPP) transgenic (Tg) mice and patient brains. Defective retrograde transport by genetic ablation of snapin in mice recapitulates late endocytic retention of BACE1 and increased APP processing at presynaptic sites. Conversely, overexpressing Snapin facilitates BACE1 trafficking and reduces synaptic BACE1 accumulation by enhancing the removal of BACE1 from distal AD axons and presynaptic terminals. Moreover, elevated Snapin expression via stereotactic hippocampal injections of adeno-associated virus particles in mutant hAPP Tg mouse brains decreases synaptic Aβ levels and ameliorates synapse loss, thus rescuing cognitive impairments associated with hAPP mice. Altogether, our study provides new mechanistic insights into the complex regulation of BACE1 trafficking and presynaptic localization through Snapin-mediated dynein-driven retrograde axonal transport, thereby suggesting a potential approach of modulating Aβ levels and attenuating synaptic deficits in AD. SIGNIFICANCE STATEMENT β-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) trafficking and synaptic localization significantly influence its β secretase activity and amyloid-β (Aβ) production. In AD brains, BACE1 is accumulated within dystrophic neurites, which is thought to augment Aβ-induced synaptotoxicity by Aβ overproduction. However, it remains largely unknown whether axonal transport regulates synaptic APP processing. Here, we demonstrate that Snapin-mediated retrograde transport plays a critical role in removing BACE1 from presynaptic terminals toward the soma, thus reducing synaptic Aβ production. Adeno-associated virus–mediated Snapin overexpression in the hippocampus of mutant hAPP mice significantly decreases synaptic Aβ levels, attenuates synapse loss, and thus rescues cognitive deficits. Our study uncovers a new pathway that controls synaptic APP processing by enhancing axonal BACE1 trafficking, thereby advancing our fundamental knowledge critical for ameliorating Aβ-linked synaptic pathology. PMID:28159908

A Standards-Based Architecture Proposal for Integrating Patient mHealth Apps to Electronic Health Record Systems.

PubMed

Marceglia, S; Fontelo, P; Rossi, E; Ackerman, M J

2015-01-01

Mobile health Applications (mHealth Apps) are opening the way to patients' responsible and active involvement with their own healthcare management. However, apart from Apps allowing patient's access to their electronic health records (EHRs), mHealth Apps are currently developed as dedicated "island systems". Although much work has been done on patient's access to EHRs, transfer of information from mHealth Apps to EHR systems is still low. This study proposes a standards-based architecture that can be adopted by mHealth Apps to exchange information with EHRs to support better quality of care. Following the definition of requirements for the EHR/mHealth App information exchange recently proposed, and after reviewing current standards, we designed the architecture for EHR/mHealth App integration. Then, as a case study, we modeled a system based on the proposed architecture aimed to support home monitoring for congestive heart failure patients. We simulated such process using, on the EHR side, OpenMRS, an open source longitudinal EHR and, on the mHealth App side, the iOS platform. The integration architecture was based on the bi-directional exchange of standard documents (clinical document architecture rel2 - CDA2). In the process, the clinician "prescribes" the home monitoring procedures by creating a CDA2 prescription in the EHR that is sent, encrypted and de-identified, to the mHealth App to create the monitoring calendar. At the scheduled time, the App alerts the patient to start the monitoring. After the measurements are done, the App generates a structured CDA2-compliant monitoring report and sends it to the EHR, thus avoiding local storage. The proposed architecture, even if validated only in a simulation environment, represents a step forward in the integration of personal mHealth Apps into the larger health-IT ecosystem, allowing the bi-directional data exchange between patients and healthcare professionals, supporting the patient's engagement in self-management and self-care.

Combining apps targeting professionals and senior citizens to improve housing accessibility and influence housing provision policies.

PubMed

Helle, Tina; Iwarsson, Susanne; Lunn, Tine Bieber; Iversen, Mogens Holm; Jonsson, Oskar; Mårtensson, Knut; Svarre, Tanja; Slaug, Björn

2015-01-01

Two separate apps that address the increasingly important issue of accessible housing for senior citizens have been developed in different project settings. One of the apps was developed to facilitate the process for professional raters to assess housing accessibility in the context of individual housing adaptations. The other app was developed for senior citizens to raise their awareness of possible accessibility problems in their current dwelling and in other apartments within the available housing stock. Both apps were developed with a high degree of active user involvement in processes utilizing multiple state of the art methods. The results are two well accepted prototype apps perceived as user-friendly and appropriate for the intended user groups. By combining these two apps, our ambition is for the professional raters to benefit by gaining knowledge of their clients' perceived needs and desires, and for senior citizens to benefit by getting access to a database of professionally rated dwellings. The ultimate goal is the generation of sound knowledge reflecting the needs and desires of senior citizens and professional requirements regarding accessible housing as a means to inform and influence housing provision policies.

The Exosome Secretory Pathway Transports Amyloid Precursor Protein Carboxyl-terminal Fragments from the Cell into the Brain Extracellular Space*

PubMed Central

Perez-Gonzalez, Rocio; Gauthier, Sebastien A.; Kumar, Asok; Levy, Efrat

2012-01-01

In vitro studies have shown that neuronal cell cultures secrete exosomes containing amyloid-β precursor protein (APP) and the APP-processing products, C-terminal fragments (CTFs) and amyloid-β (Aβ). We investigated the secretion of full-length APP (flAPP) and APP CTFs via the exosome secretory pathway in vivo. To this end, we developed a novel protocol designed to isolate exosomes secreted into mouse brain extracellular space. Exosomes with typical morphology were isolated from freshly removed mouse brains and from frozen mouse and human brain tissues, demonstrating that exosomes can be isolated from post-mortem tissue frozen for long periods of time. flAPP, APP CTFs, and enzymes that cleave both flAPP and APP CTFs were identified in brain exosomes. Although higher levels of both flAPP and APP CTFs were observed in exosomes isolated from the brains of transgenic mice overexpressing human APP (Tg2576) compared with wild-type control mice, there was no difference in the number of secreted brain exosomes. These data indicate that the levels of flAPP and APP CTFs associated with exosomes mirror the cellular levels of flAPP and APP CTFs. Interestingly, exosomes isolated from the brains of both Tg2576 and wild-type mice are enriched with APP CTFs relative to flAPP. Thus, we hypothesize that the exosome secretory pathway plays a pleiotropic role in the brain: exosome secretion is beneficial to the cell, acting as a specific releasing system of neurotoxic APP CTFs and Aβ, but the secretion of exosomes enriched with APP CTFs, neurotoxic proteins that are also a source of secreted Aβ, is harmful to the brain. PMID:23129776

Tetrahydroxystilbene glucoside modulates amyloid precursor protein processing via activation of AKT-GSK3β pathway in cells and in APP/PS1 transgenic mice.

PubMed

Yin, Xiaomin; Chen, Chen; Xu, Ting; Li, Lin; Zhang, Lan

2018-01-01

Alternative splicing of amyloid precursor protein (APP) exon 7 generates the isoforms containing a Kunitz protease inhibitor (KPI) domain. APP-KPI levels in the brain are correlated with amyloid beta (Aβ) production. Here, we determined the effect of Tetrahydroxystilbene glucoside (TSG) on the AKT-GSK3β pathway. We found GSK3β increased APP-KPI inclusion level and interacted with the splicing factor ASF. TSG was intragastrically administered to 5-month-old APP/PS1 transgenic mice for 12 months. We found that the activated the AKT-GSK3β signaling pathway suppressed APP-KPI inclusion. Moreover, TSG treatment attenuated amyloid deposition in APP/PS1 mice. This study demonstrates the neuroprotective effect of TSG on APP expression, suggesting that TSG may be beneficial for AD prevention and treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Rapid endocytosis of the low density lipoprotein receptor-related protein modulates cell surface distribution and processing of the beta-amyloid precursor protein.

PubMed

Cam, Judy A; Zerbinatti, Celina V; Li, Yonghe; Bu, Guojun

2005-04-15

The low density lipoprotein receptor-related protein (LRP) is a approximately 600-kDa multifunctional endocytic receptor that is highly expressed in the brain. LRP and its ligands apolipoprotein E, alpha2-macroglobulin, and beta-amyloid precursor protein (APP), are genetically linked to Alzheimer disease and are found in characteristic plaque deposits in brains of patients with Alzheimer disease. To identify which extracellular domains of LRP interact with APP, we used minireceptors of each of the individual LRP ligand binding domains and assessed their ability to bind and degrade a soluble APP fragment. LRP minireceptors containing ligand binding domains II and IV, but not I or III, interacted with APP. To test whether APP trafficking is directly related to the rapid endocytosis of LRP, we generated stable Chinese hamster ovary cell lines expressing either a wild-type LRP minireceptor or its endocytosis mutants. Chinese hamster ovary cells stably expressing wild-type LRP minireceptor had less cell surface APP than pcDNA3 vector-transfected cells, whereas those stably expressing endocytosis-defective LRP minireceptors accumulated APP at the cell surface. We also found that the steady-state levels of the amyloid beta-peptides (Abeta) is dictated by the relative expression levels of APP and LRP, probably reflecting the dual roles of LRP in both Abeta production and clearance. Together, these data establish a relationship between LRP rapid endocytosis and APP trafficking and proteolytic processing to generate Abeta.

Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration

PubMed Central

Schaefer, Patrick M.; von Einem, Bjoern; Walther, Paul; Calzia, Enrico; von Arnim, Christine A. F.

2016-01-01

One hallmark of Alzheimer´s disease are senile plaques consisting of amyloid beta (Aβ), which derives from the processing of the amyloid precursor protein (APP). Mitochondrial dysfunction has been linked to the pathogenesis of Alzheimer´s disease and both Aβ and APP have been reported to affect mitochondrial function in isolated systems. However, in intact cells, considering a physiological localization of APP and Aβ, it is pending what triggers the mitochondrial defect. Thus, the aim of this study was to dissect the impact of APP versus Aβ in inducing mitochondrial alterations with respect to their subcellular localization. We performed an overexpression of APP or beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), increasing APP and Aβ levels or Aβ alone, respectively. Conducting a comprehensive metabolic characterization we demonstrate that only APP overexpression reduced mitochondrial respiration, despite lower extracellular Aβ levels compared to BACE overexpression. Surprisingly, this could be rescued by a gamma secretase inhibitor, oppositionally indicating an Aβ-mediated mitochondrial toxicity. Analyzing Aβ localization revealed that intracellular levels of Aβ and an increased spatial association of APP/Aβ with mitochondria are associated with reduced mitochondrial respiration. Thus, our data provide marked evidence for a prominent role of intracellular Aβ accumulation in Alzheimer´s disease associated mitochondrial dysfunction. Thereby it highlights the importance of the localization of APP processing and intracellular transport as a decisive factor for mitochondrial function, linking two prominent hallmarks of neurodegenerative diseases. PMID:28005987

Full-length amyloid precursor protein regulates lipoprotein metabolism and amyloid-β clearance in human astrocytes.

PubMed

Fong, Lauren K; Yang, Max M; Dos Santos Chaves, Rodrigo; Reyna, Sol M; Langness, Vanessa F; Woodruff, Grace; Roberts, Elizabeth A; Young, Jessica E; Goldstein, Lawrence S B

2018-06-01

Mounting evidence suggests that alterations in cholesterol homeostasis are involved in Alzheimer's disease (AD) pathogenesis. Amyloid precursor protein (APP) or multiple fragments generated by proteolytic processing of APP have previously been implicated in the regulation of cholesterol metabolism. However, the physiological function of APP in regulating lipoprotein homeostasis in astrocytes, which are responsible for de novo cholesterol biosynthesis and regulation in the brain, remains unclear. To address this, here we used CRISPR/Cas9 genome editing to generate isogenic APP-knockout (KO) human induced pluripotent stem cells (hiPSCs) and differentiated them into human astrocytes. We found that APP-KO astrocytes have reduced cholesterol and elevated levels of sterol regulatory element-binding protein (SREBP) target gene transcripts and proteins, which were both downstream consequences of reduced lipoprotein endocytosis. To elucidate which APP fragments regulate cholesterol homeostasis and examine whether familial AD mutations in APP affect lipoprotein metabolism, we analyzed an isogenic allelic series harboring the APP Swedish and APP V717F variants. Only astrocytes homozygous for the APP Swedish (APP Swe/Swe ) mutation, which had reduced full-length APP (FL APP) due to increased β-secretase cleavage, recapitulated the APP-KO phenotypes. Astrocytic internalization of amyloid-β (Aβ), another ligand for low-density lipoprotein (LDL) receptors, was also impaired in APP-KO and APP Swe/Swe astrocytes. Finally, impairing cleavage of FL APP through β-secretase inhibition in APP Swe/Swe astrocytes reversed the LDL and Aβ endocytosis defects. In conclusion, FL APP is involved in the endocytosis of LDL receptor ligands and required for proper cholesterol homeostasis and Aβ clearance in human astrocytes. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Research on the development and preliminary application of Beijing agricultural sci-tech service hotline WebApp in agricultural consulting services

NASA Astrophysics Data System (ADS)

Yu, Weishui; Luo, Changshou; Zheng, Yaming; Wei, Qingfeng; Cao, Chengzhong

2017-09-01

To deal with the “last kilometer” problem during the agricultural science and technology information service, we analyzed the feasibility, necessity and advantages of WebApp applied to agricultural information service and discussed the modes of WebApp used in agricultural information service based on the requirements analysis and the function of WebApp. To overcome the existing App’s defects of difficult installation and weak compatibility between the mobile operating systems, the Beijing Agricultural Sci-tech Service Hotline WebApp was developed based on the HTML and JAVA technology. The WebApp has greater compatibility and simpler operation than the Native App, what’s more, it can be linked to the WeChat public platform making it spread easily and run directly without setup process. The WebApp was used to provide agricultural expert consulting services and agriculture information push, obtained a good preliminary application achievement. Finally, we concluded the creative application of WebApp in agricultural consulting services and prospected the development of WebApp in agricultural information service.

A Smartphone App for Adolescents With Sleep Disturbance: Development of the Sleep Ninja

PubMed Central

O'Dea, Bridianne; Shand, Fiona; Johnston, Lara; Frayne, Anna; Fogarty, Andrea S; Christensen, Helen

2017-01-01

Background Sleep disturbances are common in young people and have consequences for academic, social, emotional, and behavioral development. The most effective treatment is cognitive behavioral therapy for insomnia (CBT-I), with evidence suggesting that it is efficacious even when delivered digitally. Objective There are no commercially available digitally delivered CBT-I programs for use by young people. The aim of this project was to develop a smartphone app that delivers CBT-I to young people to improve sleep. Methods To inform the development of the app, young people (N=21) aged between 12 and 16 years attended one of the 3 focus groups (each with 4-10 participants). These focus groups were conducted at different stages of the development process such that the process could be iterative. Participants were asked the reasons why they might use an app to help them sleep, the kinds of features or functions that they would like to see in such an app, and any concerns they may have in using the app. Data were analyzed using a thematic analysis approach. Of the issues discussed by the participants, the researchers selected themes associated with content, functionality, and accessibility and user experience to examine, as these were most informative for the app design process. Results In terms of content, young people were interested in receiving information about recommended sleep guidelines and personalized information for their age group. They reported that keeping a sleep diary was acceptable, but they should be able to complete it flexibly, in their own time. They reported mixed views about the use of the phone’s accelerometer. Young people felt that the functionality of the app should include elements of game playing if they were to remain engaged with the app. Flexibility of use and personalized features were also desirable, and there were mixed views about the schedule of notifications and reminders. Participants reported that for the app to be accessible and usable, it should be from a trusted developer, have engaging aesthetics, have a layout that is easy to navigate, not rely on Internet coverage, and preferably be free. Participants felt that being able to conceal the purpose of the app from peers was an advantage and were willing to provide personal information to use the app if the purpose and use of that information was made clear. Overall, participants endorsed the use of the app for sleep problems among their age group and reported motivation to use it. Conclusions The Sleep Ninja is a fully-automated app that delivers CBT-I to young people, incorporating the features and information that young people reported they would expect from this app. A pilot study testing the feasibility, acceptability, and efficacy of the Sleep Ninja is now underway. PMID:28754651

Effects of acetylate hyperforin on the processing of amyloid precursor protein.

PubMed

Chen, Xiang; Feng, Wenshang; Chen, Qing; Yang, Xiangling; Yang, Depo; Wang, Dongmei; Zhong, Ling

2009-02-20

Hyperforin (HF) is a phloroglucinol compound obtained from St. John's Wort (Hypericum perforatum). Recent studies have shown that Hyperforin can be used to improve psychopathologic symptoms of Alzheimer's disease but the mechanism is not clear. This may be partly due to the difficult in studying Hyperforin, since this chemical is unstable and is sensitive to light, oxygen, and heat. In this study, we explored the effects of acetylate hyperforin (ace-HF), a stable derivative of hyperforin, on the processing of amyloid precursor protein (APP). HEK293 cells transfected with pcDNA3.1APP695sw and SH-SY5Y cells were treated with ace-HF, followed by measuring the levels of APP and sAPPα. Twelve hours of treatment led to an increase in extracellular sAPPα, but APP mRNA and protein levels were unchanged. Further studies with α-secretase and a pan PKC inhibitor, Calphostin C, indicated that ace-HF's effect on extracellular sAPPα was closely related to PKC activities and α-secretase activities. Our findings suggest that ace-HF can modulate α-secretase-mediated APP processing via a PKC signaling pathway.

Cerebrospinal fluid Aβ42 levels and APP processing pathway genes in Parkinson's disease.

PubMed

Bekris, Lynn M; Tsuang, Debby W; Peskind, Elaine R; Yu, Chang E; Montine, Thomas J; Zhang, Jing; Zabetian, Cyrus P; Leverenz, James B

2015-06-01

Of recent interest is the finding that certain cerebrospinal fluid (CSF) biomarkers traditionally linked to Alzheimer's disease (AD), specifically amyloid beta protein (Aβ), are abnormal in PD CSF. The aim of this exploratory investigation was to determine whether genetic variation within the amyloid precursor protein (APP) processing pathway genes correlates with CSF Aβ42 levels in Parkinson's disease (PD). Parkinson's disease (n = 86) and control (n = 161) DNA were genotyped for 19 regulatory region tagging single-nucleotide polymorphisms (SNPs) within nine genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN, and APH1B) involved in the cleavage of APP. The SNP genotypes were tested for their association with CSF biomarkers and PD risk while adjusting for age, sex, and APOE ɛ4 status. Significant correlation with CSF Aβ42 levels in PD was observed for two SNPs, (APP rs466448 and APH1B rs2068143). Conversely, significant correlation with CSF Aβ42 levels in controls was observed for three SNPs (APP rs214484, rs2040273, and PSEN1 rs362344). In addition, results of this exploratory investigation suggest that an APP SNP and an APH1B SNP are marginally associated with PD CSF Aβ42 levels in APOE ɛ4 noncarriers. Further hypotheses generated include that decreased CSF Aβ42 levels are in part driven by genetic variation in APP processing genes. Additional investigation into the relationship between these findings and clinical characteristics of PD, including cognitive impairment, compared with other neurodegenerative diseases, such as AD, are warranted. © 2015 International Parkinson and Movement Disorder Society. © 2015 International Parkinson and Movement Disorder Society.

Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice

PubMed Central

Kraft, Andrew W.; Hu, Xiaoyan; Yoon, Hyejin; Yan, Ping; Xiao, Qingli; Wang, Yan; Gil, So Chon; Brown, Jennifer; Wilhelmsson, Ulrika; Restivo, Jessica L.; Cirrito, John R.; Holtzman, David M.; Kim, Jungsu; Pekny, Milos; Lee, Jin-Moo

2013-01-01

The accumulation of aggregated amyloid-β (Aβ) in amyloid plaques is a neuropathological hallmark of Alzheimer's disease (AD). Reactive astrocytes are intimately associated with amyloid plaques; however, their role in AD pathogenesis is unclear. We deleted the genes encoding two intermediate filament proteins required for astrocyte activation—glial fibrillary acid protein (Gfap) and vimentin (Vim)—in transgenic mice expressing mutant human amyloid precursor protein and presenilin-1 (APP/PS1). The gene deletions increased amyloid plaque load: APP/PS1 Gfap−/−Vim−/− mice had twice the plaque load of APP/PS1 Gfap+/+Vim+/+ mice at 8 and 12 mo of age. APP expression and soluble and interstitial fluid Aβ levels were unchanged, suggesting that the deletions had no effect on APP processing or Aβ generation. Astrocyte morphology was markedly altered by the deletions: wild-type astrocytes had hypertrophied processes that surrounded and infiltrated plaques, whereas Gfap−/−Vim−/− astrocytes had little process hypertrophy and lacked contact with adjacent plaques. Moreover, Gfap and Vim gene deletion resulted in a marked increase in dystrophic neurites (2- to 3-fold higher than APP/PS1 Gfap+/+Vim+/+ mice), even after normalization for amyloid load. These results suggest that astrocyte activation limits plaque growth and attenuates plaque-related dystrophic neurites. These activities may require intimate contact between astrocyte and plaque.—Kraft, A. W., Hu, X., Yoon, H., Yan, P., Xiao, Q., Wang, Y., Gil, S. C., Brown, J., Wilhelmsson, U., Restivo, J. L., Cirrito, J. R., Holtzman, D. M., Kim, J., Pekny, M., Lee, J.-M. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. PMID:23038755

APP Function and Lipids: A Bidirectional Link

PubMed Central

Grimm, Marcus O. W.; Mett, Janine; Grimm, Heike S.; Hartmann, Tobias

2017-01-01

Extracellular neuritic plaques, composed of aggregated amyloid-β (Aβ) peptides, are one of the major histopathological hallmarks of Alzheimer’s disease (AD), a progressive, irreversible neurodegenerative disorder and the most common cause of dementia in the elderly. One of the most prominent risk factor for sporadic AD, carrying one or two aberrant copies of the apolipoprotein E (ApoE) ε4 alleles, closely links AD to lipids. Further, several lipid classes and fatty acids have been reported to be changed in the brain of AD-affected individuals. Interestingly, the observed lipid changes in the brain seem not only to be a consequence of the disease but also modulate Aβ generation. In line with these observations, protective lipids being able to decrease Aβ generation and also potential negative lipids in respect to AD were identified. Mechanistically, Aβ peptides are generated by sequential proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. The α-secretase appears to compete with β-secretase for the initial cleavage of APP, preventing Aβ production. All APP-cleaving secretases as well as APP are transmembrane proteins, further illustrating the impact of lipids on Aβ generation. Beside the pathological impact of Aβ, accumulating evidence suggests that Aβ and the APP intracellular domain (AICD) play an important role in regulating lipid homeostasis, either by direct effects or by affecting gene expression or protein stability of enzymes involved in the de novo synthesis of different lipid classes. This review summarizes the current literature addressing the complex bidirectional link between lipids and AD and APP processing including lipid alterations found in AD post mortem brains, lipids that alter APP processing and the physiological functions of Aβ and AICD in the regulation of several lipid metabolism pathways. PMID:28344547

Co-creating and Evaluating a Web-app Mapping Real-World Health Care Services for Students: The servi-Share Protocol.

PubMed

Montagni, Ilaria; Langlois, Emmanuel; Wittwer, Jérôme; Tzourio, Christophe

2017-02-16

University students aged 18-30 years are a population group reporting low access to health care services, with high rates of avoidance and delay of medical care. This group also reports not having appropriate information about available health care services. However, university students are at risk for several health problems, and regular medical consultations are recommended in this period of life. New digital devices are popular among the young, and Web-apps can be used to facilitate easy access to information regarding health care services. A small number of electronic health (eHealth) tools have been developed with the purpose of displaying real-world health care services, and little is known about how such eHealth tools can improve access to care. This paper describes the processes of co-creating and evaluating the beta version of a Web-app aimed at mapping and describing free or low-cost real-world health care services available in the Bordeaux area of France, which is specifically targeted to university students. The co-creation process involves: (1) exploring the needs of students to know and access real-world health care services; (2) identifying the real-world health care services of interest for students; and (3) deciding on a user interface, and developing the beta version of the Web-app. Finally, the evaluation process involves: (1) testing the beta version of the Web-app with the target audience (university students aged 18-30 years); (2) collecting their feedback via a satisfaction survey; and (3) planning a long-term evaluation. The co-creation process of the beta version of the Web-app was completed in August 2016 and is described in this paper. The evaluation process started on September 7, 2016. The project was completed in December 2016 and implementation of the Web-app is ongoing. Web-apps are an innovative way to increase the health literacy of young people in terms of delivery of and access to health care. The creation of Web-apps benefits from the involvement of stakeholders (eg, students and health care providers) to correctly identify the real-world health care services to be displayed. ©Ilaria Montagni, Emmanuel Langlois, Jérôme Wittwer, Christophe Tzourio. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 16.02.2017.

Co-creating and Evaluating a Web-app Mapping Real-World Health Care Services for Students: The servi-Share Protocol

PubMed Central

Langlois, Emmanuel; Wittwer, Jérôme; Tzourio, Christophe

2017-01-01

Background University students aged 18-30 years are a population group reporting low access to health care services, with high rates of avoidance and delay of medical care. This group also reports not having appropriate information about available health care services. However, university students are at risk for several health problems, and regular medical consultations are recommended in this period of life. New digital devices are popular among the young, and Web-apps can be used to facilitate easy access to information regarding health care services. A small number of electronic health (eHealth) tools have been developed with the purpose of displaying real-world health care services, and little is known about how such eHealth tools can improve access to care. Objective This paper describes the processes of co-creating and evaluating the beta version of a Web-app aimed at mapping and describing free or low-cost real-world health care services available in the Bordeaux area of France, which is specifically targeted to university students. Methods The co-creation process involves: (1) exploring the needs of students to know and access real-world health care services; (2) identifying the real-world health care services of interest for students; and (3) deciding on a user interface, and developing the beta version of the Web-app. Finally, the evaluation process involves: (1) testing the beta version of the Web-app with the target audience (university students aged 18-30 years); (2) collecting their feedback via a satisfaction survey; and (3) planning a long-term evaluation. Results The co-creation process of the beta version of the Web-app was completed in August 2016 and is described in this paper. The evaluation process started on September 7, 2016. The project was completed in December 2016 and implementation of the Web-app is ongoing. Conclusions Web-apps are an innovative way to increase the health literacy of young people in terms of delivery of and access to health care. The creation of Web-apps benefits from the involvement of stakeholders (eg, students and health care providers) to correctly identify the real-world health care services to be displayed. PMID:28209561

A Framework for Mobile Apps in Colleges and Universities: Data Mining Perspective

ERIC Educational Resources Information Center

Singh, Archana; Ranjan, Jayanthi

2016-01-01

The Enterprise mobility communication technology provides easy and quick accessibility to data and information integrated into one single touch point device. This device incorporates or integrates all the processes into small applications or App and thus increases the workforce capability of knowledge workers. "App" which is a small set…

Evaluation Method for an App Involving Kitchen Activities.

PubMed

Burzagli, Laura; Gaggioli, Andrea

2017-01-01

An app, developed for the national Italian project "Design for all", is evaluated here. This app supports the user in most of his/her cooking activities. The evaluation process integrates different technologies, such as expert interview, cognitive walkthrough and focus group, to consider different aspects that include, but are not limited to, usability and accessibility.

APP mRNA splicing is upregulated in the brain of biglycan transgenic mice.

PubMed

Bjelik, Annamária; Pákáski, Magdolna; Bereczki, Erika; Gonda, Szilvia; Juhász, Anna; Rimanóczy, Agnes; Zana, Marianna; Janka, Zoltán; Sántha, Miklós; Kálmán, János

2007-01-01

Many of the risk factors for cerebrovascular disease and atherosclerosis also increase the risk of Alzheimer's disease, characterized by the cerebral deposition of beta-amyloid plaques resulting from the abnormal processing of the transmembrane amyloid precursor protein (APP). The initiating event of cholesterol-induced atherosclerosis is the retention and accumulation of atherogenic apolipoprotein B (apoB) together with low-density lipoproteins in the vascular intima. Biglycan, a member of the small leucine-rich protein family, was suspected of contributing to this process. The individual and combined overexpressions of biglycan and apoB-100 were therefore examined on the cortical APP mRNA levels of transgenic mice by means of semiquantitative PCR. As compared with the control littermates, transgenic biglycan mice had significantly increased cortical APP695 (122%) and APP770 (157%) mRNA levels, while the double transgenic (apoB(+/-)xbiglycan(+/-)) mice did not exhibit any changes. These results provide the first experimental evidence that the atherogenic risk factor biglycan alters APP splicing and may participate in the pathogenesis of both Alzheimer and vascular dementias.

Direct imaging of APP proteolysis in living cells.

PubMed

Parenti, Niccoló; Del Grosso, Ambra; Antoni, Claudia; Cecchini, Marco; Corradetti, Renato; Pavone, Francesco S; Calamai, Martino

2017-01-01

Alzheimer's disease is a multifactorial disorder caused by the interaction of genetic, epigenetic and environmental factors. The formation of cytotoxic oligomers consisting of A β peptide is widely accepted as being one of the main key events triggering the development of Alzheimer's disease. A β peptide production results from the specific proteolytic processing of the amyloid precursor protein (APP). Deciphering the factors governing the activity of the secretases responsible for the cleavage of APP is still a critical issue. Kits available commercially measure the enzymatic activity of the secretases from cells lysates, in vitro . By contrast, we have developed a prototypal rapid bioassay that provides visible information on the proteolytic processing of APP directly in living cells. APP was fused to a monomeric variant of the green fluorescent protein and a monomeric variant of the red fluorescent protein at the C-terminal and N-terminal (mChAPPmGFP), respectively. Changes in the proteolytic processing rate in transfected human neuroblastoma and rat neuronal cells were imaged with confocal microscopy as changes in the red/green fluorescence intensity ratio. The significant decrease in the mean red/green ratio observed in cells over-expressing the β -secretase BACE1, or the α -secretase ADAM10, fused to a monomeric blue fluorescent protein confirms that the proteolytic site is still accessible. Specific siRNA was used to evaluate the contribution of endogenous BACE1. Interestingly, we found that the degree of proteolytic processing of APP is not completely homogeneous within the same single cell, and that there is a high degree of variability between cells of the same type. We were also able to follow with a fluorescence spectrometer the changes in the red emission intensity of the extracellular medium when BACE1 was overexpressed. This represents a complementary approach to fluorescence microscopy for rapidly detecting changes in the proteolytic processing of APP in real time. In order to allow the discrimination between the α - and the β -secretase activity, we have created a variant of mChAPPmGFP with a mutation that inhibits the α -secretase cleavage without perturbing the β -secretase processing. Moreover, we obtained a quantitatively robust estimate of the changes in the red/green ratio for the above conditions by using a flow cytometer able to simultaneously excite and measure the red and green fluorescence. Our novel approach lay the foundation for a bioassay suitable to study the effect of drugs or particular conditions, to investigate in an unbiased way the the proteolytic processing of APP in single living cells in order, and to elucidate the causes of the variability and the factors driving the processing of APP.

Systematic and Iterative Development of a Smartphone App to Promote Sun-Protection Among Holidaymakers: Design of a Prototype and Results of Usability and Acceptability Testing.

PubMed

Rodrigues, Angela M; Sniehotta, Falko F; Birch-Machin, Mark A; Olivier, Patrick; Araújo-Soares, Vera

2017-06-12

Sunburn and intermittent exposure to ultraviolet rays are risk factors for melanoma. Sunburn is a common experience during holidays, making tourism settings of particular interest for skin cancer prevention. Holidaymakers are a volatile populations found at different locations, which may make them difficult to reach. Given the widespread use of smartphones, evidence suggests that this might be a novel, convenient, scalable, and feasible way of reaching the target population. The main objective of this study was to describe and appraise the process of systematically developing a smartphone intervention (mISkin app) to promote sun-protection during holidays. The iterative development process of the mISkin app was conducted over four sequential stages: (1) identify evidence on the most effective behavior change techniques (BCTs) used (active ingredients) as well as theoretical predictors and theories, (2) evidence-based intervention design, (3) co-design with users of the mISkin app prototype, and (4) refinement of the app. Each stage provided key findings that were subsequently used to inform the design of the mISkin app. The sequential approach to development integrates different strands of evidence to inform the design of an evidence-based intervention. A systematic review on previously tested interventions to promote sun-protection provided cues and constraints for the design of this intervention. The development and design of the mISkin app also incorporated other sources of information, such as other literature reviews and experts' consultations. The developed prototype of the mISkin app was evaluated by engaging potential holidaymakers in the refinement and further development of the mISkin app through usability (ease-of-use) and acceptability testing of the intervention prototype. All 17 participants were satisfied with the mISkin prototype and expressed willingness to use it. Feedback on the app was integrated in the optimization process of the mISkin app. The mISkin app was designed to promote sun-protection among holidaymakers and was based on current evidence, experts' knowledge and experience, and user involvement. Based on user feedback, the app has been refined and a fully functional version is ready for formal testing in a feasibility pilot study. ©Angela M Rodrigues, Falko F Sniehotta, Mark A Birch-Machin, Patrick Olivier, Vera Araújo-Soares. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 12.06.2017.

TEAMS (Tele-Exercise and Multiple Sclerosis), a Tailored Telerehabilitation mHealth App: Participant-Centered Development and Usability Study.

PubMed

Thirumalai, Mohanraj; Rimmer, James H; Johnson, George; Wilroy, Jereme; Young, Hui-Ju; Mehta, Tapan; Lai, Byron

2018-05-24

People with multiple sclerosis face varying levels of disability and symptoms, thus requiring highly trained therapists and/or exercise trainers to design personalized exercise programs. However, for people living in geographically isolated communities, access to such trained professionals can be challenging due to a number of barriers associated with cost, access to transportation, and travel distance. Generic mobile health exercise apps often fall short of what people with multiple sclerosis need to become physically active (ie, exercise content that has been adapted to accommodate a wide range of functional limitations). This usability study describes the development process of the TEAMS (Tele-Exercise and Multiple Sclerosis) app, which is being used by people with multiple sclerosis in a large randomized controlled trial to engage in home-based telerehabilitation. Twenty-one participants with disabilities (10 people with multiple sclerosis) were involved in the double iterative design, which included the simultaneous development of the app features and exercise content (exercise videos and articles). Framed within a user-centered design approach, the development process included 2 stages: ground-level creation (focus group followed by early stage evaluations and developments), and proof of concept through 2 usability tests. Usability (effectiveness, usefulness, and satisfaction) was evaluated using a mixed-methods approach. During testing of the app's effectiveness, the second usability test resulted in an average of 1 problem per participant, a decrease of 53% compared to the initial usability test. Five themes were constructed from the qualitative data that related to app usefulness and satisfaction, namely: high perceived confidence for app usability, positive perceptions of exercise videos, viable exercise option at home, orientation and familiarity required for successful participation, and app issues. Participants acknowledged that the final app was ready to be delivered to the public after minor revisions. After including these revisions, the project team released the final app that is being used in the randomized controlled trial. A multi-level user-centered development process resulted in the development of an inclusive exercise program for people with multiple sclerosis operated through an easy-to-use app. The promotion of exercise through self-regulated mHealth programs requires a stakeholder-driven approach to app development. This ensures that app and content match the preferences and functional abilities of the end user (ie, people with varying levels of multiple sclerosis). ©Mohanraj Thirumalai, James H Rimmer, George Johnson, Jereme Wilroy, Hui-Ju Young, Tapan Mehta, Byron Lai. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 24.05.2018.

Herpes simplex virus interferes with amyloid precursor protein processing.

PubMed

Shipley, Suzanne J; Parkin, Edward T; Itzhaki, Ruth F; Dobson, Curtis B

2005-08-18

The early events underlying Alzheimer's disease (AD) remain uncertain, although environmental factors may be involved. Work in this laboratory has shown that the combination of herpes simplex virus type 1 (HSV1) in brain and carriage of the APOE-epsilon4 allele of the APOE gene strongly increases the risk of developing AD. The development of AD is thought to involve abnormal aggregation or deposition of a 39-43 amino acid protein--beta amyloid (Abeta)--within the brain. This is cleaved from the much larger transmembranal protein 'amyloid precursor protein' (APP). Any agent able to interfere directly with Abeta or APP metabolism may therefore have the capacity to contribute towards AD. One recent report showed that certain HSV1 glycoprotein peptides may aggregate like Abeta; a second study described a role for APP in transport of virus in squid axons. However to date the effects of acute herpesvirus infection on metabolism of APP in human neuronal-type cells have not been investigated. In order to find if HSV1 directly affects APP and its degradation, we have examined this protein from human neuroblastoma cells (normal and transfected with APP 695) infected with the virus, using Western blotting. We have found that acute HSV1 (and also HSV2) infection rapidly reduces full length APP levels--as might be expected--yet surprisingly markedly increases levels of a novel C-terminal fragment of APP of about 55 kDa. This band was not increased in cells treated with the protein synthesis inhibitor cycloheximide Herpes virus infection leads to rapid loss of full length APP from cells, yet also causes increased levels of a novel 55 kDa C-terminal APP fragment. These data suggest that infection can directly alter the processing of a transmembranal protein intimately linked to the aetiology of AD.

Amyloid Precursor Protein Processing and Alzheimer’s Disease

PubMed Central

O’Brien, Richard J.; Wong, Philip C.

2011-01-01

Alzheimer’s disease (AD), the leading cause of dementia worldwide, is characterized by the accumulation of the β-amyloid peptide (Aβ) within the brain along with hyperphosphorylated and cleaved forms of the microtubule-associated protein tau. Genetic, biochemical, and behavioral research suggest that physiologic generation of the neurotoxic Aβ peptide from sequential amyloid precursor protein (APP) proteolysis is the crucial step in the development of AD. APP is a single-pass transmembrane protein expressed at high levels in the brain and metabolized in a rapid and highly complex fashion by a series of sequential proteases, including the intramembranous γ-secretase complex, which also process other key regulatory molecules. Why Aβ accumulates in the brains of elderly individuals is unclear but could relate to changes in APP metabolism or Aβ elimination. Lessons learned from biochemical and genetic studies of APP processing will be crucial to the development of therapeutic targets to treat AD. PMID:21456963

An app for patient education and self-audit within an enhanced recovery program for bowel surgery: a pilot study assessing validity and usability.

PubMed

Pecorelli, Nicolò; Fiore, Julio F; Kaneva, Pepa; Somasundram, Abarna; Charlebois, Patrick; Liberman, A Sender; Stein, Barry L; Carli, Franco; Feldman, Liane S

2018-05-01

While patient engagement and clinical audit are key components of successful enhanced recovery programs (ERPs), they require substantial resource allocation. The objective of this study was to assess the validity and usability of a novel mobile device application for education and self-reporting of adherence for patients undergoing bowel surgery within an established ERP. Prospectively recruited patients undergoing bowel surgery within an ERP used a novel app specifically designed to provide daily recovery milestones and record adherence to 15 different ERP processes and six patient-reported outcomes (PROs). Validity was measured by the agreement index (Cohen's kappa coefficient for categorical, and interclass correlation coefficient (ICC) for continuous variables) between patient-reported data through the app and data recorded by a clinical auditor. Acceptability and usability of the app were measured by the System Usability Scale (SUS). Forty-five patients participated in the study (mean age 61, 64% male). Overall, patients completed 159 of 179 (89%) of the available questionnaires through the app. Median time to complete a questionnaire was 2 min 49 s (i.q.r. 2'32″-4'36″). Substantial (kappa > 0.6) or almost perfect agreement (kappa > 0.8) and strong correlation (ICC > 0.7) between data collected through the app and by the clinical auditor was found for 14 ERP processes and four PROs. Patient-reported usability was high; mean SUS score was 87 (95% CI 83-91). Only 6 (13%) patients needed technical support to use the app. Forty (89%) patients found the app was helpful to achieve their daily goals, and 34 (76%) thought it increased their motivation to recover after surgery. This novel application provides a tool to record patient adherence to care processes and PROs, with high agreement with traditional clinical audit, high usability, and patient satisfaction. Future studies should investigate the use of mobile device apps as strategies to increase adherence to perioperative interventions.

The Cognitive Processing of an Educational App with Electroencephalogram and "Eye Tracking"

ERIC Educational Resources Information Center

Cuesta-Cambra, Ubaldo; Niño-González, José Ignacio; Rodríguez-Terceño, José

2017-01-01

The use of apps in education is becoming more frequent. However, the mechanisms of attention and processing of their contents and their consequences in learning have not been sufficiently studied. The objective of this work is to analyze how information is processed and learned and how visual attention takes place. It also investigates the…

Analysis of the amyloid precursor protein role in neuritogenesis reveals a biphasic SH-SY5Y neuronal cell differentiation model.

PubMed

da Rocha, Joana Fernandes; da Cruz e Silva, Odete A B; Vieira, Sandra Isabel

2015-07-01

The existence of an intrinsic programme controlling neuritogenesis and activated during early neuronal differentiation and regeneration stages is well established. However, the identity and role of each molecular player and event, as well as how such a programme is modified by environmental signals, remain a focus of research. The amyloid precursor protein (APP) is a neuromodulator of the developing and mature nervous system, although in a highly complex manner which is far from clear. To study APP-induced neuritogenesis, the retinoic acid (RA)-induced SH-SY5Y cell differentiation model was first minutely characterized in terms of RA dose, morphological outputs and relevant biochemical markers. The findings reported here unveiled two differentiation phases for the 10 μM RA dose: 1-4 (4 days excluded) and 4-8 days, clearly defined by fold increases in the ratio between APP and acetylated Tubulin. Moreover, we describe, for the first time, a unique peak of secreted APP (sAPP)/APP ratio in the first phase. Subsequent APP and sAPP modulations confirmed that a high sAPP/APP ratio potentiates the elongation of smaller processes at the earlier neuritogenic phase. This sAPP/APP ratio drops in the second phase, as holoAPP levels increase to assist the maintenance of the longer neurites, potentially via their stabilization. © 2015 International Society for Neurochemistry.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Enciso, Marta, E-mail: m.enciso@latrobe.edu.au; Schütte, Christof, E-mail: schuette@zib.de; Zuse Institute Berlin, Berlin

We employ a recently developed coarse-grained model for peptides and proteins where the effect of pH is automatically included. We explore the effect of pH in the aggregation process of the amyloidogenic peptide KTVIIE and two related sequences, using three different pH environments. Simulations using large systems (24 peptides chains per box) allow us to describe the formation of realistic peptide aggregates. We evaluate the thermodynamic and kinetic implications of changes in sequence and pH upon peptide aggregation, and we discuss how a minimalistic coarse-grained model can account for these details.

Inhibitory effects of magnolol and honokiol on human calcitonin aggregation

PubMed Central

Guo, Caiao; Ma, Liang; Zhao, Yudan; Peng, Anlin; Cheng, Biao; Zhou, Qiaoqiao; Zheng, Ling; Huang, Kun

2015-01-01

Amyloid formation is associated with multiple amyloidosis diseases. Human calcitonin (hCT) is a typical amyloidogenic peptide, its aggregation is associated with medullary carcinoma of the thyroid (MTC), and also limits its clinical application. Magnolia officinalis is a traditional Chinese herbal medicine; its two major polyphenol components, magnolol (Mag) and honokiol (Hon), have displayed multiple functions. Polyphenols like flavonoids and their derivatives have been extensively studied as amyloid inhibitors. However, the anti-amyloidogenic property of a biphenyl backbone containing polyphenols such as Mag and Hon has not been reported. In this study, these two compounds were tested for their effects on hCT aggregation. We found that Mag and Hon both inhibited the amyloid formation of hCT, whereas Mag showed a stronger inhibitory effect; moreover, they both dose-dependently disassembled preformed hCT aggregates. Further immuno-dot blot and dynamic light scattering studies suggested Mag and Hon suppressed the aggregation of hCT both at the oligomerization and the fibrillation stages, while MTT-based and dye-leakage assays demonstrated that Mag and Hon effectively reduced cytotoxicity caused by hCT aggregates. Furthermore, isothermal titration calorimetry indicated Mag and Hon both interact with hCT. Together, our study suggested a potential anti-amyloidogenic property of these two compounds and their structure related derivatives. PMID:26324190

Cations as switches of amyloid-mediated membrane disruption mechanisms: calcium and IAPP.

PubMed

Sciacca, Michele F M; Milardi, Danilo; Messina, Grazia M L; Marletta, Giovanni; Brender, Jeffrey R; Ramamoorthy, Ayyalusamy; La Rosa, Carmelo

2013-01-08

Disruption of the integrity of the plasma membrane by amyloidogenic proteins is linked to the pathogenesis of a number of common age-related diseases. Although accumulating evidence suggests that adverse environmental stressors such as unbalanced levels of metal ions may trigger amyloid-mediated membrane damage, many features of the molecular mechanisms underlying these events are unknown. Using human islet amyloid polypeptide (hIAPP, aka amylin), an amyloidogenic peptide associated with β-cell death in type 2 diabetes, we demonstrate that the presence of Ca(2+) ions inhibits membrane damage occurring immediately after the interaction of freshly dissolved hIAPP with the membrane, but significantly enhances fiber-dependent membrane disruption. In particular, dye leakage, quartz crystal microbalance, atomic force microscopy, and NMR experiments show that Ca(2+) ions promote a shallow membrane insertion of hIAPP, which leads to the removal of lipids from the bilayer through a detergent-like mechanism triggered by fiber growth. Because both types of membrane-damage mechanisms are common to amyloid toxicity by most amyloidogenic proteins, it is likely that unregulated ion homeostasis, amyloid aggregation, and membrane disruption are all parts of a self-perpetuating cycle that fuels amyloid cytotoxicity. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Chain Collapse of an Amyloidogenic Intrinsically Disordered Protein

PubMed Central

Jain, Neha; Bhattacharya, Mily; Mukhopadhyay, Samrat

2011-01-01

Natively unfolded or intrinsically disordered proteins (IDPs) are under intense scrutiny due to their involvement in both normal biological functions and abnormal protein misfolding disorders. Polypeptide chain collapse of amyloidogenic IDPs is believed to play a key role in protein misfolding, oligomerization, and aggregation leading to amyloid fibril formation, which is implicated in a number of human diseases. In this work, we used bovine κ-casein, which serves as an archetypal model protein for amyloidogenic IDPs. Using a variety of biophysical tools involving both prediction and spectroscopic techniques, we first established that monomeric κ-casein adopts a collapsed premolten-globule-like conformational ensemble under physiological conditions. Our time-resolved fluorescence and light-scattering data indicate a change in the mean hydrodynamic radius from ∼4.6 nm to ∼1.9 nm upon chain collapse. We then took the advantage of two cysteines separated by 77 amino-acid residues and covalently labeled them using thiol-reactive pyrene maleimide. This dual-labeled protein demonstrated a strong excimer formation upon renaturation from urea- and acid-denatured states under both equilibrium and kinetic conditions, providing compelling evidence of polypeptide chain collapse under physiological conditions. The implication of the IDP chain collapse in protein aggregation and amyloid formation is also discussed. PMID:21961598

Mechanism of insulin fibrillation: the structure of insulin under amyloidogenic conditions resembles a protein-folding intermediate.

PubMed

Hua, Qing-xin; Weiss, Michael A

2004-05-14

Insulin undergoes aggregation-coupled misfolding to form a cross-beta assembly. Such fibrillation has long complicated its manufacture and use in the therapy of diabetes mellitus. Of interest as a model for disease-associated amyloids, insulin fibrillation is proposed to occur via partial unfolding of a monomeric intermediate. Here, we describe the solution structure of human insulin under amyloidogenic conditions (pH 2.4 and 60 degrees C). Use of an enhanced sensitivity cryogenic probe at high magnetic field avoids onset of fibrillation during spectral acquisition. A novel partial fold is observed in which the N-terminal segments of the A- and B-chains detach from the core. Unfolding of the N-terminal alpha-helix of the A-chain exposes a hydrophobic surface formed by native-like packing of the remaining alpha-helices. The C-terminal segment of the B-chain, although not well ordered, remains tethered to this partial helical core. We propose that detachment of N-terminal segments makes possible aberrant protein-protein interactions in an amyloidogenic nucleus. Non-cooperative unfolding of the N-terminal A-chain alpha-helix resembles that observed in models of proinsulin folding intermediates and foreshadows the extensive alpha --> beta transition characteristic of mature fibrils.

Nicergoline stimulates protein kinase C mediated alpha-secretase processing of the amyloid precursor protein in cultured human neuroblastoma SH-SY5Y cells.

PubMed

Cedazo-Minguez, A; Bonecchi, L; Winblad, B; Post, C; Wong, E H; Cowburn, R F; Benatti, L

1999-10-01

We investigated the ability of the antidementia agents, nicergoline, aniracetam and hydergine to stimulate PKC mediated alpha-secretase amyloid precursor protein (APP) processing in cultured human neuroblastoma SH-SY5Y cells. Western immunoblotting of cell conditioned media using the Mabs 22C11 and 6E10 revealed the presence of 2 bands with molecular mass of 90 and 120 kDa, corresponding to possible alternatively glycosylated forms of secreted APP (APPs). Short-term (30 min and 2 h) treatment of cells with nicergoline gave an increased intensity of both bands, compared to non-treated cells. Maximal nicergoline effects, of the order of 150-200% over basal APPs release, were seen at concentrations between 1 and 10 microM. Under the same condition, 1 microM PdBu, used as a positive control, gave 500-1000% increases of basal APPs release. In contrast, aniracetam and hydergine, did not show any effect on APPs secretion. 2 h treatment with nicergoline had no effect on cellular full-length APP levels, as determined by immunoblotting of cell extracts with 22C11 and CT15 antibodies. Immunoblotting with PKC isoform specific antibodies of soluble and membrane fractions prepared from 2 h treated cells, showed that nicergoline (50 microM) and PdBu (1 microM) both induced translocation of PKC alpha, gamma and epsilon, but not PKC beta. The involvement of PKC in mediating nicergoline stimulated APPs release was also studied using specific inhibitors. 1 microM calphostin C, a broad range PKC inhibitor, significantly reduced both PdBu (1 microM) and nicergoline (10 microM) induced APPs release. In contrast, Go6976 (1 microM), a selective PKC alpha and beta1 inhibitor, as well as the cAMP-dependent protein kinase inhibitor, H89 (1 microM) were without effect. These results indicate that nicergoline can modulate alpha-secretase APP processing by a PKC dependent mechanism that is likely to involve the gamma and epsilon isoforms of this enzyme.

A Standards-Based Architecture Proposal for Integrating Patient mHealth Apps to Electronic Health Record Systems

PubMed Central

Fontelo, P.; Rossi, E.; Ackerman, MJ

2015-01-01

Summary Background Mobile health Applications (mHealth Apps) are opening the way to patients’ responsible and active involvement with their own healthcare management. However, apart from Apps allowing patient’s access to their electronic health records (EHRs), mHealth Apps are currently developed as dedicated “island systems”. Objective Although much work has been done on patient’s access to EHRs, transfer of information from mHealth Apps to EHR systems is still low. This study proposes a standards-based architecture that can be adopted by mHealth Apps to exchange information with EHRs to support better quality of care. Methods Following the definition of requirements for the EHR/mHealth App information exchange recently proposed, and after reviewing current standards, we designed the architecture for EHR/mHealth App integration. Then, as a case study, we modeled a system based on the proposed architecture aimed to support home monitoring for congestive heart failure patients. We simulated such process using, on the EHR side, OpenMRS, an open source longitudinal EHR and, on the mHealth App side, the iOS platform. Results The integration architecture was based on the bi-directional exchange of standard documents (clinical document architecture rel2 – CDA2). In the process, the clinician “prescribes” the home monitoring procedures by creating a CDA2 prescription in the EHR that is sent, encrypted and de-identified, to the mHealth App to create the monitoring calendar. At the scheduled time, the App alerts the patient to start the monitoring. After the measurements are done, the App generates a structured CDA2-compliant monitoring report and sends it to the EHR, thus avoiding local storage. Conclusions The proposed architecture, even if validated only in a simulation environment, represents a step forward in the integration of personal mHealth Apps into the larger health-IT ecosystem, allowing the bi-directional data exchange between patients and healthcare professionals, supporting the patient’s engagement in self-management and self-care. PMID:26448794

Expert Involvement Predicts mHealth App Downloads: Multivariate Regression Analysis of Urology Apps

PubMed Central

Osório, Luís; Cavadas, Vitor; Fraga, Avelino; Carrasquinho, Eduardo; Cardoso de Oliveira, Eduardo; Castelo-Branco, Miguel; Roobol, Monique J

2016-01-01

Background Urological mobile medical (mHealth) apps are gaining popularity with both clinicians and patients. mHealth is a rapidly evolving and heterogeneous field, with some urology apps being downloaded over 10,000 times and others not at all. The factors that contribute to medical app downloads have yet to be identified, including the hypothetical influence of expert involvement in app development. Objective The objective of our study was to identify predictors of the number of urology app downloads. Methods We reviewed urology apps available in the Google Play Store and collected publicly available data. Multivariate ordinal logistic regression evaluated the effect of publicly available app variables on the number of apps being downloaded. Results Of 129 urology apps eligible for study, only 2 (1.6%) had >10,000 downloads, with half having ≤100 downloads and 4 (3.1%) having none at all. Apps developed with expert urologist involvement (P=.003), optional in-app purchases (P=.01), higher user rating (P<.001), and more user reviews (P<.001) were more likely to be installed. App cost was inversely related to the number of downloads (P<.001). Only data from the Google Play Store and the developers’ websites, but not other platforms, were publicly available for analysis, and the level and nature of expert involvement was not documented. Conclusions The explicit participation of urologists in app development is likely to enhance its chances to have a higher number of downloads. This finding should help in the design of better apps and further promote urologist involvement in mHealth. Official certification processes are required to ensure app quality and user safety. PMID:27421338

Quality of Publicly Available Physical Activity Apps: Review and Content Analysis

PubMed Central

Alkhaldi, Ghadah; Slee, April; Hamilton, Fiona L; Murray, Elizabeth

2018-01-01

Background Within the new digital health landscape, the rise of health apps creates novel prospects for health promotion. The market is saturated with apps that aim to increase physical activity (PA). Despite the wide distribution and popularity of PA apps, there are limited data on their effectiveness, user experience, and safety of personal data. Objective The purpose of this review and content analysis was to evaluate the quality of the most popular PA apps on the market using health care quality indicators. Methods The top-ranked 400 free and paid apps from iTunes and Google Play stores were screened. Apps were included if the primary behavior targeted was PA, targeted users were adults, and the apps had stand-alone functionality. The apps were downloaded on mobile phones and assessed by 2 reviewers against the following quality assessment criteria: (1) users’ data privacy and security, (2) presence of behavior change techniques (BCTs) and quality of the development and evaluation processes, and (3) user ratings and usability. Results Out of 400 apps, 156 met the inclusion criteria, of which 65 apps were randomly selected to be downloaded and assessed. Almost 30% apps (19/65) did not have privacy policy. Every app contained at least one BCT, with an average number of 7 and a maximum of 13 BCTs. All but one app had commercial affiliation, 12 consulted an expert, and none reported involving users in the app development. Only 12 of 65 apps had a peer-reviewed study connected to the app. User ratings were high, with only a quarter of the ratings falling below 4 stars. The median usability score was excellent—86.3 out of 100. Conclusions Despite the popularity of PA apps available on the commercial market, there were substantial shortcomings in the areas of data safety and likelihood of effectiveness of the apps assessed. The limited quality of the apps may represent a missed opportunity for PA promotion. PMID:29563080

Mobile Apps to Support and Assess Foreign Language Learning

ERIC Educational Resources Information Center

Berns, Anke; Palomo-Duarte, Manuel; Dodero, Juan Manuel; Ruiz-Ladrón, Juan Miguel; Márquez, Andrea Calderón

2015-01-01

In the last two decades there have been many attempts to integrate all kinds of mobile devices and apps to support formal as well as informal learning processes. However, most of the available apps still support mainly individual learning, using mobile devices to deliver content rather than providing learners with the opportunity to interact with…

Co-Designing Mobile Apps to Assist in Clinical Nursing Education: A Study Protocol.

PubMed

O'Connor, Siobhan; Andrews, Tom

2016-01-01

Mobile applications (apps) to train health professionals is gaining momentum as the benefits of mobile learning (mLearning) are becoming apparent in complex clinical environments. However, most educational apps are generic, off-the-shelf pieces of software that do not take into consideration the unique needs of nursing students. The proposed study will apply a user-centred design process to create a tailored mobile app for nursing students to learn and apply clinical skills in practice. The app will be piloted and evaluated to understand how nursing students use mobile technology in clinical settings to support their learning and educational needs.

Suppression of angiogenesis by atmospheric pressure plasma in human aortic endothelial cells

NASA Astrophysics Data System (ADS)

Gweon, Bomi; Kim, Hyeonyu; Kim, Kijung; Kim, Mina; Shim, Eunyoung; Kim, Sunja; Choe, Wonho; Shin, Jennifer H.

2014-03-01

Atmospheric pressure plasma (APP) has been recognized as a promising tool for cancer therapy based on its ability to remove cancer cells by causing apoptosis and necrosis. However, the effect of APP on the neighboring tissues of tumors remains unknown. Moreover, the role of APP on the vessels near tumors could be very important, because once a tumor becomes vascularized, the potential for metastasis can increase dramatically. We show in the present study that APP can induce cell cycle arrest in endothelial cells and further suppress the angiogenesis process. These results strongly support the use of APP in cancer treatment.

APP metabolism regulates tau proteostasis in human cerebral cortex neurons.

PubMed

Moore, Steven; Evans, Lewis D B; Andersson, Therese; Portelius, Erik; Smith, James; Dias, Tatyana B; Saurat, Nathalie; McGlade, Amelia; Kirwan, Peter; Blennow, Kaj; Hardy, John; Zetterberg, Henrik; Livesey, Frederick J

2015-05-05

Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer's disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Patient characteristics and process factors associated with antipsychotic polypharmacy in a nationwide sample of psychiatric inpatients in Italy.

PubMed

Santone, Giovanni; Bellantuono, Cesario; Rucci, Paola; Picardi, Angelo; Preti, Antonio; de Girolamo, Giovanni

2011-05-01

The present study investigated: (i) the rate of prescription of antipsychotic (AP) polypharmacy (APP) in a large, representative sample of psychiatric inpatients; and (ii) the relationship between APP prescription and the characteristics of patients and facilities. The sample included 1022 psychiatric patients scheduled to be discharged from acute inpatient facilities with drug therapies including AP. Demographic and clinical data were obtained from the treating physician or retrieved from patients' records through a standardized Patient Form. Patients were administered the 24-item Brief Psychiatric Rating Scale. Three indicators were used to describe the process of care in the facilities: a Restrictiveness score, a Standardization score, and a Treatment score. A multilevel mixed-effect logistic regression was used to predict APP using patient and facility as the variables. APP was prescribed to 333 (32.5%) patients, the most common patterns being a first-generation and a second-generation AP (n = 178, 17.6%) or of two first-generation APs (n = 80, 7.8%). Patients with a diagnosis of schizophrenia and poorer insight into illness at admission were significantly more likely to receive APP. The availability of more complex therapeutic interventions in the facility was also associated with APP. In our nationwide sample of psychiatric inpatients, APP was frequently prescribed to treat the more severe patients. However, it was also associated with process of care characteristics such as delivery of more complex therapeutic interventions, and was therefore not used only to control patient behavior. Copyright © 2010 John Wiley & Sons, Ltd.

An Aberrant Phosphorylation of Amyloid Precursor Protein Tyrosine Regulates Its Trafficking and the Binding to the Clathrin Endocytic Complex in Neural Stem Cells of Alzheimer's Disease Patients

PubMed Central

Poulsen, Ebbe T.; Iannuzzi, Filomena; Rasmussen, Helle F.; Maier, Thorsten J.; Enghild, Jan J.; Jørgensen, Arne L.; Matrone, Carmela

2017-01-01

Alzheimer's disease (AD) is the most common cause of dementia and is likely caused by defective amyloid precursor protein (APP) trafficking and processing in neurons leading to amyloid plaques containing the amyloid-β (Aβ) APP peptide byproducts. Understanding how APP is targeted to selected destinations inside neurons and identifying the mechanisms responsible for the generation of Aβ are thus the keys for the advancement of new therapies. We previously developed a mouse model with a mutation at tyrosine (Tyr) 682 in the C-terminus of APP. This residue is needed for APP to bind to the coating protein Clathrin and to the Clathrin adaptor protein AP2 as well as for the correct APP trafficking and sorting in neurons. By extending these findings to humans, we found that APP binding to Clathrin is decreased in neural stem cells from AD sufferers. Increased APP Tyr phosphorylation alters APP trafficking in AD neurons and it is associated to Fyn Tyr kinase activation. We show that compounds affecting Tyr kinase activity and counteracting defects in AD neurons can control APP location and compartmentalization. APP Tyr phosphorylation is thus a potential therapeutic target for AD. PMID:28360834

Mobile phone applications in Parkinson's disease: A systematic review.

PubMed

Linares-Del Rey, M; Vela-Desojo, L; Cano-de la Cuerda, R

2017-05-23

Parkinson's disease (PD) is the second most common neurodegenerative disease. However, diagnosing, assessing, and treating these patients is a complex process requiring continuous monitoring. In this context, smartphones may be useful in the management of patients with PD. The purpose of this study is to perform a systematic review of the literature addressing the use of mobile phone applications (apps) in PD. We conducted a literature search of articles published in English or Spanish between 2011 and 2016 analysing or validating apps specifically designed for or useful in PD. In addition, we searched for apps potentially useful for PD patients in the leading app stores. The literature and app searches yielded a total of 125 apps, 56 of which were classified as potentially useful in PD and 69 as specifically designed for PD (23 information apps, 29 assessment apps, 13 treatment apps, and 4 assessment and treatment apps). Numerous mobile apps are potentially useful in or specifically designed for PD management. However, scientific evidence of their usefulness is scarce and of poor quality. Further studies are needed to validate these tools and regulate their use. Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Popularity Modeling for Mobile Apps: A Sequential Approach.

PubMed

Zhu, Hengshu; Liu, Chuanren; Ge, Yong; Xiong, Hui; Chen, Enhong

2015-07-01

The popularity information in App stores, such as chart rankings, user ratings, and user reviews, provides an unprecedented opportunity to understand user experiences with mobile Apps, learn the process of adoption of mobile Apps, and thus enables better mobile App services. While the importance of popularity information is well recognized in the literature, the use of the popularity information for mobile App services is still fragmented and under-explored. To this end, in this paper, we propose a sequential approach based on hidden Markov model (HMM) for modeling the popularity information of mobile Apps toward mobile App services. Specifically, we first propose a popularity based HMM (PHMM) to model the sequences of the heterogeneous popularity observations of mobile Apps. Then, we introduce a bipartite based method to precluster the popularity observations. This can help to learn the parameters and initial values of the PHMM efficiently. Furthermore, we demonstrate that the PHMM is a general model and can be applicable for various mobile App services, such as trend based App recommendation, rating and review spam detection, and ranking fraud detection. Finally, we validate our approach on two real-world data sets collected from the Apple Appstore. Experimental results clearly validate both the effectiveness and efficiency of the proposed popularity modeling approach.

A Smartphone App for Adolescents With Sleep Disturbance: Development of the Sleep Ninja.

PubMed

Werner-Seidler, Aliza; O'Dea, Bridianne; Shand, Fiona; Johnston, Lara; Frayne, Anna; Fogarty, Andrea S; Christensen, Helen

2017-07-28

Sleep disturbances are common in young people and have consequences for academic, social, emotional, and behavioral development. The most effective treatment is cognitive behavioral therapy for insomnia (CBT-I), with evidence suggesting that it is efficacious even when delivered digitally. There are no commercially available digitally delivered CBT-I programs for use by young people. The aim of this project was to develop a smartphone app that delivers CBT-I to young people to improve sleep. To inform the development of the app, young people (N=21) aged between 12 and 16 years attended one of the 3 focus groups (each with 4-10 participants). These focus groups were conducted at different stages of the development process such that the process could be iterative. Participants were asked the reasons why they might use an app to help them sleep, the kinds of features or functions that they would like to see in such an app, and any concerns they may have in using the app. Data were analyzed using a thematic analysis approach. Of the issues discussed by the participants, the researchers selected themes associated with content, functionality, and accessibility and user experience to examine, as these were most informative for the app design process. In terms of content, young people were interested in receiving information about recommended sleep guidelines and personalized information for their age group. They reported that keeping a sleep diary was acceptable, but they should be able to complete it flexibly, in their own time. They reported mixed views about the use of the phone's accelerometer. Young people felt that the functionality of the app should include elements of game playing if they were to remain engaged with the app. Flexibility of use and personalized features were also desirable, and there were mixed views about the schedule of notifications and reminders. Participants reported that for the app to be accessible and usable, it should be from a trusted developer, have engaging aesthetics, have a layout that is easy to navigate, not rely on Internet coverage, and preferably be free. Participants felt that being able to conceal the purpose of the app from peers was an advantage and were willing to provide personal information to use the app if the purpose and use of that information was made clear. Overall, participants endorsed the use of the app for sleep problems among their age group and reported motivation to use it. The Sleep Ninja is a fully-automated app that delivers CBT-I to young people, incorporating the features and information that young people reported they would expect from this app. A pilot study testing the feasibility, acceptability, and efficacy of the Sleep Ninja is now underway. ©Aliza Werner-Seidler, Bridianne O'Dea, Fiona Shand, Lara Johnston, Anna Frayne, Andrea S Fogarty, Helen Christensen. Originally published in JMIR Mental Health (http://mental.jmir.org), 28.07.2017.

Amyloid precursor protein regulates migration and metalloproteinase gene expression in prostate cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miyazaki, Toshiaki; Ikeda, Kazuhiro; Horie-Inoue, Kuniko

Highlights: • APP knockdown reduced proliferation and migration of prostate cancer cells. • APP knockdown reduced expression of metalloproteinase and EMT-related genes. • APP overexpression promoted LNCaP cell migration. • APP overexpression increased expression of metalloproteinase and EMT-related genes. - Abstract: Amyloid precursor protein (APP) is a type I transmembrane protein, and one of its processed forms, β-amyloid, is considered to play a central role in the development of Alzheimer’s disease. We previously showed that APP is a primary androgen-responsive gene in prostate cancer and that its increased expression is correlated with poor prognosis for patients with prostate cancer. APPmore » has also been implicated in several human malignancies. Nevertheless, the mechanism underlying the pro-proliferative effects of APP on cancers is still not well-understood. In the present study, we explored a pathophysiological role for APP in prostate cancer cells using siRNA targeting APP (siAPP). The proliferation and migration of LNCaP and DU145 prostate cancer cells were significantly suppressed by siAPP. Differentially expressed genes in siAPP-treated cells compared to control siRNA-treated cells were identified by microarray analysis. Notably, several metalloproteinase genes, such as ADAM10 and ADAM17, and epithelial–mesenchymal transition (EMT)-related genes, such as VIM, and SNAI2, were downregulated in siAPP-treated cells as compared to control cells. The expression of these genes was upregulated in LNCaP cells stably expressing APP when compared with control cells. APP-overexpressing LNCaP cells exhibited enhanced migration in comparison to control cells. These results suggest that APP may contribute to the proliferation and migration of prostate cancer cells by modulating the expression of metalloproteinase and EMT-related genes.« less

Development of a Mobile App for Family Planning Providers.

PubMed

Halsall, Viannella; Rogers, Jennifer; Witt, Jacki; Song, Sejun; Nguyen, Hoang Duc Huy; Kelly, Patricia

To provide an overview of lessons learned during the development process of an app for iOS and Android based on national recommendations for providing quality family planning services. After a review of existing apps was conducted to determine whether an app of clinical recommendations for family planning existed, a team of clinicians, training specialists, and app developers created a resource app by first drafting a comprehensive content map. A prototype of the app was then pilot tested using smart tablets by a volunteer convenience sample of women's healthcare professionals. Outcomes measured included usability, acceptability, download analytics, and satisfaction by clinicians as reported through an investigator-developed tool. Sixty-nine professionals tested a prototype of the app, and completed a user satisfaction tool. Overall, user feedback was positive, and a zoom function was added to the final version as a result of the pilot test. Within 3 months of being publicly available, the app was downloaded 677 times, with 97% of downloads occurring on smart phones, 76% downloads occurring on iOS devices, and 24% on Android devices. This trend persisted throughout the following 3 months. Clinicians with an interest in developing an app should consider a team approach to development, pilot test the app prior to wider distribution, and develop a web-based version of the app to be used by clinicians who are unable to access smart devices in their practice setting.

The Role of Gay Identity Confusion and Outness in Sex-Seeking on Mobile Dating Apps Among Men Who Have Sex With Men: A Conditional Process Analysis.

PubMed

Chan, Lik Sam

2017-01-01

Mobile dating apps are now a popular platform for men who have sex with men (MSM) to connect with others. Based on the uses and gratifications (U&G) theory, this study explores the relationship between sex-seeking and the number of casual sex partners met through MSM-based mobile dating apps (Grindr, Jack'd, and SCRUFF). The conditional process analysis (N = 401) shows that this relationship was significant and was mediated by the intensity of app use. That is, sex-seeking indirectly affected the number of casual sex partners through the intensity of app use. Furthermore, gay identity confusion and outness to the world moderated this indirect effect: it was stronger when the user was either more confused about his sexuality or was less out to the world. This research introduces an alternative way to incorporate psychographics variables into the U&G framework.

The use of atmospheric pressure plasma as a curing process for canned ground ham.

PubMed

Lee, Juri; Jo, Kyung; Lim, Yubong; Jeon, Hee Joon; Choe, Jun Ho; Jo, Cheorun; Jung, Samooel

2018-02-01

This study investigated the potential use of atmospheric pressure plasma (APP) treatment as a curing process for canned ground ham. APP treatment for 60min while mixing increased the nitrite content in the meat batters from 0.64 to 60.50mgkg -1 while the pH and the total content of aerobic bacteria in the meat batters were unchanged. The canned ground hams cured by the APP treatment for 30min displayed no difference in their physicochemical qualities, such as nitrosyl hemochrome, color, residual nitrite, texture, lipid oxidation, and protein oxidation, compared with those of canned ground hams cured with sodium nitrite or celery powder at 42mgkg -1 of nitrite. The canned ground hams cured by the APP treatment received a higher score in taste and overall acceptability than those cured with sodium nitrite. Canned ground ham can be cured by the APP treatment without nitrite additives. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of acetylate hyperforin on the processing of amyloid precursor protein

PubMed Central

Chen, Xiang; Feng, Wenshang; Chen, Qing; Yang, Xiangling; Yang, Depo; Wang, Dongmei; Zhong, Ling

2009-01-01

Hyperforin (HF) is a phloroglucinol compound obtained from St. John's Wort (Hypericum perforatum). Recent studies have shown that Hyperforin can be used to improve psychopathologic symptoms of Alzheimer's disease but the mechanism is not clear. This may be partly due to the difficult in studying Hyperforin, since this chemical is unstable and is sensitive to light, oxygen, and heat. In this study, we explored the effects of acetylate hyperforin (ace-HF), a stable derivative of hyperforin, on the processing of amyloid precursor protein (APP). HEK293 cells transfected with pcDNA3.1APP695sw and SH-SY5Y cells were treated with ace-HF, followed by measuring the levels of APP and sAPPα. Twelve hours of treatment led to an increase in extracellular sAPPα, but APP mRNA and protein levels were unchanged. Further studies with α-secretase and a pan PKC inhibitor, Calphostin C, indicated that ace-HF's effect on extracellular sAPPα was closely related to PKC activities and α-secretase activities. Our findings suggest that ace-HF can modulate α-secretase-mediated APP processing via a PKC signaling pathway. PMID:21383880

TEAMS (Tele-Exercise and Multiple Sclerosis), a Tailored Telerehabilitation mHealth App: Participant-Centered Development and Usability Study

PubMed Central

Rimmer, James H; Johnson, George; Wilroy, Jereme; Young, Hui-Ju; Mehta, Tapan; Lai, Byron

2018-01-01

Background People with multiple sclerosis face varying levels of disability and symptoms, thus requiring highly trained therapists and/or exercise trainers to design personalized exercise programs. However, for people living in geographically isolated communities, access to such trained professionals can be challenging due to a number of barriers associated with cost, access to transportation, and travel distance. Generic mobile health exercise apps often fall short of what people with multiple sclerosis need to become physically active (ie, exercise content that has been adapted to accommodate a wide range of functional limitations). Objective This usability study describes the development process of the TEAMS (Tele-Exercise and Multiple Sclerosis) app, which is being used by people with multiple sclerosis in a large randomized controlled trial to engage in home-based telerehabilitation. Methods Twenty-one participants with disabilities (10 people with multiple sclerosis) were involved in the double iterative design, which included the simultaneous development of the app features and exercise content (exercise videos and articles). Framed within a user-centered design approach, the development process included 2 stages: ground-level creation (focus group followed by early stage evaluations and developments), and proof of concept through 2 usability tests. Usability (effectiveness, usefulness, and satisfaction) was evaluated using a mixed-methods approach. Results During testing of the app’s effectiveness, the second usability test resulted in an average of 1 problem per participant, a decrease of 53% compared to the initial usability test. Five themes were constructed from the qualitative data that related to app usefulness and satisfaction, namely: high perceived confidence for app usability, positive perceptions of exercise videos, viable exercise option at home, orientation and familiarity required for successful participation, and app issues. Participants acknowledged that the final app was ready to be delivered to the public after minor revisions. After including these revisions, the project team released the final app that is being used in the randomized controlled trial. Conclusions A multi-level user-centered development process resulted in the development of an inclusive exercise program for people with multiple sclerosis operated through an easy-to-use app. The promotion of exercise through self-regulated mHealth programs requires a stakeholder-driven approach to app development. This ensures that app and content match the preferences and functional abilities of the end user (ie, people with varying levels of multiple sclerosis). PMID:29798832

The Na+/H+ exchanger NHE6 modulates endosomal pH to control processing of amyloid precursor protein in a cell culture model of Alzheimer disease.

PubMed

Prasad, Hari; Rao, Rajini

2015-02-27

Early intervention may be key to safe and effective therapies in patients with Alzheimer disease. Endosomal dysfunction is an early step in neurodegeneration. Endosomes are a major site of production of Aβ peptide from the processing of amyloid precursor protein (APP) by clipping enzymes (β- and γ-secretases). The β-secretase enzyme BACE1 requires acidic lumen pH for optimum function, and acid pH promotes Aβ aggregation. The Na(+)/H(+) exchanger NHE6 provides a leak pathway for protons, limiting luminal acidification by proton pumps. Like APP, NHE6 expression was induced upon differentiation of SH-SY5Y neuroblastoma cells and localized to an endosomal compartment. Therefore, we investigated whether NHE6 expression altered APP localization and processing in a stably transfected cell culture model of human APP expression. We show that co-expression with NHE6 or treatment with the Na(+)/H(+) ionophore monensin shifted APP away from the trans-Golgi network into early and recycling endosomes in HEK293 cells. NHE6 alkalinized the endosomal lumen, similar to monensin, and significantly attenuated APP processing and Aβ secretion. In contrast, Aβ production was elevated upon NHE6 knockdown. We show that NHE6 transcript and protein levels are lowered in Alzheimer brains relative to control. These findings, taken together with emerging genetic evidence linking endosomal Na(+)/H(+) exchangers with Alzheimer disease, suggest that proton leak pathways may regulate Aβ generation and contribute to disease etiology. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

The Na+/H+ Exchanger NHE6 Modulates Endosomal pH to Control Processing of Amyloid Precursor Protein in a Cell Culture Model of Alzheimer Disease*

PubMed Central

Prasad, Hari; Rao, Rajini

2015-01-01

Early intervention may be key to safe and effective therapies in patients with Alzheimer disease. Endosomal dysfunction is an early step in neurodegeneration. Endosomes are a major site of production of Aβ peptide from the processing of amyloid precursor protein (APP) by clipping enzymes (β- and γ-secretases). The β-secretase enzyme BACE1 requires acidic lumen pH for optimum function, and acid pH promotes Aβ aggregation. The Na+/H+ exchanger NHE6 provides a leak pathway for protons, limiting luminal acidification by proton pumps. Like APP, NHE6 expression was induced upon differentiation of SH-SY5Y neuroblastoma cells and localized to an endosomal compartment. Therefore, we investigated whether NHE6 expression altered APP localization and processing in a stably transfected cell culture model of human APP expression. We show that co-expression with NHE6 or treatment with the Na+/H+ ionophore monensin shifted APP away from the trans-Golgi network into early and recycling endosomes in HEK293 cells. NHE6 alkalinized the endosomal lumen, similar to monensin, and significantly attenuated APP processing and Aβ secretion. In contrast, Aβ production was elevated upon NHE6 knockdown. We show that NHE6 transcript and protein levels are lowered in Alzheimer brains relative to control. These findings, taken together with emerging genetic evidence linking endosomal Na+/H+ exchangers with Alzheimer disease, suggest that proton leak pathways may regulate Aβ generation and contribute to disease etiology. PMID:25561733

The low density lipoprotein receptor-related protein 1B retains beta-amyloid precursor protein at the cell surface and reduces amyloid-beta peptide production.

PubMed

Cam, Judy A; Zerbinatti, Celina V; Knisely, Jane M; Hecimovic, Silva; Li, Yonghe; Bu, Guojun

2004-07-09

The low density lipoprotein (LDL) receptor-related protein 1B (LRP1B) is a newly identified member of the LDL receptor family that shares high homology with the LDL receptor-related protein (LRP). LRP1B was originally described as a putative tumor suppressor in lung cancer cells; however, its expression profile in several regions of adult human brain suggests it may have additional functions in the central nervous system. Since LRP1B has overlapping ligand binding properties with LRP, we investigated whether LRP1B, like LRP, could interact with the beta-amyloid precursor protein (APP) and modulate its processing to amyloid-beta peptides (Abetas). Using an LRP1B minireceptor (mLRP1B4) generated to study the trafficking of LRP1B, we found that mLRP1B4 and APP form an immunoprecipitable complex. Furthermore mLRP1B4 bound and facilitated the degradation of a soluble isoform of APP containing a Kunitz proteinase inhibitor domain but not soluble APP lacking a Kunitz proteinase inhibitor domain. A functional consequence of mLRP1B4 expression was a significant accumulation of APP at the cell surface, which is likely related to the slow endocytosis rate of LRP1B. More importantly, mLRP1B4-expressing cells that accumulated cell surface APP produced less Abeta and secreted more soluble APP. These findings reveal that LRP1B is a novel binding partner of APP that functions to decrease APP processing to Abeta. Consequently LRP1B expression could function to protect against the pathogenesis of Alzheimer's disease.

There’s an App for That: A Guide for Healthcare Practitioners and Researchers on Smartphone Technology

PubMed Central

Trevena, Lyndal

2015-01-01

Smartphone technology is nascent compared to other technologies; however, it has shown an unprecedented uptake amongst lay consumers and professionals. This article presents the history, components, and key features of smartphones, as well as their related concepts and how they work, and it also delineates the process of smartphone applications (apps) development and publishing in the app stores. It also describes and discusses smartphone technology utilisation for health consumers, healthcare professionals, and health researchers, as well as the regulations of health-related apps. PMID:26392848

Use of and Beliefs About Mobile Phone Apps for Diabetes Self-Management: Surveys of People in a Hospital Diabetes Clinic and Diabetes Health Professionals in New Zealand.

PubMed

Boyle, Leah; Grainger, Rebecca; Hall, Rosemary M; Krebs, Jeremy D

2017-06-30

People with diabetes mellitus (DM) are using mobile phone apps to support self-management. The numerous apps available to assist with diabetes management have a variety of functions. Some functions, like insulin dose calculators, have significant potential for harm. The study aimed to establish (1) whether people with DM in Wellington, New Zealand, use apps for DM self-management and evaluate desirable features of apps and (2) whether health professionals (HPs) in New Zealand treating people with DM recommend apps to patients, the features HPs regard as important, and their confidence with recommending apps. A survey of patients seen at a hospital diabetes clinic over 12 months (N=539) assessed current app use and desirable features. A second survey of HPs attending a diabetes conference (n=286) assessed their confidence with app recommendations and perceived usefulness. Of the 189 responders (35.0% response rate) to the patient survey, 19.6% (37/189) had used a diabetes app. App users were younger and in comparison to other forms of diabetes mellitus, users prominently had type 1 DM. The most favored feature of the app users was a glucose diary (87%, 32/37), and an insulin calculator was the most desirable function for a future app (46%, 17/37). In non-app users, the most desirable feature for a future app was a glucose diary (64.4%, 98/152). Of the 115 responders (40.2% response rate) to the HPs survey, 60.1% (68/113) had recommended a diabetes app. Diaries for blood glucose levels and carbohydrate counting were considered the most useful app features and the features HPs felt most confident to recommend. HPs were least confident in recommending insulin calculation apps. The use of apps to record blood glucose was the most favored function in apps used by people with diabetes, with interest in insulin dose calculating function. HPs do not feel confident in recommending insulin dose calculators. There is an urgent need for an app assessment process to give confidence in the quality and safety of diabetes management apps to people with diabetes (potential app users) and HPs (potential app prescribers). ©Leah Boyle, Rebecca Grainger, Rosemary M Hall, Jeremy D Krebs. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 30.06.2017.

Development of an Ecological Momentary Assessment Mobile App for a Low-Literacy, Mexican American Population to Collect Disordered Eating Behaviors

PubMed Central

Stein, Karen F; Chaudry, Beenish; Trabold, Nicole

2016-01-01

Background Ecological momentary assessment (EMA) is a popular method for understanding population health in which participants report their experiences while in naturally occurring contexts in order to increase the reliability and ecological validity of the collected data (as compared to retrospective recall). EMA studies, however, have relied primarily on text-based questionnaires, effectively eliminating low-literacy populations from the samples. Objective To provide a case study of design of an EMA mobile app for a low-literacy population. In particular, we present the design process and final design of an EMA mobile app for low literate, Mexican American women to record unhealthy eating and weight control behaviors (UEWCBs). Methods An iterative, user-centered design process was employed to develop the mobile app. An existing EMA protocol to measure UEWCBs in college-enrolled Mexican American women was used as the starting point for the application. The app utilizes an icon interface, with optional audio prompts, that is culturally sensitive and usable by a low-literacy population. A total of 41 women participated over the course of 4 phases of the design process, which included 2 interview and task-based phases (n=8, n=11), focus groups (n=15), and a 5-day, in situ deployment (n=7). Results Participants’ mental models of UEWCBs differed substantially from prevailing definitions found in the literature, prompting a major reorganization of the app interface. Differences in health literacy and numeracy were better identified with the Newest Vital Sign tool, as compared with the Short Assessment of Health Literacy tool. Participants had difficulty imagining scenarios in the interviews to practice recording a specific UEWCB; instead, usability was best tested in situ. Participants were able to use the EMA mobile app over the course of 5 days to record UEWCBs. Conclusions Results suggest that the iterative, user-centered design process was essential for designing the app to be made usable by the target population. Simply taking the protocol designed for a higher-literacy population and replacing words with icons and/or audio would have been unsuccessful with this population. PMID:27418020

Oiling the gate: a mobile application to improve the admissions process from the emergency department to an academic community hospital inpatient medicine service.

PubMed

Fung, Russell; Hyde, Jensen Hart; Davis, Mike

2018-01-01

The process of admitting patients from the emergency department (ED) to an academic internal medicine (AIM) service in a community teaching hospital is one fraught with variability and disorder. This results in an inconsistent volume of patients admitted to academic versus private hospitalist services and results in frustration of both ED and AIM clinicians. We postulated that implementation of a mobile application (app) would improve provider satisfaction and increase admissions to the academic service. The app was designed and implemented to be easily accessible to ED physicians, regularly updated by academic residents on call, and a real-time source of the number of open AIM admission spots. We found a significant improvement in ED and AIM provider satisfaction with the admission process. There was also a significant increase in admissions to the AIM service after implementation of the app. We submit that the implementation of a mobile app is a viable, cost-efficient, and effective method to streamline the admission process from the ED to AIM services at community-based hospitals.

The amyloid precursor protein and postnatal neurogenesis/neuroregeneration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen Yanan; Tang, Bor Luen

2006-03-03

The amyloid precursor protein (APP) is the source of amyloid-beta (A{beta}) peptide, produced via its sequential cleavage {beta}- and {gamma}-secretases. Various biophysical forms of A{beta} (and the mutations of APP which results in their elevated levels) have been implicated in the etiology and early onset of Alzheimer's disease. APP's evolutionary conservation and the existence of APP-like isoforms (APLP1 and APLP2) which lack the A{beta} sequence, however, suggest that these might have important physiological functions that are unrelated to A{beta} production. Soluble N-terminal fragments of APP have been known to be neuroprotective, and the interaction of its cytoplasmic C-terminus with amore » myriad of proteins associates it with diverse processes such as axonal transport and transcriptional regulation. The notion for an essential postnatal function of APP has been demonstrated genetically, as mice deficient in both APP and APLP2 or all three APP isoforms exhibit early postnatal lethality and neuroanatomical abnormalities. Recent findings have also brought to light two possible functions of the APP family in Brain-regulation of neural progenitor cell proliferation and axonal outgrowth after injury. Interestingly, these two apparently related neurogenic/neuroregenerative functions of APP involve two separate domains of the molecule.« less

Redundancy and divergence in the amyloid precursor protein family.

PubMed

Shariati, S Ali M; De Strooper, Bart

2013-06-27

Gene duplication provides genetic material required for functional diversification. An interesting example is the amyloid precursor protein (APP) protein family. The APP gene family has experienced both expansion and contraction during evolution. The three mammalian members have been studied quite extensively in combined knock out models. The underlying assumption is that APP, amyloid precursor like protein 1 and 2 (APLP1, APLP2) are functionally redundant. This assumption is primarily supported by the similarities in biochemical processing of APP and APLPs and on the fact that the different APP genes appear to genetically interact at the level of the phenotype in combined knockout mice. However, unique features in each member of the APP family possibly contribute to specification of their function. In the current review, we discuss the evolution and the biology of the APP protein family with special attention to the distinct properties of each homologue. We propose that the functions of APP, APLP1 and APLP2 have diverged after duplication to contribute distinctly to different neuronal events. Our analysis reveals that APLP2 is significantly diverged from APP and APLP1. Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Lovastatin inhibits amyloid precursor protein (APP) beta-cleavage through reduction of APP distribution in Lubrol WX extractable low density lipid rafts.

PubMed

Won, Je-Seong; Im, Yeong-Bin; Khan, Mushfiquddin; Contreras, Miguel; Singh, Avtar K; Singh, Inderjit

2008-05-01

Previous studies have described that statins (inhibitors of cholesterol and isoprenoid biosynthesis) inhibit the output of amyloid-beta (Abeta) in the animal model and thus decrease risk of Alzheimer's disease. However, their action mechanism(s) in Abeta precursor protein (APP) processing and Abeta generation is not fully understood. In this study, we report that lovastatin treatment reduced Abeta output in cultured hippocampal neurons as a result of reduced APP levels and beta-secretase activities in low density Lubrol WX (non-ionic detergent) extractable lipid rafts (LDLR). Rather than altering cholesterol levels in lipid raft fractions and thus disrupting lipid raft structure, lovastatin decreased Abeta generation through down-regulating geranylgeranyl-pyrophosphate dependent endocytosis pathway. The inhibition of APP endocytosis by treatment with lovastatin and reduction of APP levels in LDLR fractions by treatment with phenylarsine oxide (a general endocytosis inhibitor) support the involvement of APP endocytosis in APP distribution in LDLR fractions and subsequent APP beta-cleavage. Moreover, lovastatin-mediated down-regulation of endocytosis regulators, such as early endosomal antigen 1, dynamin-1, and phosphatidylinositol 3-kinase activity, indicates that lovastatin modulates APP endocytosis possibly through its pleiotropic effects on endocytic regulators. Collectively, these data report that lovastatin mediates inhibition of LDLR distribution and beta-cleavage of APP in a geranylgeranyl-pyrophosphate and endocytosis-dependent manner.

LOVASTATIN INHIBITS AMYLOID PRECURSOR PROTEIN (APP) β-CLEAVAGE THROUGH REDUCTION OF APP DISTRIBUTION IN LUBROL WX EXTRACTABLE LOW DENSITY LIPID RAFTS

PubMed Central

Won, Je-Seong; Im, Yeong-Bin; Khan, Mushfiquddin; Contreras, Miguel; Singh, Avtar K.; Singh, Inderjit

2009-01-01

Previous studies have described that statins (inhibitors of cholesterol and isoprenoid biosynthesis) inhibit the output of amyloid-β (Aβ) in the animal model and thus decrease risk of Alzheimer's disease. However, their action mechanism(s) in APP processing and Aβ generation is not fully understood. Here we report that lovastatin treatment reduced Aβ output in cultured hippocampal neurons as a result of reduced Aβ precursor protein (APP) levels and β-secretase activities in low density Lubrol WX (non-ionic detergent) extractable lipid rafts (LDLR). Rather than altering cholesterol levels in lipid raft fractions and thus disrupting lipid raft structure, lovastatin decreased Aβ generation through down-regulating geranylgeranyl-pyrophosphate (GGPP) dependent endocytosis pathway. The inhibition of APP endocytosis by treatment with lovastatin and reduction of APP levels in LDLR fractions by treatment with phenylarsine oxide (a general endocytosis inhibitor) support the involvement of APP endocytosis in APP distribution in LDLR fractions and subsequent APP β-cleavage. Moreover, lovastatin-mediated down-regulation of endocytosis regulators, such as EEA1, dynamin-I and phosphatidylinositol-3 kinase activity, indicates that lovastatin modulates APP endocytosis possibly through its pleiotropic effects on endocytic regulators. Collectively, these data report that lovastatin mediates inhibition of LDLR distribution and β-cleavage of APP in a GGPP and endocytosis dependent manner. PMID:18266936

MEDication reminder APPs to improve medication adherence in Coronary Heart Disease (MedApp-CHD) Study: a randomised controlled trial protocol

PubMed Central

Chow, Clara K; Thiagalingam, Aravinda; Rogers, Kris; Chalmers, John; Redfern, Julie

2017-01-01

Introduction The growing number of smartphone health applications available in the app stores makes these apps a promising tool to help reduce the global problem of non-adherence to long-term medications. However, to date, there is limited evidence that available medication reminder apps are effective. This study aims to determine the impact of medication reminder apps on adherence to cardiovascular medication when compared with usual care for people with coronary heart disease (CHD) and to determine whether an advanced app compared with a basic app is associated with higher adherence. Methods and analysis Randomised controlled trial with follow-up at 3 months to evaluate the feasibility and effectiveness of medication reminder apps on medication adherence compared with usual care. An estimated sample size of 156 patients with CHD will be randomised to one of three groups (usual care group, basic medication reminder app group and advanced medication reminder app group). The usual care group will receive standard care for CHD with no access to a medication reminder app. The basic medication reminder app group will have access to a medication reminder app with a basic feature of providing simple daily reminders with no interactivity. The advanced medication reminder app group will have access to a medication reminder app with additional interactive and customisable features. The primary outcome is medication adherence measured by the eight-item Morisky Medication Adherence Scale at 3 months. Secondary outcomes include clinical measurements of blood pressure and cholesterol levels, and medication knowledge. A process evaluation will also be performed to assess the feasibility of the intervention by evaluating the acceptability, utility and engagement with the apps. Ethics and dissemination Ethical approval has been obtained from the Western Sydney Local Health Network Human Research Ethics Committee (AU/RED/HREC/1/WMEAD/3). Study findings will be disseminated via usual scientific forums. Trial registration number ACTRN12616000661471; Pre-results PMID:28993388

Simplified Novel Application (SNApp) framework: a guide to developing and implementing second-generation mobile applications for behavioral health research.

PubMed

Fillo, Jennifer; Staplefoote-Boynton, B Lynette; Martinez, Angel; Sontag-Padilla, Lisa; Shadel, William G; Martino, Steven C; Setodji, Claude M; Meeker, Daniella; Scharf, Deborah

2016-12-01

Advances in mobile technology and mobile applications (apps) have opened up an exciting new frontier for behavioral health researchers, with a "second generation" of apps allowing for the simultaneous collection of multiple streams of data in real time. With this comes a host of technical decisions and ethical considerations unique to this evolving approach to research. Drawing on our experience developing a second-generation app for the simultaneous collection of text message, voice, and self-report data, we provide a framework for researchers interested in developing and using second-generation mobile apps to study health behaviors. Our Simplified Novel Application (SNApp) framework breaks the app development process into four phases: (1) information and resource gathering, (2) software and hardware decisions, (3) software development and testing, and (4) study start-up and implementation. At each phase, we address common challenges and ethical issues and make suggestions for effective and efficient app development. Our goal is to help researchers effectively balance priorities related to the function of the app with the realities of app development, human subjects issues, and project resource constraints.

Amyloid precursor protein expression is enhanced in human platelets from subjects with Alzheimer's disease and frontotemporal lobar degeneration: a real-time PCR study.

PubMed

Vignini, Arianna; Morganti, Stefano; Salvolini, Eleonora; Sartini, Davide; Luzzi, Simona; Fiorini, Rosamaria; Provinciali, Leandro; Di Primio, Roberto; Mazzanti, Laura; Emanuelli, Monica

2013-12-01

Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) represent the most frequent causes of early-onset and late-onset degenerative dementia, respectively. A correct diagnosis entails the choice of appropriate therapies. In this view the present study aimed to identify biomarkers that could improve the differential diagnosis. We recently found an overexpression of platelet amyloid precursor protein (APP) in AD; furthermore, recent studies have suggested the presence of changes in APP processing in FTLD. In this context, we analyzed the mRNA expression level of Total APP (TOT) and APP containing a Kunitz-type serine protease inhibitor domain (KPI) in platelets obtained from AD patients, subjects with FTLD, and healthy subjects. In addition, we evaluated the correlation between platelet APP mRNA expression levels and cognitive impairment.Differential gene expression measurements revealed a significant up-regulation of APP TOT and APP KPI in both AD and FTLD patients compared to the controls (being AD/Controls: 1.67 for APP TOT and 1.47 for APP KPI; FTLD/Controls: 1.62 for APP TOT and 1.51 for APP KPI; p < 0.05), although it is interesting to note that in FTLD patients this expression did not correlate with the severity of cognitive impairment.This could be related to a reduced beta-amyloid (Aβ) formation, caused by an alteration of secretase enzymatic activity, even though a post-transcriptional regulation of APP mRNAs in FTLD cannot be excluded.

Amyloid precursor protein expression is enhanced in human platelets from subjects with Alzheimer's disease and Frontotemporal lobar degeneration: A Real-time PCR study.

PubMed

Vignini, Arianna; Morganti, Stefano; Salvolini, Eleonora; Sartini, Davide; Luzzi, Simona; Fiorini, Rosamaria; Provinciali, Leandro; Di Primio, Roberto; Mazzanti, Laura; Emanuelli, Monica

2013-10-26

Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) represent the most frequent causes of early-onset and late-onset degenerative dementia, respectively. A correct diagnosis entails the choice of appropriate therapies. In this view the present study aimed to identify biomarkers that could improve the differential diagnosis. We recently found an overexpression of platelet amyloid precursor protein (APP) in AD; furthermore, recent studies have suggested the presence of changes in APP processing in FTLD. In this context, we analyzed the mRNA expression level of Total APP (TOT) and APP containing a Kunitz-type serine protease inhibitor domain (KPI) in platelets obtained from AD patients, subjects with FTLD, and healthy subjects. In addition, we evaluated the correlation between platelet APP mRNA expression levels and cognitive impairment. Differential gene expression measurements revealed a significant up-regulation of APP TOT and APP KPI in both AD and FTLD patients compared to the controls (being AD/Controls: 1.67 for APP TOT and 1.47 for APP KPI; FTLD/Controls: 1.62 for APP TOT and 1.51 for APP KPI; p<0.05) , although it is interesting to note that in FTLD patients this expression did not correlate with the severity of cognitive impairment. This could be related to a reduced beta-amyloid (Aβ) formation, caused by an alteration of secretase enzymatic activity, even though a post-transcriptional regulation of APP mRNAs in FTLD cannot be excluded. © 2013.

32 CFR 513.4 - Conditions creditors must meet before getting help in debt processing.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., Oklahoma, and Wyoming. (4) DOD Standards of Fairness (app B) define fair and just dealings with soldiers... Relief Act of 1940, as amended (50 U.S.C. app, section 501 et seq., (1970)) if applicable. (See DA Pam 27... Standards of Fairness (app B) showing compliance with one of the following: (A) The Truth-in-Lending Act. (B...

Teaching in a World with Photomath

ERIC Educational Resources Information Center

Webel, Corey; Otten, Samuel

2015-01-01

In October 2014, an interesting new app became freely available in the Apple Store®. It is called PhotoMath®: (1) Hold a phone or tablet up to a mathematics problem in a textbook; (2) The app shows the answer to the problem; and (3) Select Steps to see the step-by-step process for getting from the problem to the solution. The app works for simple…

Development of a Culturally Appropriate Bilingual Electronic App About Hepatitis B for Indigenous Australians: Towards Shared Understandings.

PubMed

Davies, Jane; Bukulatjpi, Sarah; Sharma, Suresh; Caldwell, Luci; Johnston, Vanessa; Davis, Joshua Saul

2015-06-10

Hepatitis B is endemic in Indigenous communities in Northern Australia; however, there is a lack of culturally appropriate educational tools. Health care workers and educators in this setting have voiced a desire for visual, interactive tools in local languages. Mobile phones are increasingly used and available in remote Indigenous communities. In this context, we identified the need for a tablet-based health education app about hepatitis B, developed in partnership with an Australian remote Indigenous community. To develop a culturally appropriate bilingual app about hepatitis B for Indigenous Australians in Arnhem Land using a participatory action research (PAR) framework. This project was a partnership between the Menzies School of Health Research, Miwatj Aboriginal Health Corporation, Royal Darwin Hospital Liver Clinic, and Dreamedia Darwin. We have previously published a qualitative study that identified major knowledge gaps about hepatitis B in this community, and suggested that a tablet-based app would be an appropriate and popular tool to improve this knowledge. The process of developing the app was based on PAR principles, particularly ongoing consultation, evaluation, and discussion with the community throughout each iterative cycle. Stages included development of the storyboard, the translation process (forward translation and backtranslation), prelaunch community review, launch and initial community evaluation, and finally, wider launch and evaluation at a viral hepatitis conference. We produced an app called "Hep B Story" for use with iPad, iPhone, Android tablets, and mobile phones or personal computers. The app is culturally appropriate, audiovisual, interactive, and users can choose either English or Yolŋu Matha (the most common language in East Arnhem Land) as their preferred language. The initial evaluation demonstrated a statistically significant improvement in Hep B-related knowledge for 2 of 3 questions (P=.01 and .02, respectively) and overwhelmingly positive opinion regarding acceptability and ease of use (median rating of 5, on a 5-point Likert-type scale when users were asked if they would recommend the app to others). We describe the process of development of a bilingual hepatitis B-specific app for Indigenous Australians, using a PAR framework. The approach was found to be successful with positive evaluations.

Herpes simplex virus interferes with amyloid precursor protein processing

PubMed Central

Shipley, Suzanne J; Parkin, Edward T; Itzhaki, Ruth F; Dobson, Curtis B

2005-01-01

Background The early events underlying Alzheimer's disease (AD) remain uncertain, although environmental factors may be involved. Work in this laboratory has shown that the combination of herpes simplex virus type 1 (HSV1) in brain and carriage of the APOE-ε4 allele of the APOE gene strongly increases the risk of developing AD. The development of AD is thought to involve abnormal aggregation or deposition of a 39–43 amino acid protein – β amyloid (Aβ) – within the brain. This is cleaved from the much larger transmembranal protein 'amyloid precursor protein' (APP). Any agent able to interfere directly with Aβ or APP metabolism may therefore have the capacity to contribute towards AD. One recent report showed that certain HSV1 glycoprotein peptides may aggregate like Aβ; a second study described a role for APP in transport of virus in squid axons. However to date the effects of acute herpesvirus infection on metabolism of APP in human neuronal-type cells have not been investigated. In order to find if HSV1 directly affects APP and its degradation, we have examined this protein from human neuroblastoma cells (normal and transfected with APP 695) infected with the virus, using Western blotting. Results We have found that acute HSV1 (and also HSV2) infection rapidly reduces full length APP levels – as might be expected – yet surprisingly markedly increases levels of a novel C-terminal fragment of APP of about 55 kDa. This band was not increased in cells treated with the protein synthesis inhibitor cycloheximide Conclusion Herpes virus infection leads to rapid loss of full length APP from cells, yet also causes increased levels of a novel 55 kDa C-terminal APP fragment. These data suggest that infection can directly alter the processing of a transmembranal protein intimately linked to the aetiology of AD. PMID:16109164

Spatial Segregation of γ-Secretase and Substrates in Distinct Membrane Domains*

PubMed Central

Vetrivel, Kulandaivelu S.; Cheng, Haipeng; Kim, Seong-Hun; Chen, Ying; Barnes, Natalie Y.; Parent, Ange‘le T.; Sisodia, Sangram S.; Thinakaran, Gopal

2005-01-01

γ-Secretase facilitates the regulated intramembrane proteolysis of select type I membrane proteins that play diverse physiological roles in multiple cell types and tissue. In this study, we used biochemical approaches to examine the distribution of amyloid precursor protein (APP) and several additional γ-secretase substrates in membrane microdomains. We report that APP C-terminal fragments (CTFs) and γ-secretase reside in Lubrol WX detergent-insoluble membranes (DIM) of cultured cells and adult mouse brain. APP CTFs that accumulate in cells lacking γ-secretase activity preferentially associate with DIM. Cholesterol depletion and magnetic im-munoisolation studies indicate recruitment of APP CTFs into cholesterol- and sphingolipid-rich lipid rafts, and co-residence of APP CTFs, PS1, and syntaxin 6 in DIM patches derived from the trans-Golgi network. Photoaffinity cross-linking studies provided evidence for the preponderance of active γ-secretase in lipid rafts of cultured cells and adult brain. Remarkably, unlike the case of APP, CTFs derived from Notch1, Jagged2, deleted in colorectal cancer (DCC), and N-cadherin remain largely detergent-soluble, indicative of their spatial segregation in non-raft domains. In embryonic brain, the majority of PS1 and nicastrin is present in Lubrol WX-soluble membranes, wherein the CTFs derived from APP, Notch1, DCC, and N-cadherin also reside. We suggest that γ-secretase residence in non-raft membranes facilitates proteolysis of diverse substrates during embryonic development but that the translocation of γ-secretase to lipid rafts in adults ensures processing of certain substrates, including APP CTFs, while limiting processing of other potential substrates. PMID:15886206

Spatial segregation of gamma-secretase and substrates in distinct membrane domains.

PubMed

Vetrivel, Kulandaivelu S; Cheng, Haipeng; Kim, Seong-Hun; Chen, Ying; Barnes, Natalie Y; Parent, Angèle T; Sisodia, Sangram S; Thinakaran, Gopal

2005-07-08

Gamma-secretase facilitates the regulated intramembrane proteolysis of select type I membrane proteins that play diverse physiological roles in multiple cell types and tissue. In this study, we used biochemical approaches to examine the distribution of amyloid precursor protein (APP) and several additional gamma-secretase substrates in membrane microdomains. We report that APP C-terminal fragments (CTFs) and gamma-secretase reside in Lubrol WX detergent-insoluble membranes (DIM) of cultured cells and adult mouse brain. APP CTFs that accumulate in cells lacking gamma-secretase activity preferentially associate with DIM. Cholesterol depletion and magnetic immunoisolation studies indicate recruitment of APP CTFs into cholesterol- and sphingolipid-rich lipid rafts, and co-residence of APP CTFs, PS1, and syntaxin 6 in DIM patches derived from the trans-Golgi network. Photoaffinity cross-linking studies provided evidence for the preponderance of active gamma-secretase in lipid rafts of cultured cells and adult brain. Remarkably, unlike the case of APP, CTFs derived from Notch1, Jagged2, deleted in colorectal cancer (DCC), and N-cadherin remain largely detergent-soluble, indicative of their spatial segregation in non-raft domains. In embryonic brain, the majority of PS1 and nicastrin is present in Lubrol WX-soluble membranes, wherein the CTFs derived from APP, Notch1, DCC, and N-cadherin also reside. We suggest that gamma-secretase residence in non-raft membranes facilitates proteolysis of diverse substrates during embryonic development but that the translocation of gamma-secretase to lipid rafts in adults ensures processing of certain substrates, including APP CTFs, while limiting processing of other potential substrates.

Mobile Visualization and Analysis Tools for Spatial Time-Series Data

NASA Astrophysics Data System (ADS)

Eberle, J.; Hüttich, C.; Schmullius, C.

2013-12-01

The Siberian Earth System Science Cluster (SIB-ESS-C) provides access and analysis services for spatial time-series data build on products from the Moderate Resolution Imaging Spectroradiometer (MODIS) and climate data from meteorological stations. Until now a webportal for data access, visualization and analysis with standard-compliant web services was developed for SIB-ESS-C. As a further enhancement a mobile app was developed to provide an easy access to these time-series data for field campaigns. The app sends the current position from the GPS receiver and a specific dataset (like land surface temperature or vegetation indices) - selected by the user - to our SIB-ESS-C web service and gets the requested time-series data for the identified pixel back in real-time. The data is then being plotted directly in the app. Furthermore the user has possibilities to analyze the time-series data for breaking points and other phenological values. These processings are executed on demand of the user on our SIB-ESS-C web server and results are transfered to the app. Any processing can also be done at the SIB-ESS-C webportal. The aim of this work is to make spatial time-series data and analysis functions available for end users without the need of data processing. In this presentation the author gives an overview on this new mobile app, the functionalities, the technical infrastructure as well as technological issues (how the app was developed, our made experiences).

Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster.

PubMed

Kumita, Janet R; Helmfors, Linda; Williams, Jocy; Luheshi, Leila M; Menzer, Linda; Dumoulin, Mireille; Lomas, David A; Crowther, Damian C; Dobson, Christopher M; Brorsson, Ann-Christin

2012-01-01

We have created a Drosophila model of lysozyme amyloidosis to investigate the in vivo behavior of disease-associated variants. To achieve this objective, wild-type (WT) protein and the amyloidogenic variants F57I and D67H were expressed in Drosophila melanogaster using the UAS-gal4 system and both the ubiquitous and retinal expression drivers Act5C-gal4 and gmr-gal4. The nontransgenic w(1118) Drosophila line was used as a control throughout. We utilized ELISA experiments to probe lysozyme protein levels, scanning electron microscopy for eye phenotype classification, and immunohistochemistry to detect the unfolded protein response (UPR) activation. We observed that expressing the destabilized F57I and D67H lysozymes triggers UPR activation, resulting in degradation of these variants, whereas the WT lysozyme is secreted into the fly hemolymph. Indeed, the level of WT was up to 17 times more abundant than the variant proteins. In addition, the F57I variant gave rise to a significant disruption of the eye development, and this correlated to pronounced UPR activation. These results support the concept that the onset of familial amyloid disease is linked to an inability of the UPR to degrade completely the amyloidogenic lysozymes prior to secretion, resulting in secretion of these destabilized variants, thereby leading to deposition and associated organ damage.

Extensive Diversity of Prion Strains Is Defined by Differential Chaperone Interactions and Distinct Amyloidogenic Regions

PubMed Central

Stein, Kevin C.; True, Heather L.

2014-01-01

Amyloidogenic proteins associated with a variety of unrelated diseases are typically capable of forming several distinct self-templating conformers. In prion diseases, these different structures, called prion strains (or variants), confer dramatic variation in disease pathology and transmission. Aggregate stability has been found to be a key determinant of the diverse pathological consequences of different prion strains. Yet, it remains largely unclear what other factors might account for the widespread phenotypic variation seen with aggregation-prone proteins. Here, we examined a set of yeast prion variants of the [RNQ+] prion that differ in their ability to induce the formation of another yeast prion called [PSI+]. Remarkably, we found that the [RNQ+] variants require different, non-contiguous regions of the Rnq1 protein for both prion propagation and [PSI+] induction. This included regions outside of the canonical prion-forming domain of Rnq1. Remarkably, such differences did not result in variation in aggregate stability. Our analysis also revealed a striking difference in the ability of these [RNQ+] variants to interact with the chaperone Sis1. Thus, our work shows that the differential influence of various amyloidogenic regions and interactions with host cofactors are critical determinants of the phenotypic consequences of distinct aggregate structures. This helps reveal the complex interdependent factors that influence how a particular amyloid structure may dictate disease pathology and progression. PMID:24811344

A New Folding Kinetic Mechanism for Human Transthyretin and the Influence of the Amyloidogenic V30M Mutation.

PubMed

Jesus, Catarina S H; Almeida, Zaida L; Vaz, Daniela C; Faria, Tiago Q; Brito, Rui M M

2016-08-31

Protein aggregation into insoluble amyloid fibrils is the hallmark of several neurodegenerative diseases, chief among them Alzheimer's and Parkinson's. Although caused by different proteins, these pathologies share some basic molecular mechanisms with familial amyloidotic polyneuropathy (FAP), a rare hereditary neuropathy caused by amyloid formation and deposition by transthyretin (TTR) in the peripheral and autonomic nervous systems. Among the amyloidogenic TTR mutations known, V30M-TTR is the most common in FAP. TTR amyloidogenesis (ATTR) is triggered by tetramer dissociation, followed by partial unfolding and aggregation of the low conformational stability monomers formed. Thus, tetramer dissociation kinetics, monomer conformational stability and competition between refolding and aggregation pathways do play a critical role in ATTR. Here, we propose a new model to analyze the refolding kinetics of WT-TTR and V30M-TTR, showing that at pH and protein concentrations close to physiological, a two-step mechanism with a unimolecular first step followed by a second-order second step adjusts well to the experimental data. Interestingly, although sharing the same kinetic mechanism, V30M-TTR refolds at a much slower rate than WT-TTR, a feature that may favor the formation of transient species leading to kinetic partition into amyloidogenic pathways and, thus, significantly increasing the probability of amyloid formation in vivo.

Probing the interplay between amyloidogenic proteins and membranes using lipid monolayers and bilayers.

PubMed

Relini, Annalisa; Marano, Nadia; Gliozzi, Alessandra

2014-05-01

Many degenerative diseases such as Alzheimer's and Parkinson's involve proteins that have a tendency to misfold and aggregate eventually forming amyloid fibers. This review describes the use of monolayers, bilayers, supported membranes, and vesicles as model systems that have helped elucidate the mechanisms and consequences of the interactions between amyloidogenic proteins and membranes. These are twofold: membranes favor the formation of amyloid structures and these induce damage in those membranes. We describe studies that show how interfaces, especially charged ones, favor amyloidogenic protein aggregation by several means. First, surfaces increase the effective protein concentration reducing a three-dimensional system to a two-dimensional one. Second, charged surfaces allow electrostatic interactions with the protein. Anionic lipids as well as rafts, rich in cholesterol and gangliosides, prove to play an especially important role. Finally, these amphipathic systems also offer a hydrophobic environment favoring conformational changes, oligomerization, and eventual formation of mature fibers. In addition, we examine several models for membrane permeabilization: protein pores, leakage induced by extraction of lipids, chaotic pores, and membrane tension, presenting illustrative examples of experimental evidence in support of these models. The picture that emerges from recent work is one where more than one mechanism is in play. Which mechanism prevails depends on the protein, its aggregation state, and the lipid environment in which the interactions occur. © 2013.

A New Folding Kinetic Mechanism for Human Transthyretin and the Influence of the Amyloidogenic V30M Mutation

PubMed Central

Jesus, Catarina S. H.; Almeida, Zaida L.; Vaz, Daniela C.; Faria, Tiago Q.; Brito, Rui M. M.

2016-01-01

Protein aggregation into insoluble amyloid fibrils is the hallmark of several neurodegenerative diseases, chief among them Alzheimer’s and Parkinson’s. Although caused by different proteins, these pathologies share some basic molecular mechanisms with familial amyloidotic polyneuropathy (FAP), a rare hereditary neuropathy caused by amyloid formation and deposition by transthyretin (TTR) in the peripheral and autonomic nervous systems. Among the amyloidogenic TTR mutations known, V30M-TTR is the most common in FAP. TTR amyloidogenesis (ATTR) is triggered by tetramer dissociation, followed by partial unfolding and aggregation of the low conformational stability monomers formed. Thus, tetramer dissociation kinetics, monomer conformational stability and competition between refolding and aggregation pathways do play a critical role in ATTR. Here, we propose a new model to analyze the refolding kinetics of WT-TTR and V30M-TTR, showing that at pH and protein concentrations close to physiological, a two-step mechanism with a unimolecular first step followed by a second-order second step adjusts well to the experimental data. Interestingly, although sharing the same kinetic mechanism, V30M-TTR refolds at a much slower rate than WT-TTR, a feature that may favor the formation of transient species leading to kinetic partition into amyloidogenic pathways and, thus, significantly increasing the probability of amyloid formation in vivo. PMID:27589730

Application of low-cost methodologies for mobile phone app development.

PubMed

Zhang, Melvyn; Cheow, Enquan; Ho, Cyrus Sh; Ng, Beng Yeong; Ho, Roger; Cheok, Christopher Cheng Soon

2014-12-09

The usage of mobile phones and mobile phone apps in the recent decade has indeed become more prevalent. Previous research has highlighted a method of using just the Internet browser and a text editor to create an app, but this does not eliminate the challenges faced by clinicians. More recently, two methodologies of app development have been shared, but there has not been any disclosures pertaining to the costs involved. In addition, limitations such as the distribution and dissemination of the apps have not been addressed. The aims of this research article are to: (1) highlight a low-cost methodology that clinicians without technical knowledge could use to develop educational apps; (2) clarify the respective costs involved in the process of development; (3) illustrate how limitations pertaining to dissemination could be addressed; and (4) to report initial utilization data of the apps and to share initial users' self-rated perception of the apps. In this study, we will present two techniques of how to create a mobile app using two of the well-established online mobile app building websites. The costs of development are specified and the methodology of dissemination of the apps will be shared. The application of the low-cost methodologies in the creation of the "Mastering Psychiatry" app for undergraduates and "Déjà vu" app for postgraduates will be discussed. A questionnaire survey has been administered to undergraduate students collating their perceptions towards the app. For the Mastering Psychiatry app, a cumulative total of 722 users have used the mobile app since inception, based on our analytics. For the Déjà vu app, there has been a cumulative total of 154 downloads since inception. The utilization data demonstrated the receptiveness towards these apps, and this is reinforced by the positive perceptions undergraduate students (n=185) had towards the low-cost self-developed apps. This is one of the few studies that have demonstrated the low-cost methodologies of app development; as well as student and trainee receptivity toward self-created Web-based mobile phone apps. The results obtained have demonstrated that these Web-based low-cost apps are applicable in the real life, and suggest that the methodologies shared in this research paper might be of benefit for other specialities and disciplines.

Application of Low-Cost Methodologies for Mobile Phone App Development

PubMed Central

Ng, Beng Yeong; Ho, Roger; Cheok, Christopher Cheng Soon

2014-01-01

Background The usage of mobile phones and mobile phone apps in the recent decade has indeed become more prevalent. Previous research has highlighted a method of using just the Internet browser and a text editor to create an app, but this does not eliminate the challenges faced by clinicians. More recently, two methodologies of app development have been shared, but there has not been any disclosures pertaining to the costs involved. In addition, limitations such as the distribution and dissemination of the apps have not been addressed. Objective The aims of this research article are to: (1) highlight a low-cost methodology that clinicians without technical knowledge could use to develop educational apps; (2) clarify the respective costs involved in the process of development; (3) illustrate how limitations pertaining to dissemination could be addressed; and (4) to report initial utilization data of the apps and to share initial users’ self-rated perception of the apps. Methods In this study, we will present two techniques of how to create a mobile app using two of the well-established online mobile app building websites. The costs of development are specified and the methodology of dissemination of the apps will be shared. The application of the low-cost methodologies in the creation of the “Mastering Psychiatry” app for undergraduates and “Déjà vu” app for postgraduates will be discussed. A questionnaire survey has been administered to undergraduate students collating their perceptions towards the app. Results For the Mastering Psychiatry app, a cumulative total of 722 users have used the mobile app since inception, based on our analytics. For the Déjà vu app, there has been a cumulative total of 154 downloads since inception. The utilization data demonstrated the receptiveness towards these apps, and this is reinforced by the positive perceptions undergraduate students (n=185) had towards the low-cost self-developed apps. Conclusions This is one of the few studies that have demonstrated the low-cost methodologies of app development; as well as student and trainee receptivity toward self-created Web-based mobile phone apps. The results obtained have demonstrated that these Web-based low-cost apps are applicable in the real life, and suggest that the methodologies shared in this research paper might be of benefit for other specialities and disciplines. PMID:25491323

Targeting Parents for Childhood Weight Management: Development of a Theory-Driven and User-Centered Healthy Eating App.

PubMed

Curtis, Kristina Elizabeth; Lahiri, Sudakshina; Brown, Katherine Elizabeth

2015-06-18

The proliferation of health promotion apps along with mobile phones' array of features supporting health behavior change offers a new and innovative approach to childhood weight management. However, despite the critical role parents play in children's weight related behaviors, few industry-led apps aimed at childhood weight management target parents. Furthermore, industry-led apps have been shown to lack a basis in behavior change theory and evidence. Equally important remains the issue of how to maximize users' engagement with mobile health (mHealth) interventions where there is growing consensus that inputs from the commercial app industry and the target population should be an integral part of the development process. The aim of this study is to systematically design and develop a theory and evidence-driven, user-centered healthy eating app targeting parents for childhood weight management, and clearly document this for the research and app development community. The Behavior Change Wheel (BCW) framework, a theoretically-based approach for intervention development, along with a user-centered design (UCD) philosophy and collaboration with the commercial app industry, guided the development process. Current evidence, along with a series of 9 focus groups (total of 46 participants) comprised of family weight management case workers, parents with overweight and healthy weight children aged 5-11 years, and consultation with experts, provided data to inform the app development. Thematic analysis of focus groups helped to extract information related to relevant theoretical, user-centered, and technological components to underpin the design and development of the app. Inputs from parents and experts working in the area of childhood weight management helped to identify the main target behavior: to help parents provide appropriate food portion sizes for their children. To achieve this target behavior, the behavioral diagnosis revealed the need for eliciting change in parents' capability, motivation, and opportunity in 10-associated Theoretical Domains Framework (TDF) domains. Of the 9 possible intervention functions, 6 were selected to bring about this change which guided the selection of 21 behavior change techniques. Parents' preferences for healthy eating app features revolved around four main themes (app features, time saving and convenience, aesthetics, and gamification) whereupon a criterion was applied to guide the selection on which preferences should be integrated into the design of the app. Collaboration with the app company helped to build on users' preferences for elements of gamification such as points, quizzes, and levels to optimize user engagement. Feedback from parents on interactive mock-ups helped to inform the final development of the prototype app. Here, we fully explicate a systematic approach applied in the development of a family-oriented, healthy eating health promotion app grounded in theory and evidence, and balanced with users' preferences to help maximize its engagement with the target population.

Identification of BACE2 as an avid ß-amyloid-degrading protease

PubMed Central

2012-01-01

Background Proteases that degrade the amyloid ß-protein (Aß) have emerged as key players in the etiology and potential treatment of Alzheimer’s disease (AD), but it is unlikely that all such proteases have been identified. To discover new Aß-degrading proteases (AßDPs), we conducted an unbiased, genome-scale, functional cDNA screen designed to identify proteases capable of lowering net Aß levels produced by cells, which were subsequently characterized for Aß-degrading activity using an array of downstream assays. Results The top hit emerging from the screen was ß-site amyloid precursor protein-cleaving enzyme 2 (BACE2), a rather unexpected finding given the well-established role of its close homolog, BACE1, in the production of Aß. BACE2 is known to be capable of lowering Aß levels via non-amyloidogenic processing of APP. However, in vitro, BACE2 was also found to be a particularly avid AßDP, with a catalytic efficiency exceeding all known AßDPs except insulin-degrading enzyme (IDE). BACE1 was also found to degrade Aß, albeit ~150-fold less efficiently than BACE2. Aß is cleaved by BACE2 at three peptide bonds—Phe19-Phe20, Phe20-Ala21, and Leu34-Met35—with the latter cleavage site being the initial and principal one. BACE2 overexpression in cultured cells was found to lower net Aß levels to a greater extent than multiple, well-established AßDPs, including neprilysin (NEP) and endothelin-converting enzyme-1 (ECE1), while showing comparable effectiveness to IDE. Conclusions This study identifies a new functional role for BACE2 as a potent AßDP. Based on its high catalytic efficiency, its ability to degrade Aß intracellularly, and other characteristics, BACE2 represents a particulary strong therapeutic candidate for the treatment or prevention of AD. PMID:22986058

The Impact of WhatsApp Use on Success in Education Process

ERIC Educational Resources Information Center

Cetinkaya, Levent

2017-01-01

The purpose of this study is to explore the effects of WhatsApp use for education and determine the opinions of students towards the process. The study was designed in mixed research model which combines both qualitative and quantitative data. In the quantitative aspect of the study, quasi-experimental design, with a pretest-posttest control…

Liquid Crystal Based Sensor to Detect Beta-Sheet Formation of Peptides

NASA Astrophysics Data System (ADS)

Sadati, Monirosadat; Izmitli Apik, Aslin; Abbott, Nicholas L.; de Pablo, Juan J.

2015-03-01

Protein aggregation into amyloid fibrils is involved in the progression of Alzheimer's, typeII diabetes and Huntington's diseases. Although larger aggregates remain important for clinical determination, small oligomers are of great interest due to their potentially toxic nature. It is therefore crucial to develop methods that probe the aggregation process at early stages and in the vicinity of biological membranes. Here, we present a simple method that relies on liquid crystalline materials and a Langmuir monolayer at the aqueous-liquid crystal (LC) interface. The approach is based on the LC's specific response to β-sheet structures, which abound in amyloid fibrils. When the system is observed under polarized light, the fibrils formed by amyloidogenic peptides give rise to the formation of elongated and branched structures in the LCs. Moreover, the PolScope measurements prove that the LCs are predominantly aligned along the fibrils when exposed to a β-sheet forming peptide. In contrast, non-amyloidogenic peptides form ellipsoidal domains of irregularly tilted LCs. This method is capable of reporting aggregation at lipid-aqueous interfaces at nanomolar concentrations of the peptide, and much earlier than commonly used fluorescence-based techniques. We thank Prof. Oleg D. Levrentovich and Young-Ki Kim from the Liquid Crystal Institute of Kent State University for the use of their PolScope instrument. This work was partially supported by the Swiss National Science Foundation (P300P2_151342).

Generic amyloidogenicity of mammalian prion proteins from species susceptible and resistant to prions.

PubMed

Nyström, Sofie; Hammarström, Per

2015-05-11

Prion diseases are lethal, infectious diseases associated with prion protein (PrP) misfolding. A large number of mammals are susceptible to both sporadic and acquired prion diseases. Although PrP is highly conserved and ubiquitously expressed in all mammals, not all species exhibit prion disease. By employing full length recombinant PrP from five known prion susceptible species (human, cattle, cat, mouse and hamster) and two species considered to be prion resistant (pig and dog) the amyloidogenicity of these PrPs has been delineated. All the mammalian PrPs, even from resistant species, were swiftly converted from the native state to amyloid-like structure when subjected to a native condition conversion assay. The PrPs displayed amyloidotypic tinctorial and ultrastructural hallmarks. Self-seeded conversion of the PrPs displayed significantly decreased lag phases demonstrating that nucleation dependent polymerization is a dominating mechanism in the fibrillation process. Fibrils from Aβ1-40, Aβ1-42, Lysozyme, Insulin and Transthyretin did not accelerate conversion of HuPrP whereas fibrils from HuPrP90-231 and HuPrP121-231 as well as full length PrPs of all PrPs efficiently seeded conversion showing specificity of the assay requiring the C-terminal PrP sequence. Our findings have implications for PrP misfolding and could have ramifications in the context of prion resistant species and silent carriers.

Amyloidosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Glenner, G.G.; Osserman, E.F.

1986-01-01

The subjects covered in this Symposium range through almost every clinical medical specialty. From an average of one paper in each of the past three Symposiums, the explosive interest in cerebral amyloidosis has led to the presentation of 12 papers on this subject in the present volume. The genetically predisposed familial amyloidotic processes, such as the polyneuropathies and familial Mediterranean fever have also stimulated extensive and intriguing investigations which have revealed the striking effect of a single amino acid substitution in transforming a normal protein into a lethal ''amyloidogenic'' one. This Symposium clearly depicts the advances since the first amyloidmore » fibril protein was definitively identified and defined 14 years ago. Since all amyloid fibril proteins so far described are variants of normal proteins, attention to gene abnormalities now becomes a significant focus as well as the pathogenic sequences which lead in these cases to twisted BETA-pleated sheet (amyloid) fibril formation. Tentative concepts such as the ''amyloidogenic protein precursor of the fibril,'' ''proteolysis as one mechanism of fibril formation,'' ''Congo red birefringence as a marker for the twisted BETA-pleated sheet protein'' are now substantiated by recurring confirmation. Even a prophylactic treatment for one of the amyloidotic conditions, familial Mediterranean fever, is now available. Predictably, as the pathogeneses of the amyloid diseases are individually deciphered, highly specific and directed therapies will evolve to treat their devastated victims.« less

Embedding technology into inter-professional best practices in home safety evaluation.

PubMed

Burns, Suzanne Perea; Pickens, Noralyn Davel

2017-08-01

To explore inter-professional home evaluators' perspectives and needs for building useful and acceptable decision-support tools for the field of home modifications. Twenty semi-structured interviews were conducted with a range of home modification professionals from different regions of the United States. The interview transcripts were analyzed with a qualitative, descriptive, perspective approach. Technology supports current best practice and has potential to inform decision making through features that could enhance home evaluation processes, quality, efficiency and inter-professional communication. Technological advances with app design have created numerous opportunities for the field of home modifications. Integrating technology and inter-professional best practices will improve home safety evaluation and intervention development to meet client-centred and societal needs. Implications for rehabilitation Understanding home evaluators technology needs for home safety evaluations contributes to the development of app-based assessments. Integrating inter-professional perspectives of best practice and technological needs in an app for home assessments improves processes. Novice and expert home evaluators would benefit from decision support systems embedded in app-based assessments. Adoption of app-based assessment would improve efficiency while remaining client-centred.

App Factory: A flexible approach to rehabilitation engineering in an era of rapid technology advancement.

PubMed

Jones, Michael; Mueller, James; Morris, John

2017-01-01

This article describes a flexible and effective approach to research and development in an era of rapid technological advancement. The approach relies on secondary dispersal of grant funds to commercial developers through a competitive selection process. This "App Factory" model balances the practical reliance on multi-year funding needed to sustain a rehabilitation engineering research center (RERC), with the need for agility and adaptability of development efforts undertaken in a rapidly changing technology environment. This approach also allows us to take advantage of technical expertise needed to accomplish a particular development task, and provides incentives to deliver successful products in a cost-effective manner. In this article, we describe the App Factory structure, process, and results achieved to date; and we discuss the lessons learned and the potential relevance of this approach for other grant-funded research and development efforts. Data presented on the direct costs and number of downloads of the 16 app development projects funded in the App Factory's first 3 years show that it can be an effective means for supporting focused, short-term assistive technology development projects.

The Analysis Of Smartphone Apps In Geomatics Education

NASA Astrophysics Data System (ADS)

Teo, T.-A.; Wu, H.-M.; Shih, T.-Y.; Tsai, F.

2014-04-01

Geomatics is a discipline of collecting, processing and analysing geospatial data. Data collection is a core process of geomatics which usually adopt precise equipment to measure geospatial data. With the development of technology, a smartphone in this present era is not simply for communication; several low cost measurement devices such as Global Positioning System (GPS), gyro and camera are assembled in a smartphone. Although the devices assembled in a smartphone could not meet the needs of accuracy requirement for many geomatics applications, millions of mobile applications (Apps) can be downloaded and installed from Google Play and Apple Store freely, and a variety of sensors can be chosen for user. Considering that the popularity and convenience of a smartphone, and assuming that the accuracy of those collected data is acceptable for learning purposes, it is expected that a smartphone can be employed in geomatics for hand-on education. For example, Vespucci OSM Editor is an App to edit the OpenStreetMap on Android. The user may have the hand-on experience on GPS positioning, web services and mapping via Vespucci OSM Editor. The aim of this paper is to collect and analyze different Apps for geomatics education. The Apps are classified into four categories, namely, surveying, remote sensing, GPS and Geographic Information System (GIS). In this paper, more than 20 free Apps are collected and analysed for different hand-on studies in geomatics education. Finally, all the related Apps are listed on a website for updating.

Identifying Medication Management Smartphone App Features Suitable for Young Adults With Developmental Disabilities: Delphi Consensus Study

PubMed Central

Salgado, Teresa M; Fedrigon, Alexa; Riccio Omichinski, Donna; Meade, Michelle A

2018-01-01

Background Smartphone apps can be a tool to facilitate independent medication management among persons with developmental disabilities. At present, multiple medication management apps exist in the market, but only 1 has been specifically designed for persons with developmental disabilities. Before initiating further app development targeting this population, input from stakeholders including persons with developmental disabilities, caregivers, and professionals regarding the most preferred features should be obtained. Objective The aim of this study was to identify medication management app features that are suitable to promote independence in the medication management process by young adults with developmental disabilities using a Delphi consensus method. Methods A compilation of medication management app features was performed by searching the iTunes App Store, United States, in February 2016, using the following terms: adherence, medication, medication management, medication list, and medication reminder. After identifying features within the retrieved apps, a final list of 42 features grouped into 4 modules (medication list, medication reminder, medication administration record, and additional features) was included in a questionnaire for expert consensus rating. A total of 52 experts in developmental disabilities, including persons with developmental disabilities, caregivers, and professionals, were invited to participate in a 3-round Delphi technique. The purpose was to obtain consensus on features that are preferred and suitable to promote independence in the medication management process among persons with developmental disabilities. Consensus for the first, second, and third rounds was defined as ≥90%, ≥80%, and ≥75% agreement, respectively. Results A total of 75 responses were received over the 3 Delphi rounds—30 in the first round, 24 in the second round, and 21 in the third round. At the end of the third round, cumulative consensus was achieved for 60% (12/20) items in the medication list module, 100% (3/3) in the medication reminder module, 67% (2/3) in the medication administration record module, and 63% (10/16) in the additional features module. In addition to the medication list, medication reminder, and medication administration record features, experts selected the following top 3 most important additional features: automatic refills through pharmacies; ability to share medication information from the app with providers; and ability to share medication information from the app with family, friends, and caregivers. The top 3 least important features included a link to an official drug information source, privacy settings and password protection, and prescription refill reminders. Conclusions Although several mobile apps for medication management exist, few are specifically designed to support persons with developmental disabilities in the complex medication management process. Of the 42 different features assessed, 64% (27/42) achieved consensus for inclusion in a future medication management app. This study provides information on the features of a medication management app that are most important to persons with developmental disabilities, caregivers, and professionals. PMID:29792292

Amyloid precursor protein modulates ERK-1 and -2 signaling.

PubMed

Venezia, Valentina; Nizzari, Mario; Repetto, Emanuela; Violani, Elisabetta; Corsaro, Alessandro; Thellung, Stefano; Villa, Valentina; Carlo, Pia; Schettini, Gennaro; Florio, Tullio; Russo, Claudio

2006-12-01

The amyloid precursor protein (APP) is a transmembrane protein with a short cytoplasmic tail whose physiological function is unclear, although it is well documented that the proteolytic processing of APP could influence the development of Alzheimer's disease (AD) through the formation of membrane-bound C-terminal fragments (CTFs) and of beta-amyloid peptides (Abeta). We have recently shown that tyrosine-phosphorylated APP and CTFs may interact with Grb2 and ShcA adaptor proteins and that this coupling occurs at a higher extent in AD subjects only. To study the interaction between APP or CTFs and ShcA/Grb2 and to investigate their molecular target we have used as experimental model two different cell lines: H4 human neuroglioma cells and APP/APLP null mouse embryonic fibroblast cells (MEFs). Here we show that in H4 cells APP interacts with Grb2; conversely in APP/APLP-null MEF cells this interaction is possible only after the reintroduction of human APP by transfection. We have also shown that in MEF cells the transfection of a plasmid encoding for human APP wild-type enhances the phosphorylation of ERK-1 and -2 as revealed by Western blotting and immunofluorescence experiments. Finally, also in H4 cells the overexpression of APP upregulates the levels of phospho-ERK-1 and -2. In summary our data suggest that APP may influence phospho-ERK-1 and -2 signaling through its binding with Grb2 and ShcA adaptors. The meaning of this event is not clear, but APP interaction with these adaptors could be relevant to regulate mitogenic pathway.

"WhatsApp"ening in orthopedic care: a concise report from a 300-bedded tertiary care teaching center.

PubMed

Khanna, Vishesh; Sambandam, Senthil N; Gul, Arif; Mounasamy, Varatharaj

2015-07-01

Smartphones have emerged as essential tools providing assistance in patient care, monitoring, rehabilitation, communication, diagnosis, teaching, research and reference. Among innumerable communication apps, WhatsApp has been widely popular and cost effective. The aim of our study was to report the impact of introduction of a smartphone app "WhatsApp" as an intradepartmental communication tool on (1) awareness of patient-related information, (2) efficiency of the handover process and (3) duration of traditional morning handovers among orthopedic residents in a 300-bedded tertiary care teaching center. Written handovers and paging used for communication at our center led to occasional inefficiencies among residents. Widespread use, low cost, availability and double password protection (phone lock and WhatsApp lock) made WhatsApp's group conversation feature an ideal tool for intradepartmental patient-related communication. Twenty-five consecutive admissions before and after WhatsApp (BW, AW) were included in the study. Eight orthopedic residents attempted fifty randomly arranged questions based on the twenty-five patients in each study period. A null hypothesis that introduction of WhatsApp group would neither increase the awareness of patient-related information nor improve the efficiency of the handovers among residents was assumed. A significant improvement observed in scores obtained by residents in the AW group led to rejection of the null hypothesis. The residents also reported swifter and efficient handovers after the introduction of WhatsApp. Our results indicate that the introduction of a smartphone app "WhatsApp" as an intradepartmental communication tool can bring about an improvement in patient-related awareness, communication and handovers among orthopedic residents.

Developing a Mobile App for Prevention and Treatment of Pressure Injuries.

PubMed

Salomé, Geraldo Magela; Ferreira, Lydia Masako

2018-02-01

This descriptive study describes the planning and development of a mobile application (app) for prevention and treatment of pressure injuries for use by providers in a university research center. The app delineates risk factors for pressure injury development, provides an evaluation of the wound, recommends wound cleansing procedures, performs pressure injury staging, and recommends treatment interventions. A mobile app was developed using a contextualized instructional design, which involves a constructivist proposal and planning, developing, and applying specific didactic situations, thus incorporating mechanisms that favor contextualization. A literature search was conducted to identify relevant studies for the construction of the mobile app. The development process involved the selection of app tools, definition of the navigation structure, and planning of the environment configuration. The environment for downloading the app software on the Internet and installing it on the mobile device was created. The literature search yielded 18 articles, 2 books, and 1 master's degree thesis. A mobile app was created with an easy-to-use graphic interface. The app stores the patient's demographic characteristics and provides an evaluation of his/her wound, a list of risk factors for pressure injury development, wound cleansing procedures, and treatment interventions. The developed app may be useful in clinical practice, helping to prevent pressure injuries and promote select nursing interventions for the treatment of patients with pressure injury.

Putting education in "educational" apps: lessons from the science of learning.

PubMed

Hirsh-Pasek, Kathy; Zosh, Jennifer M; Golinkoff, Roberta Michnick; Gray, James H; Robb, Michael B; Kaufman, Jordy

2015-05-01

Children are in the midst of a vast, unplanned experiment, surrounded by digital technologies that were not available but 5 years ago. At the apex of this boom is the introduction of applications ("apps") for tablets and smartphones. However, there is simply not the time, money, or resources available to evaluate each app as it enters the market. Thus, "educational" apps-the number of which, as of January 2015, stood at 80,000 in Apple's App Store (Apple, 2015)-are largely unregulated and untested. This article offers a way to define the potential educational impact of current and future apps. We build upon decades of work on the Science of Learning, which has examined how children learn best. From this work, we abstract a set of principles for two ultimate goals. First, we aim to guide researchers, educators, and designers in evidence-based app development. Second, by creating an evidence-based guide, we hope to set a new standard for evaluating and selecting the most effective existing children's apps. In short, we will show how the design and use of educational apps aligns with known processes of children's learning and development and offer a framework that can be used by parents and designers alike. Apps designed to promote active, engaged, meaningful, and socially interactive learning-four "pillars" of learning-within the context of a supported learning goal are considered educational. © The Author(s) 2015.

Modern use of smartphone applications in the perioperative management in microsurgical breast reconstruction.

PubMed

Patel, Nakul Gamanlal; Rozen, Warren Matthew; Marsh, Daniel; Chow, Whitney T H; Vickers, Tobias; Khan, Lubna; Miller, George S; Hunter-Smith, David J; Ramakrishnan, Venkat V

2016-04-01

Advances in mobile telecommunication, improved mobile internet and affordability have led to a significant increase in smartphone use within medicine. The capability of instant messaging, photography, videography, word processing, drawing and internet access allow significant potential in this small portable device. Smartphone use within medicine has grown tremendously worldwide given its affordability, improved internet and capabilities. We have searched for apps specifically helpful in the perioperative care of microsurgical breast reconstructive patients. The useful apps have been subdivided: (I) communication apps-multimedia messaging, WhatsApp, PicSafeMedi: allow efficient communication via text, picture and video messages leading to earlier assessment and definitive management of free flaps; (II) storage apps-Notability, Elogbook: electronic storage of patient notes and logbooks of case which can be shared with others if required; (III) educational apps-FlapApp, Touch Surgery, PubMed on tap: step by step guides to surgical procedures to aid learning and medical journal database; (IV) flap monitoring app-SilpaRamanitor: free flap monitoring app based on photographic analysis for earlier detection of compromised flaps. There has been remarkable growth in smartphones use among surgeons. Apps are being developed for every conceivable use. The future will be in wearable smart devices that allow continuous monitoring with the potential to instigate change should deviations from the norm occur. The smart watch is the start of this digital revolution.

The use of smartphone health apps and other mobile health (mHealth) technologies in dietetic practice: a three country study.

PubMed

Chen, J; Lieffers, J; Bauman, A; Hanning, R; Allman-Farinelli, M

2017-08-01

Smartphone health applications (apps) and other mobile health (mHealth) technologies may assist dietitians in improving the efficiency of patient care. The present study investigated the use of health apps and text messaging in dietetic practice and formulated intervention recommendations for supporting app uptake by dietitians based on the behavioural 'COM-B' system, where interactions between capability, opportunity and motivation influence behaviour. A 52-item online survey tool, taking 20 min to complete, was developed and piloted, with questions exploring the use of health apps and text messaging in dietetic practice, types of apps dietitians recommended and that patients used, and barriers and enablers to app use in dietetic practice. The Australian, New Zealand and British dietetic associations distributed the survey to their members. A 5% response rate was achieved internationally, with 570 completed responses included for further analysis. Health apps, namely nutrition apps, were used by 62% of dietitians in their practice, primarily as an information resource (74%) and for patient self-monitoring (60%). The top two nutrition apps recommended were MyFitnessPal ® (62%) and the Monash University Low FODMAP Diet ® (44%). Text messaging was used by 51% of respondents, mainly for appointment-related purposes (84%). Although the reported use of smartphone health apps in dietetic practice is high, health apps and other mHealth technologies are not currently being used for behaviour change, nor are they an integral part of the nutrition care process. Dietetic associations should provide training, education and advocacy to enable the profession to more effectively engage with and implement apps into their practice. © 2017 The British Dietetic Association Ltd.

Attention and Cognitive Bias Modification Apps: Review of the Literature and of Commercially Available Apps.

PubMed

Zhang, Melvyn; Ying, JiangBo; Song, Guo; Fung, Daniel Ss; Smith, Helen

2018-05-24

Automatic processes, such as attentional biases or interpretative biases, have been purported to be responsible for several psychiatric disorders. Recent reviews have highlighted that cognitive biases may be modifiable. Advances in eHealth and mHealth have been harnessed for the delivery of cognitive bias modification. While several studies have evaluated mHealth-based bias modification intervention, no review, to our knowledge, has synthesized the evidence for it. In addition, no review has looked at commercial apps and their functionalities and methods of bias modification. A review is essential in determining whether scientifically validated apps are available commercially and the proportion of commercial apps that have been evaluated scientifically. The objective of this review was primarily to determine the proportion of attention or cognitive bias modification apps that have been evaluated scientifically and secondarily to determine whether the scientifically evaluated apps were commercially available. We also sought to identify commercially available bias modification apps and determine the functionalities of these apps, the methods used for attention or cognitive bias modification, and whether these apps had been evaluated scientifically. To identify apps in the published literature, we searched PubMed, MEDLINE, PsycINFO, and Scopus for studies published from 2000 to April 17, 2018. The search terms used were "attention bias" OR "cognitive bias" AND "smartphone" OR "smartphone application" OR "smartphone app" OR "mobile phones" OR "mobile application" OR mobile app" OR "personal digital assistant." To identify commercial apps, we conducted a manual cross-sectional search between September 15 and 25, 2017 in the Apple iTunes and Google Play app stores. The search terms used to identify the apps were "attention bias" and "cognitive bias." We also conducted a manual search on the apps with published evaluations. The effectiveness of bias modification was reported in 7 of 8 trials that we identified in the published literature. Only 1 of the 8 previously evaluated apps was commercially available. The 17 commercial apps we identified tended to use either an attention visual search or gamified task. Only 1 commercial app had been evaluated in the published literature. This is perhaps the first review to synthesize the evidence for published mHealth attention bias apps. Our review demonstrated that evidence for mHealth attention bias apps is inconclusive, and quite a few commercial apps have not been validated scientifically. ©Melvyn Zhang, JiangBo Ying, Guo Song, Daniel SS Fung, Helen Smith. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 24.05.2018.

Exploring the Far Side of Mobile Health: Information Security and Privacy of Mobile Health Apps on iOS and Android

PubMed Central

Dehling, Tobias; Gao, Fangjian; Schneider, Stephan

2015-01-01

Background Mobile health (mHealth) apps aim at providing seamless access to tailored health information technology and have the potential to alleviate global health burdens. Yet, they bear risks to information security and privacy because users need to reveal private, sensitive medical information to redeem certain benefits. Due to the plethora and diversity of available mHealth apps, implications for information security and privacy are unclear and complex. Objective The objective of this study was to establish an overview of mHealth apps offered on iOS and Android with a special focus on potential damage to users through information security and privacy infringements. Methods We assessed apps available in English and offered in the categories “Medical” and “Health & Fitness” in the iOS and Android App Stores. Based on the information retrievable from the app stores, we established an overview of available mHealth apps, tagged apps to make offered information machine-readable, and clustered the discovered apps to identify and group similar apps. Subsequently, information security and privacy implications were assessed based on health specificity of information available to apps, potential damage through information leaks, potential damage through information manipulation, potential damage through information loss, and potential value of information to third parties. Results We discovered 24,405 health-related apps (iOS; 21,953; Android; 2452). Absence or scarceness of ratings for 81.36% (17,860/21,953) of iOS and 76.14% (1867/2452) of Android apps indicates that less than a quarter of mHealth apps are in more or less widespread use. Clustering resulted in 245 distinct clusters, which were consolidated into 12 app archetypes grouping clusters with similar assessments of potential damage through information security and privacy infringements. There were 6426 apps that were excluded during clustering. The majority of apps (95.63%, 17,193/17,979; of apps) pose at least some potential damage through information security and privacy infringements. There were 11.67% (2098/17,979) of apps that scored the highest assessments of potential damages. Conclusions Various kinds of mHealth apps collect and offer critical, sensitive, private medical information, calling for a special focus on information security and privacy of mHealth apps. In order to foster user acceptance and trust, appropriate security measures and processes need to be devised and employed so that users can benefit from seamlessly accessible, tailored mHealth apps without exposing themselves to the serious repercussions of information security and privacy infringements. PMID:25599627

Exploring the Far Side of Mobile Health: Information Security and Privacy of Mobile Health Apps on iOS and Android.

PubMed

Dehling, Tobias; Gao, Fangjian; Schneider, Stephan; Sunyaev, Ali

2015-01-19

Mobile health (mHealth) apps aim at providing seamless access to tailored health information technology and have the potential to alleviate global health burdens. Yet, they bear risks to information security and privacy because users need to reveal private, sensitive medical information to redeem certain benefits. Due to the plethora and diversity of available mHealth apps, implications for information security and privacy are unclear and complex. The objective of this study was to establish an overview of mHealth apps offered on iOS and Android with a special focus on potential damage to users through information security and privacy infringements. We assessed apps available in English and offered in the categories "Medical" and "Health & Fitness" in the iOS and Android App Stores. Based on the information retrievable from the app stores, we established an overview of available mHealth apps, tagged apps to make offered information machine-readable, and clustered the discovered apps to identify and group similar apps. Subsequently, information security and privacy implications were assessed based on health specificity of information available to apps, potential damage through information leaks, potential damage through information manipulation, potential damage through information loss, and potential value of information to third parties. We discovered 24,405 health-related apps (iOS; 21,953; Android; 2452). Absence or scarceness of ratings for 81.36% (17,860/21,953) of iOS and 76.14% (1867/2452) of Android apps indicates that less than a quarter of mHealth apps are in more or less widespread use. Clustering resulted in 245 distinct clusters, which were consolidated into 12 app archetypes grouping clusters with similar assessments of potential damage through information security and privacy infringements. There were 6426 apps that were excluded during clustering. The majority of apps (95.63%, 17,193/17,979; of apps) pose at least some potential damage through information security and privacy infringements. There were 11.67% (2098/17,979) of apps that scored the highest assessments of potential damages. Various kinds of mHealth apps collect and offer critical, sensitive, private medical information, calling for a special focus on information security and privacy of mHealth apps. In order to foster user acceptance and trust, appropriate security measures and processes need to be devised and employed so that users can benefit from seamlessly accessible, tailored mHealth apps without exposing themselves to the serious repercussions of information security and privacy infringements.

Apps seeking theories: results of a study on the use of health behavior change theories in cancer survivorship mobile apps.

PubMed

Vollmer Dahlke, Deborah; Fair, Kayla; Hong, Y Alicia; Beaudoin, Christopher E; Pulczinski, Jairus; Ory, Marcia G

2015-03-27

Thousands of mobile health apps are now available for use on mobile phones for a variety of uses and conditions, including cancer survivorship. Many of these apps appear to deliver health behavior interventions but may fail to consider design considerations based in human computer interface and health behavior change theories. This study is designed to assess the presence of and manner in which health behavior change and health communication theories are applied in mobile phone cancer survivorship apps. The research team selected a set of criteria-based health apps for mobile phones and assessed each app using qualitative coding methods to assess the application of health behavior change and communication theories. Each app was assessed using a coding derived from the taxonomy of 26 health behavior change techniques by Abraham and Michie with a few important changes based on the characteristics of mHealth apps that are specific to information processing and human computer interaction such as control theory and feedback systems. A total of 68 mobile phone apps and games built on the iOS and Android platforms were coded, with 65 being unique. Using a Cohen's kappa analysis statistic, the inter-rater reliability for the iOS apps was 86.1 (P<.001) and for the Android apps, 77.4 (P<.001). For the most part, the scores for inclusion of theory-based health behavior change characteristics in the iOS platform cancer survivorship apps were consistently higher than those of the Android platform apps. For personalization and tailoring, 67% of the iOS apps (24/36) had these elements as compared to 38% of the Android apps (12/32). In the area of prompting for intention formation, 67% of the iOS apps (34/36) indicated these elements as compared to 16% (5/32) of the Android apps. Mobile apps are rapidly emerging as a way to deliver health behavior change interventions that can be tailored or personalized for individuals. As these apps and games continue to evolve and include interactive and adaptive sensors and other forms of dynamic feedback, their content and interventional elements need to be grounded in human computer interface design and health behavior and communication theory and practice.

Apps Seeking Theories: Results of a Study on the Use of Health Behavior Change Theories in Cancer Survivorship Mobile Apps

PubMed Central

Fair, Kayla; Hong, Y Alicia; Beaudoin, Christopher E; Pulczinski, Jairus; Ory, Marcia G

2015-01-01

Background Thousands of mobile health apps are now available for use on mobile phones for a variety of uses and conditions, including cancer survivorship. Many of these apps appear to deliver health behavior interventions but may fail to consider design considerations based in human computer interface and health behavior change theories. Objective This study is designed to assess the presence of and manner in which health behavior change and health communication theories are applied in mobile phone cancer survivorship apps. Methods The research team selected a set of criteria-based health apps for mobile phones and assessed each app using qualitative coding methods to assess the application of health behavior change and communication theories. Each app was assessed using a coding derived from the taxonomy of 26 health behavior change techniques by Abraham and Michie with a few important changes based on the characteristics of mHealth apps that are specific to information processing and human computer interaction such as control theory and feedback systems. Results A total of 68 mobile phone apps and games built on the iOS and Android platforms were coded, with 65 being unique. Using a Cohen’s kappa analysis statistic, the inter-rater reliability for the iOS apps was 86.1 (P<.001) and for the Android apps, 77.4 (P<.001). For the most part, the scores for inclusion of theory-based health behavior change characteristics in the iOS platform cancer survivorship apps were consistently higher than those of the Android platform apps. For personalization and tailoring, 67% of the iOS apps (24/36) had these elements as compared to 38% of the Android apps (12/32). In the area of prompting for intention formation, 67% of the iOS apps (34/36) indicated these elements as compared to 16% (5/32) of the Android apps. Conclusions Mobile apps are rapidly emerging as a way to deliver health behavior change interventions that can be tailored or personalized for individuals. As these apps and games continue to evolve and include interactive and adaptive sensors and other forms of dynamic feedback, their content and interventional elements need to be grounded in human computer interface design and health behavior and communication theory and practice. PMID:25830810

A user-centered model for designing consumer mobile health (mHealth) applications (apps).

PubMed

Schnall, Rebecca; Rojas, Marlene; Bakken, Suzanne; Brown, William; Carballo-Dieguez, Alex; Carry, Monique; Gelaude, Deborah; Mosley, Jocelyn Patterson; Travers, Jasmine

2016-04-01

Mobile technologies are a useful platform for the delivery of health behavior interventions. Yet little work has been done to create a rigorous and standardized process for the design of mobile health (mHealth) apps. This project sought to explore the use of the Information Systems Research (ISR) framework as guide for the design of mHealth apps. Our work was guided by the ISR framework which is comprised of 3 cycles: Relevance, Rigor and Design. In the Relevance cycle, we conducted 5 focus groups with 33 targeted end-users. In the Rigor cycle, we performed a review to identify technology-based interventions for meeting the health prevention needs of our target population. In the Design Cycle, we employed usability evaluation methods to iteratively develop and refine mock-ups for a mHealth app. Through an iterative process, we identified barriers and facilitators to the use of mHealth technology for HIV prevention for high-risk MSM, developed 'use cases' and identified relevant functional content and features for inclusion in a design document to guide future app development. Findings from our work support the use of the ISR framework as a guide for designing future mHealth apps. Results from this work provide detailed descriptions of the user-centered design and system development and have heuristic value for those venturing into the area of technology-based intervention work. Findings from this study support the use of the ISR framework as a guide for future mHealth app development. Use of the ISR framework is a potentially useful approach for the design of a mobile app that incorporates end-users' design preferences. Copyright © 2016 Elsevier Inc. All rights reserved.

Design and evaluation of a mobile application to assist the self-monitoring of the chronic kidney disease in developing countries.

PubMed

Sobrinho, Alvaro; da Silva, Leandro Dias; Perkusich, Angelo; Pinheiro, Maria Eliete; Cunha, Paulo

2018-01-12

The chronic kidney disease (CKD) is a worldwide critical problem, especially in developing countries. CKD patients usually begin their treatment in advanced stages, which requires dialysis and kidney transplantation, and consequently, affects mortality rates. This issue is faced by a mobile health (mHealth) application (app) that aims to assist the early diagnosis and self-monitoring of the disease progression. A user-centered design (UCD) approach involving health professionals (nurse and nephrologists) and target users guided the development process of the app between 2012 and 2016. In-depth interviews and prototyping were conducted along with healthcare professionals throughout the requirements elicitation process. Elicited requirements were translated into a native mHealth app targeting the Android platform. Afterward, the Cohen's Kappa coefficient statistics was applied to evaluate the agreement between the app and three nephrologists who analyzed test results collected from 60 medical records. Finally, eight users tested the app and were interviewed about usability and user perceptions. A mHealth app was designed to assist the CKD early diagnosis and self-monitoring considering quality attributes such as safety, effectiveness, and usability. A global Kappa value of 0.7119 showed a substantial degree of agreement between the app and three nephrologists. Results of face-to-face interviews with target users indicated a good user satisfaction. However, the task of CKD self-monitoring proved difficult because most of the users did not fully understand the meaning of specific biomarkers (e.g., creatinine). The UCD approach provided mechanisms to develop the app based on the real needs of users. Even with no perfect Kappa degree of agreement, results are satisfactory because it aims to refer patients to nephrologists in early stages, where they may confirm the CKD diagnosis.

MEDication reminder APPs to improve medication adherence in Coronary Heart Disease (MedApp-CHD) Study: a randomised controlled trial protocol.

PubMed

Santo, Karla; Chow, Clara K; Thiagalingam, Aravinda; Rogers, Kris; Chalmers, John; Redfern, Julie

2017-10-08

The growing number of smartphone health applications available in the app stores makes these apps a promising tool to help reduce the global problem of non-adherence to long-term medications. However, to date, there is limited evidence that available medication reminder apps are effective. This study aims to determine the impact of medication reminder apps on adherence to cardiovascular medication when compared with usual care for people with coronary heart disease (CHD) and to determine whether an advanced app compared with a basic app is associated with higher adherence. Randomised controlled trial with follow-up at 3 months to evaluate the feasibility and effectiveness of medication reminder apps on medication adherence compared with usual care. An estimated sample size of 156 patients with CHD will be randomised to one of three groups (usual care group, basic medication reminder app group and advanced medication reminder app group). The usual care group will receive standard care for CHD with no access to a medication reminder app. The basic medication reminder app group will have access to a medication reminder app with a basic feature of providing simple daily reminders with no interactivity. The advanced medication reminder app group will have access to a medication reminder app with additional interactive and customisable features. The primary outcome is medication adherence measured by the eight-item Morisky Medication Adherence Scale at 3 months. Secondary outcomes include clinical measurements of blood pressure and cholesterol levels, and medication knowledge. A process evaluation will also be performed to assess the feasibility of the intervention by evaluating the acceptability, utility and engagement with the apps. Ethical approval has been obtained from the Western Sydney Local Health Network Human Research Ethics Committee (AU/RED/HREC/1/WMEAD/3). Study findings will be disseminated via usual scientific forums. ACTRN12616000661471; Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Yang; Gong, Hao; Sun, Yue

Highlights: Black-Right-Pointing-Pointer We dissect how individual disulfide bond affects the amyloidogenicity of insulin. Black-Right-Pointing-Pointer A controlled reduction system for insulin is established in this study. Black-Right-Pointing-Pointer Disulfide breakage is associated with unfolding and increased amyloidogenicity. Black-Right-Pointing-Pointer Breakage of A6-A11 is associated with significantly increased cytotoxicity. Black-Right-Pointing-Pointer Analogs without A6-A11 have a higher potency to form high order toxic oligomers. -- Abstract: Disulfide bonds play a critical role in the stability and folding of proteins. Here, we used insulin as a model system, to investigate the role of its individual disulfide bond during the amyloid formation of insulin. Tris(2-carboxyethyl)phosphine (TCEP) wasmore » applied to reduce two of the three disulfide bonds in porcine insulin and the reduced disulfide bonds were then alkylated by iodoacetamide. Three disulfide bond-modified insulin analogs, INS-2 (lack of A6-A11), INS-3 (lack of A7-B7) and INS-6 (lack of both A6-A11 and A7-B7), were obtained. Far-UV circular dichroism (CD) spectroscopy results indicated that the secondary structure of INS-2 was the closest to insulin under neutral conditions, followed by INS-3 and INS-6, whereas in an acidic solution all analogs were essentially unfolded. To test how these modifications affect the amyloidogenicity of insulin, thioflavin-T (ThT) fluorescence and transmission electronic microscopy (TEM) were performed. Our results showed that all analogs were more prone to aggregation than insulin, with the order of aggregation rates being INS-6 > INS-3 > INS-2. Cross-linking of unmodified proteins (PICUP) assay results showed that analogs without A6-A11 (INS-2 and INS-6) have a higher potential for oligomerization than insulin and INS-3, which is accompanied with a higher cytotoxicity as the hemolytic assays of human erythrocytes suggested. The results indicated that breakage of A7-B7 induced more unfolding of the insulin structure and a higher amyloidogenicity than breakage of A6-A11, but breakage of A6-A11 caused a significant cytotoxicity increase and a higher potency to form high order toxic oligomers.« less

What makes a good clinical app? Introducing the RCP Health Informatics Unit checklist.

PubMed

Wyatt, Jeremy C; Thimbleby, Harold; Rastall, Paul; Hoogewerf, Jan; Wooldridge, Darren; Williams, John

2015-12-01

Doctors increasingly rely on medical apps running on smart phones or tablet computers to support their work. However, these apps vary hugely in the quality of their data input screens, internal data processing, the methods used to handle sensitive patient data and how they communicate their output to the user. Inspired by Donabedian's approach to assessing quality and the principles of good user interface design, the Royal College of Physicians' Health Informatics Unit has developed and piloted an 18-item checklist to help clinicians assess the structure, functions and impact of medical apps. Use of this checklist should help clinicians to feel more confident about using medical apps themselves, about recommending them to their staff or prescribing them for patients. © Royal College of Physicians 2015. All rights reserved.

Development of smartphone applications for nutrition and physical activity behavior change.

PubMed

Hebden, Lana; Cook, Amelia; van der Ploeg, Hidde P; Allman-Farinelli, Margaret

2012-08-22

Young adults (aged 18 to 35) are a population group at high risk for weight gain, yet we know little about how to intervene in this group. Easy access to treatment and support with self-monitoring of their behaviors may be important. Smartphones are gaining in popularity with this population group and software applications ("apps") used on these mobile devices are a novel technology that can be used to deliver brief health behavior change interventions directly to individuals en masse, with potentially favorable cost-utility. However, existing apps for modifying nutrition or physical activity behaviors may not always reflect best practice guidelines for weight management. This paper describes the process of developing four apps aimed at modifying key lifestyle behaviors associated with weight gain during young adulthood, including physical activity, and consumption of take-out foods (fast food), fruit and vegetables, and sugar-sweetened drinks. The development process involved: (1) deciding on the behavior change strategies, relevant guidelines, graphic design, and potential data collection; (2) selecting the platform (Web-based versus native); (3) creating the design, which required decisions about the user interface, architecture of the relational database, and programming code; and (4) testing the prototype versions with the target audience (young adults aged 18 to 35). The four apps took 18 months to develop, involving the fields of marketing, nutrition and dietetics, physical activity, and information technology. Ten subjects provided qualitative feedback about using the apps. The slow running speed of the apps (due to a reliance on an active Internet connection) was the primary issue identified by this group, as well as the requirement to log in to the apps. Smartphone apps may be an innovative medium for delivering individual health behavior change intervention en masse, but researchers must give consideration to the target population, available technologies, existing commercial apps, and the possibility that their use will be irregular and short-lived.

Development and Testing of a Mobile Phone App for Self-Monitoring of Calcium Intake in Young Women.

PubMed

Tay, Ilona; Garland, Suzanne; Gorelik, Alexandra; Wark, John Dennis

2017-03-07

Interventions to prevent osteoporosis by increasing dairy intake or physical activity in young women have been limited to increasing osteoporosis knowledge and awareness. However, findings have shown that this does not always lead to a change in behaviors. Self-monitoring using mobile devices in behavioral interventions has yielded significant and positive outcomes. Yet, to our knowledge, mobile self-monitoring has not been used as an intervention strategy to increase calcium intake, particularly in young women, for better bone health outcomes. As development and testing of mobile app-based interventions requires a sequence of steps, our study focused on testing the acceptability and usability of Calci-app, a dietary app to self-monitor calcium consumption, before it is used in a behavioral change intervention in young women aged 18-25 years. Calci-app development followed 4 steps: (1) conceptualization, (2) development and pretesting, (3) pilot testing, and (4) mixed methods evaluation. We present the development process of Calci-app and evaluation of the acceptability and usability of the app in young women. Overall, 78% (31/40) of study participants completed the 5-day food record with high compliance levels (defined as more than 3 days of full or partial completion). There was a significant reduction in the proportion of participants completing all meal entries over the 5 days (P=.01). Participants generally found Calci-app easy and convenient to use, but it was time-consuming and they expressed a lack of motivation to use the app. We present a detailed description of the development process of Calci-app and an evaluation of its usability and acceptability to self-monitor dietary calcium intake. The findings from this preliminary study demonstrated acceptable use of Calci-app to self-monitor calcium consumption. However, for regular and long-term use the self-monitoring function in Calci-app could be expanded to allow participants to view their total daily calcium intake compared with the recommended daily intake. Additionally, to facilitate sustainable lifestyle behavior modifications, a combination of various behavior change techniques should be considered, such as education, goal setting, and advice to participants based on their stage of change. The feedback on barriers and facilitators from testing Calci-app will be used to design a bone health mHealth intervention to modify risky lifestyle behaviors in young women for better bone health outcomes. ©Ilona Tay, Suzanne Garland, Alexandra Gorelik, John Dennis Wark. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 07.03.2017.

Targeting Parents for Childhood Weight Management: Development of a Theory-Driven and User-Centered Healthy Eating App

PubMed Central

Lahiri, Sudakshina; Brown, Katherine Elizabeth

2015-01-01

Background The proliferation of health promotion apps along with mobile phones' array of features supporting health behavior change offers a new and innovative approach to childhood weight management. However, despite the critical role parents play in children’s weight related behaviors, few industry-led apps aimed at childhood weight management target parents. Furthermore, industry-led apps have been shown to lack a basis in behavior change theory and evidence. Equally important remains the issue of how to maximize users’ engagement with mobile health (mHealth) interventions where there is growing consensus that inputs from the commercial app industry and the target population should be an integral part of the development process. Objective The aim of this study is to systematically design and develop a theory and evidence-driven, user-centered healthy eating app targeting parents for childhood weight management, and clearly document this for the research and app development community. Methods The Behavior Change Wheel (BCW) framework, a theoretically-based approach for intervention development, along with a user-centered design (UCD) philosophy and collaboration with the commercial app industry, guided the development process. Current evidence, along with a series of 9 focus groups (total of 46 participants) comprised of family weight management case workers, parents with overweight and healthy weight children aged 5-11 years, and consultation with experts, provided data to inform the app development. Thematic analysis of focus groups helped to extract information related to relevant theoretical, user-centered, and technological components to underpin the design and development of the app. Results Inputs from parents and experts working in the area of childhood weight management helped to identify the main target behavior: to help parents provide appropriate food portion sizes for their children. To achieve this target behavior, the behavioral diagnosis revealed the need for eliciting change in parents’ capability, motivation, and opportunity in 10-associated Theoretical Domains Framework (TDF) domains. Of the 9 possible intervention functions, 6 were selected to bring about this change which guided the selection of 21 behavior change techniques. Parents’ preferences for healthy eating app features revolved around four main themes (app features, time saving and convenience, aesthetics, and gamification) whereupon a criterion was applied to guide the selection on which preferences should be integrated into the design of the app. Collaboration with the app company helped to build on users’ preferences for elements of gamification such as points, quizzes, and levels to optimize user engagement. Feedback from parents on interactive mock-ups helped to inform the final development of the prototype app. Conclusions Here, we fully explicate a systematic approach applied in the development of a family-oriented, healthy eating health promotion app grounded in theory and evidence, and balanced with users’ preferences to help maximize its engagement with the target population. PMID:26088692

The Use of Communication Apps by Medical Staff in the Australian Health Care System: Survey Study on Prevalence and Use

PubMed Central

Wickramasinghe, Nilmini; Claydon-Platt, Damian; Balakrishnan, Vikram; Smart, Philip

2018-01-01

Background The use of communication apps on mobile phones offers an efficient, unobtrusive, and portable mode of communication for medical staff. The potential enhancements in patient care and education appear significant, with clinical details able to be shared quickly within multidisciplinary teams, supporting rapid integration of disparate information, and more efficient patient care. However, sharing patient data in this way also raises legal and ethical issues. No data is currently available demonstrating how widespread the use of these apps are, doctor’s attitudes towards them, or what guides clinician choice of app. Objective The objective of this study was to quantify and qualify the use of communication apps among medical staff in clinical situations, their role in patient care, and knowledge and attitudes towards safety, key benefits, potential disadvantages, and policy implications. Methods Medical staff in hospitals across Victoria (Australia) were invited to participate in an anonymous 33-question survey. The survey collected data on respondent’s demographics, their use of communication apps in clinical settings, attitudes towards communication apps, perceptions of data “safety,” and why one communication app was chosen over others. Results Communication apps in Victorian hospitals are in widespread use from students to consultants, with WhatsApp being the primary app used. The median number of messages shared per day was 12, encompassing a range of patient information. All respondents viewed these apps positively in quickly communicating patient information in a clinical setting; however, all had concerns about the privacy implications arising from sharing patient information in this way. In total, 67% (60/90) considered patient data “moderately safe” on these apps, and 50% (46/90) were concerned the use of these apps was inconsistent with current legislation and policy. Apps were more likely to be used if they were fast, easy to use, had an easy login process, and were already in widespread use. Conclusions Communication app use by medical personnel in Victorian hospitals is pervasive. These apps contribute to enhanced communication between medical staff, but their use raises compliance issues, most notably with Australian privacy legislation. Development of privacy-compliant apps such as MedX needs to prioritize a user-friendly interface and market the product as a privacy-compliant comparator to apps previously adapted to health care settings. PMID:29426813

Supply and Demand in mHealth Apps for Persons With Multiple Sclerosis: Systematic Search in App Stores and Scoping Literature Review.

PubMed

Giunti, Guido; Guisado Fernández, Estefanía; Dorronzoro Zubiete, Enrique; Rivera Romero, Octavio

2018-05-23

Multiple sclerosis (MS) is a non-curable chronic inflammatory disease of the central nervous system that affects more than 2 million people worldwide. MS-related symptoms impact negatively on the quality of life of persons with MS, who need to be active in the management of their health. mHealth apps could support these patient groups by offering useful tools, providing reliable information, and monitoring symptoms. A previous study from this group identified needs, barriers, and facilitators for the use of mHealth solutions among persons with MS. It is unknown how commercially available health apps meet these needs. The main objective of this review was to assess how the features present in MS apps meet the reported needs of persons with MS. We followed a combination of scoping review methodology and systematic assessment of features and content of mHealth apps. A search strategy was defined for the two most popular app stores (Google Play and Apple App Store) to identify relevant apps. Reviewers independently conducted a screening process to filter apps according to the selection criteria. Interrater reliability was assessed through the Fleiss-Cohen coefficient (k=.885). Data from the included MS apps were extracted and explored according to classification criteria. An initial total of 581 potentially relevant apps was found. After removing duplicates and applying inclusion and exclusion criteria, 30 unique apps were included in the study. A similar number of apps was found in both stores. The majority of the apps dealt with disease management and disease and treatment information. Most apps were developed by small and medium-sized enterprises, followed by pharmaceutical companies. Patient education and personal data management were among the most frequently included features in these apps. Energy management and remote monitoring were often not present in MS apps. Very few contained gamification elements. Currently available MS apps fail to meet the needs and demands of persons with MS. There is a need for health professionals, researchers, and industry partners to collaborate in the design of mHealth solutions for persons with MS to increase adoption and engagement. ©Guido Giunti, Estefanía Guisado Fernández, Enrique Dorronzoro Zubiete, Octavio Rivera Romero. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 23.05.2018.

Towards data warehousing and mining of protein unfolding simulation data.

PubMed

Berrar, Daniel; Stahl, Frederic; Silva, Candida; Rodrigues, J Rui; Brito, Rui M M; Dubitzky, Werner

2005-10-01

The prediction of protein structure and the precise understanding of protein folding and unfolding processes remains one of the greatest challenges in structural biology and bioinformatics. Computer simulations based on molecular dynamics (MD) are at the forefront of the effort to gain a deeper understanding of these complex processes. Currently, these MD simulations are usually on the order of tens of nanoseconds, generate a large amount of conformational data and are computationally expensive. More and more groups run such simulations and generate a myriad of data, which raises new challenges in managing and analyzing these data. Because the vast range of proteins researchers want to study and simulate, the computational effort needed to generate data, the large data volumes involved, and the different types of analyses scientists need to perform, it is desirable to provide a public repository allowing researchers to pool and share protein unfolding data. To adequately organize, manage, and analyze the data generated by unfolding simulation studies, we designed a data warehouse system that is embedded in a grid environment to facilitate the seamless sharing of available computer resources and thus enable many groups to share complex molecular dynamics simulations on a more regular basis. To gain insight into the conformational fluctuations and stability of the monomeric forms of the amyloidogenic protein transthyretin (TTR), molecular dynamics unfolding simulations of the monomer of human TTR have been conducted. Trajectory data and meta-data of the wild-type (WT) protein and the highly amyloidogenic variant L55P-TTR represent the test case for the data warehouse. Web and grid services, especially pre-defined data mining services that can run on or 'near' the data repository of the data warehouse, are likely to play a pivotal role in the analysis of molecular dynamics unfolding data.

Development of a Culturally Appropriate Bilingual Electronic App About Hepatitis B for Indigenous Australians: Towards Shared Understandings

PubMed Central

Bukulatjpi, Sarah; Sharma, Suresh; Caldwell, Luci; Johnston, Vanessa; Davis, Joshua Saul

2015-01-01

Background Hepatitis B is endemic in Indigenous communities in Northern Australia; however, there is a lack of culturally appropriate educational tools. Health care workers and educators in this setting have voiced a desire for visual, interactive tools in local languages. Mobile phones are increasingly used and available in remote Indigenous communities. In this context, we identified the need for a tablet-based health education app about hepatitis B, developed in partnership with an Australian remote Indigenous community. Objective To develop a culturally appropriate bilingual app about hepatitis B for Indigenous Australians in Arnhem Land using a participatory action research (PAR) framework. Methods This project was a partnership between the Menzies School of Health Research, Miwatj Aboriginal Health Corporation, Royal Darwin Hospital Liver Clinic, and Dreamedia Darwin. We have previously published a qualitative study that identified major knowledge gaps about hepatitis B in this community, and suggested that a tablet-based app would be an appropriate and popular tool to improve this knowledge. The process of developing the app was based on PAR principles, particularly ongoing consultation, evaluation, and discussion with the community throughout each iterative cycle. Stages included development of the storyboard, the translation process (forward translation and backtranslation), prelaunch community review, launch and initial community evaluation, and finally, wider launch and evaluation at a viral hepatitis conference. Results We produced an app called “Hep B Story” for use with iPad, iPhone, Android tablets, and mobile phones or personal computers. The app is culturally appropriate, audiovisual, interactive, and users can choose either English or Yolŋu Matha (the most common language in East Arnhem Land) as their preferred language. The initial evaluation demonstrated a statistically significant improvement in Hep B-related knowledge for 2 of 3 questions (P=.01 and .02, respectively) and overwhelmingly positive opinion regarding acceptability and ease of use (median rating of 5, on a 5-point Likert-type scale when users were asked if they would recommend the app to others). Conclusions We describe the process of development of a bilingual hepatitis B-specific app for Indigenous Australians, using a PAR framework. The approach was found to be successful with positive evaluations. PMID:26063474

Decreasing the expression of PICALM reduces endocytosis and the activity of β-secretase: implications for Alzheimer's disease.

PubMed

Thomas, Rhian S; Henson, Alex; Gerrish, Amy; Jones, Lesley; Williams, Julie; Kidd, Emma J

2016-07-18

Polymorphisms in the gene for phosphatidylinositol binding clathrin assembly protein (PICALM), an endocytic-related protein, are associated with a small, increased risk of developing Alzheimer's disease (AD), strongly suggesting that changes in endocytosis are involved in the aetiology of the disease. We have investigated the involvement of PICALM in the processing of amyloid precursor protein (APP) to understand how PICALM could be linked to the development of AD. We used siRNA to deplete levels of PICALM, its isoforms and clathrin heavy chain in the human brain-derived H4 neuroglioma cell line that expresses endogenous levels of APP. We then used Western blotting, ELISA and immunohistochemistry to detect intra- and extracellular protein levels of endocytic-related proteins, APP and APP metabolites including β-amyloid (Aβ). Levels of functional endocytosis were quantified using ALEXA 488-conjugated transferrin and flow cytometry as a marker of clathrin-mediated endocytosis (CME). Following depletion of all the isoforms of PICALM by siRNA in H4 cells, levels of intracellular APP, intracellular β-C-terminal fragment (β-CTF) and secreted sAPPβ (APP fragments produced by β-secretase cleavage) were significantly reduced but Aβ40 was not affected. Functional endocytosis was significantly reduced after both PICALM and clathrin depletion, highlighting the importance of PICALM in this process. However, depletion of clathrin did not affect APP but did reduce β-CTF levels. PICALM depletion altered the intracellular distribution of clathrin while clathrin reduction affected the subcellular pattern of PICALM labelling. Both PICALM and clathrin depletion reduced the expression of BACE1 mRNA and PICALM siRNA reduced protein levels. Individual depletion of PICALM isoforms 1 and 2 did not affect APP levels while clathrin depletion had a differential effect on the isoforms, increasing isoform 1 while decreasing isoform 2 expression. The depletion of PICALM in brain-derived cells has significant effects on the processing of APP, probably by reducing CME. In particular, it affects the production of β-CTF which is increasingly considered to be an important mediator in AD independent of Aβ. Thus a decrease in PICALM expression in the brain could be beneficial to slow or prevent the development of AD.

Increased Alzheimer's disease-like pathology in the APP/ PS1ΔE9 mouse model lacking Nrf2 through modulation of autophagy.

PubMed

Joshi, Gururaj; Gan, Kok Ann; Johnson, Delinda A; Johnson, Jeffrey A

2015-02-01

The presence of senile plaques is one of the major pathologic hallmarks of the brain with Alzheimer's disease (AD). The plaques predominantly contain insoluble amyloid β-peptide, a cleavage product of the larger amyloid precursor protein (APP). Two enzymes, named β and γ secretase, generate the neurotoxic amyloid-β peptide from APP. Mature APP is also turned over endogenously by autophagy, more specifically by the endosomal-lysosomal pathway. A defective lysosomal system is known to be pathogenic in AD. Modulation of NF-E2 related factor 2 (Nrf2) has been shown in several neurodegenerative disorders, and Nrf2 has become a potential therapeutic target for various neurodegenerative disorders, including AD, Parkinson's disease, and amyotrophic lateral sclerosis. In the current study, we explored the effect of genetic ablation of Nrf2 on APP/Aβ processing and/or aggregation as well as changes in autophagic dysfunction in APP/PS1 mice. There was a significant increase in inflammatory response in APP/PS1 mice lacking Nrf2. This was accompanied by increased intracellular levels of APP, Aβ (1-42), and Aβ (1-40), without a change total full-length APP. There was a shift of APP and Aβ into the insoluble fraction, as well as increased poly-ubiquitin conjugated proteins in mice lacking Nrf2. APP/PS1-mediated autophagic dysfunction is also enhanced in Nrf2-deficient mice. Finally, neurons in the APP/PS1/Nrf2-/- mice had increased accumulation of multivesicular bodies, endosomes, and lysosomes. These outcomes provide a better understanding of the role of Nrf2 in modulating autophagy in an AD mouse model and may help design better Nrf2 targeted therapeutics that could be efficacious in the treatment of AD. Published by Elsevier Inc.

MicroRNA-153 Physiologically Inhibits Expression of Amyloid-β Precursor Protein in Cultured Human Fetal Brain Cells and Is Dysregulated in a Subset of Alzheimer Disease Patients*

PubMed Central

Long, Justin M.; Ray, Balmiki; Lahiri, Debomoy K.

2012-01-01

Regulation of amyloid-β (Aβ) precursor protein (APP) expression is complex. MicroRNAs (miRNAs) are expected to participate in the molecular network that controls this process. The composition of this network is, however, still undefined. Elucidating the complement of miRNAs that regulate APP expression should reveal novel drug targets capable of modulating Aβ production in AD. Here, we investigated the contribution of miR-153 to this regulatory network. A miR-153 target site within the APP 3′-untranslated region (3′-UTR) was predicted by several bioinformatic algorithms. We found that miR-153 significantly reduced reporter expression when co-transfected with an APP 3′-UTR reporter construct. Mutation of the predicted miR-153 target site eliminated this reporter response. miR-153 delivery in both HeLa cells and primary human fetal brain cultures significantly reduced APP expression. Delivery of a miR-153 antisense inhibitor to human fetal brain cultures significantly elevated APP expression. miR-153 delivery also reduced expression of the APP paralog APLP2. High functional redundancy between APP and APLP2 suggests that miR-153 may target biological pathways in which they both function. Interestingly, in a subset of human AD brain specimens with moderate AD pathology, miR-153 levels were reduced. This same subset also exhibited elevated APP levels relative to control specimens. Therefore, endogenous miR-153 inhibits expression of APP in human neurons by specifically interacting with the APP 3′-UTR. This regulatory interaction may have relevance to AD etiology, where low miR-153 levels may drive increased APP expression in a subset of AD patients. PMID:22733824

The Amyloid Precursor Protein (APP) Triplicated Gene Impairs Neuronal Precursor Differentiation and Neurite Development through Two Different Domains in the Ts65Dn Mouse Model for Down Syndrome*

PubMed Central

Trazzi, Stefania; Fuchs, Claudia; Valli, Emanuele; Perini, Giovanni; Bartesaghi, Renata; Ciani, Elisabetta

2013-01-01

Intellectual disability in Down syndrome (DS) appears to be related to severe proliferation impairment during brain development. Recent evidence shows that it is not only cellular proliferation that is heavily compromised in DS, but also cell fate specification and dendritic maturation. The amyloid precursor protein (APP), a gene that is triplicated in DS, plays a key role in normal brain development by influencing neural precursor cell proliferation, cell fate specification, and neuronal maturation. APP influences these processes via two separate domains, the APP intracellular domain (AICD) and the soluble secreted APP. We recently found that the proliferation impairment of neuronal precursors (NPCs) from the Ts65Dn mouse model for DS was caused by derangement of the Shh pathway due to overexpression of patched1(Ptch1), its inhibitory regulator. Ptch1 overexpression was related to increased levels within the APP/AICD system. The overall goal of this study was to determine whether APP contributes to neurogenesis impairment in DS by influencing in addition to proliferation, cell fate specification, and neurite development. We found that normalization of APP expression restored the reduced neuronogenesis, the increased astrogliogenesis, and the reduced neurite length of trisomic NPCs, indicating that APP overexpression underpins all aspects of neurogenesis impairment. Moreover, we found that two different domains of APP impair neuronal differentiation and maturation in trisomic NPCs. The APP/AICD system regulates neuronogenesis and neurite length through the Shh pathway, whereas the APP/secreted AP system promotes astrogliogenesis through an IL-6-associated signaling cascade. These results provide novel insight into the mechanisms underlying brain development alterations in DS. PMID:23740250

Attention and Cognitive Bias Modification Apps: Review of the Literature and of Commercially Available Apps

PubMed Central

Ying, JiangBo; Song, Guo; Fung, Daniel SS; Smith, Helen

2018-01-01

Background Automatic processes, such as attentional biases or interpretative biases, have been purported to be responsible for several psychiatric disorders. Recent reviews have highlighted that cognitive biases may be modifiable. Advances in eHealth and mHealth have been harnessed for the delivery of cognitive bias modification. While several studies have evaluated mHealth-based bias modification intervention, no review, to our knowledge, has synthesized the evidence for it. In addition, no review has looked at commercial apps and their functionalities and methods of bias modification. A review is essential in determining whether scientifically validated apps are available commercially and the proportion of commercial apps that have been evaluated scientifically. Objective The objective of this review was primarily to determine the proportion of attention or cognitive bias modification apps that have been evaluated scientifically and secondarily to determine whether the scientifically evaluated apps were commercially available. We also sought to identify commercially available bias modification apps and determine the functionalities of these apps, the methods used for attention or cognitive bias modification, and whether these apps had been evaluated scientifically. Methods To identify apps in the published literature, we searched PubMed, MEDLINE, PsycINFO, and Scopus for studies published from 2000 to April 17, 2018. The search terms used were “attention bias” OR “cognitive bias” AND “smartphone” OR “smartphone application” OR “smartphone app” OR “mobile phones” OR “mobile application” OR mobile app” OR “personal digital assistant.” To identify commercial apps, we conducted a manual cross-sectional search between September 15 and 25, 2017 in the Apple iTunes and Google Play app stores. The search terms used to identify the apps were “attention bias” and “cognitive bias.” We also conducted a manual search on the apps with published evaluations. Results The effectiveness of bias modification was reported in 7 of 8 trials that we identified in the published literature. Only 1 of the 8 previously evaluated apps was commercially available. The 17 commercial apps we identified tended to use either an attention visual search or gamified task. Only 1 commercial app had been evaluated in the published literature. Conclusions This is perhaps the first review to synthesize the evidence for published mHealth attention bias apps. Our review demonstrated that evidence for mHealth attention bias apps is inconclusive, and quite a few commercial apps have not been validated scientifically. PMID:29793899

Acute phase proteins in healthy goats: establishment of reference intervals.

PubMed

Heller, Meera C; Johns, Jennifer L

2015-03-01

Acute inflammatory processes can trigger increased production of acute phase proteins (APPs) that can be useful biomarkers of inflammation. APPs are diverse and include proteins involved in coagulation, opsonization, iron regulation, and limitation of tissue injury. Haptoglobin, serum amyloid A, and alpha-1 acid glycoprotein have been proposed as useful APPs in goats. APPs can differ markedly by species, therefore species-specific reference intervals and studies are necessary. The objective of this study was to determine species-specific reference intervals for 4 APPs in goats. Haptoglobin, serum amyloid A, lipopolysaccharide binding protein, and alpha-1 acid glycoprotein were measured in in 54 clinically normal adult goats. APPs were measured using goat-specific commercial enzyme-linked immunosorbent assay kits. Results were analyzed by 1-way analysis of variance to compare sexes and breeding status. Reference Value Advisor was used to calculate reference limits according to the IFCC-CLSI guidelines. Only 1 APP was found to vary in healthy animals; serum haptoglobin was increased in lactating animals and decreased in pregnant does in their second trimester when compared with open, nonlactating does. No sex-based differences were seen for any of the APPs measured. We report normal reference intervals for 4 serum APPs that may be useful as disease markers. Haptoglobin should be interpreted with caution in animals with unknown pregnancy status. Further studies are needed to determine whether these APPs are useful biomarkers in goat disease states. © 2015 The Author(s).

Development and Testing of a Smartphone Application Prototype for Oral Health Promotion.

PubMed

Nolen, Sara L; Giblin-Scanlon, Lori J; Boyd, Linda D; Rainchuso, Lori

2018-04-01

Purpose: The purpose of this study was to develop and test a smartphone application (app) prototype, ToothSense, as an oral health promotion tool for the prevention of Early Childhood Caries (ECC) based on the Theory of Planned Behavior (TPB). Methods: A quantitative and qualitative design process based on the TPB was used for the app development in the first phase of the study. A behavioral intervention technologic model was used to document the app features design, accounting for Doshi's intervention strategies for the TPB. Beta-testing of the app was hosted via an online software program. Testers were presented with a series of tasks and prompts followed by a 5-point Likert-scale questionnaire that quantitatively measured perceptions of the app's interactive design based on Jakob Nielsen's principles and behavioral strategies. A Net Promotor Score was calculated to determine the tester's likelihood to recommend the app prototype. Audio and video aspects of the app were qualitatively measured using a template approach. Results: Beta testers agreed the app met the majority of the five usability statements. The Net Promotor Score indicated a likelihood to recommend the app prototype. Thematic analyses revealed the following themes: interface design, navigation, terminology, information, and oral health promotion. Conclusion: Beta testing results from this study provided health promotion project design information for the prevention of ECC using the TPB and highlighted the importance and usability of smartphone app for oral health promotion. Copyright © 2018 The American Dental Hygienists’ Association.

Can existing mobile apps support healthier food purchasing behaviour? Content analysis of nutrition content, behaviour change theory and user quality integration.

PubMed

Flaherty, Sarah-Jane; McCarthy, Mary; Collins, Alan; McAuliffe, Fionnuala

2018-02-01

To assess the quality of nutrition content and the integration of user quality components and behaviour change theory relevant to food purchasing behaviour in a sample of existing mobile apps. Descriptive comparative analysis of eleven mobile apps comprising an assessment of their alignment with existing evidence on nutrition, behaviour change and user quality, and their potential ability to support healthier food purchasing behaviour. Mobile apps freely available for public use in GoogePlay were assessed and scored according to agreed criteria to assess nutrition content quality and integration of behaviour change theory and user quality components. A sample of eleven mobile apps that met predefined inclusion criteria to ensure relevance and good quality. The quality of the nutrition content varied. Improvements to the accuracy and appropriateness of nutrition content are needed to ensure mobile apps support a healthy behaviour change process and are accessible to a wider population. There appears to be a narrow focus towards behaviour change with an overemphasis on behavioural outcomes and a small number of behaviour change techniques, which may limit effectiveness. A significant effort from the user was required to use the mobile apps appropriately which may negatively influence user acceptability and subsequent utilisation. Existing mobile apps may offer a potentially effective approach to supporting healthier food purchasing behaviour but improvements in mobile app design are required to maximise their potential effectiveness. Engagement of mobile app users and nutrition professionals is recommended to support effective design.

VLITL is a major cross-β-sheet signal for fibrinogen Aα-chain frameshift variants

PubMed Central

Garnier, Cyrille; Briki, Fatma; Le Pogamp, Patrick; Dogan, Ahmet; Rioux-Leclercq, Nathalie; Goude, Renan; Beugnet, Caroline; Martin, Laurent; Delpech, Marc; Bridoux, Frank; Grateau, Gilles; Doucet, Jean

2017-01-01

The first case of hereditary fibrinogen Aα-chain amyloidosis was recognized >20 years ago, but disease mechanisms still remain unknown. Here we report detailed clinical and proteomics studies of a French kindred with a novel amyloidogenic fibrinogen Aα-chain frameshift variant, Phe521Leufs, causing a severe familial form of renal amyloidosis. Next, we focused our investigations to elucidate the molecular basis that render this Aα-chain variant amyloidogenic. We show that a 49-mer peptide derived from the C-terminal part of the Phe521Leufs chain is deposited as fibrils in the patient’s kidneys, establishing that only a small portion of Phe521Leufs directly contributes to amyloid formation in vivo. In silico analysis indicated that this 49-mer Aα-chain peptide contained a motif (VLITL), with a high intrinsic propensity for β-aggregation at residues 44 to 48 of human renal fibrils. To experimentally verify the amyloid propensity of VLITL, we generated synthetic Phe521Leufs-derived peptides and compared their capacity for fibril formation in vitro with that of their VLITL-deleted counterparts. We show that VLITL forms typical amyloid fibrils in vitro and is a major signal for cross-β-sheet self-association of the 49-mer Phe521Leufs peptide identified in vivo, whereas its absence abrogates fibril formation. This study provides compelling evidence that VLITL confers amyloidogenic properties to Aα-chain frameshift variants, yielding a previously unknown molecular basis for the pathogenesis of Aα-chain amyloidosis. PMID:29089309

Amyloid-like self-assembly of peptide sequences from the adenovirus fiber shaft: insights from molecular dynamics simulations.

PubMed

Tamamis, Phanourios; Kasotakis, Emmanouil; Mitraki, Anna; Archontis, Georgios

2009-11-26

The self-assembly of peptides and proteins into nanostructures is related to the fundamental problems of protein folding and misfolding and has potential applications in medicine, materials science and nanotechnology. Natural peptides, corresponding to sequence repeats from self-assembling proteins, may constitute elementary building blocks of such nanostructures. In this work, we study by implicit-solvent replica-exchange simulations the self-assembly of two amyloidogenic sequences derived from the naturally occurring fiber shaft of the adenovirus, the octapeptide NSGAITIG (asparagine-serine-glycine-alanine-isoleucine-threonine-isoleucine-glycine) and its hexapeptide counterpart, GAITIG. In accordance with their amyloidogenic capacity, both peptides form readily intermolecular beta-sheets, stabilized by extensive main- and side-chain contacts involving the C-terminal moieties (segments 3-8 and 2-6, respectively). The structural and energetic properties of these sheets are analyzed extensively. The N-terminal residues Asn1 and Ser2 of the octapeptide remain disordered in the sheets, suggesting that these residues are exposed at the exterior of the fibrils and accessible. On the basis of insight provided by the simulations, cysteine residues were recently substituted at positions 1 and 2 of NSGAITIG; the newly designed peptides maintain their amyloidogenic properties and can bind to silver, gold and platinum nanoparticles [Kasotakis et al. Biopolymers 2009, 92, 164-172]. Computational investigation can identify suitable positions for rational modification of peptide building blocks, aiming at the fabrication of novel biomaterials.

The Importance of a Gatekeeper Residue on the Aggregation of Transthyretin

PubMed Central

Sant'Anna, Ricardo; Braga, Carolina; Varejão, Nathalia; Pimenta, Karinne M.; Graña-Montes, Ricardo; Alves, Aline; Cortines, Juliana; Cordeiro, Yraima; Ventura, Salvador; Foguel, Debora

2014-01-01

Protein aggregation into β-sheet-enriched amyloid fibrils is associated with an increasing number of human disorders. The adoption of such amyloid conformations seems to constitute a generic property of polypeptide chains. Therefore, during evolution, proteins have adopted negative design strategies to diminish their intrinsic propensity to aggregate, including enrichment of gatekeeper charged residues at the flanks of hydrophobic aggregation-prone segments. Wild type transthyretin (TTR) is responsible for senile systemic amyloidosis, and more than 100 mutations in the TTR gene are involved in familial amyloid polyneuropathy. The TTR 26–57 segment bears many of these aggressive amyloidogenic mutations as well as the binding site for heparin. We demonstrate here that Lys-35 acts as a gatekeeper residue in TTR, strongly decreasing its amyloidogenic potential. This protective effect is sequence-specific because Lys-48 does not affect TTR aggregation. Lys-35 is part of the TTR basic heparin-binding motif. This glycosaminoglycan blocks the protective effect of Lys-35, probably by neutralization of its side chain positive charge. A K35L mutation emulates this effect and results in the rapid self-assembly of the TTR 26–57 region into amyloid fibrils. This mutation does not affect the tetrameric protein stability, but it strongly increases its aggregation propensity. Overall, we illustrate how TTR is yet another amyloidogenic protein exploiting negative design to prevent its massive aggregation, and we show how blockage of conserved protective features by endogenous factors or mutations might result in increased disease susceptibility. PMID:25086037

COPS5 (Jab1) protein increases β site processing of amyloid precursor protein and amyloid β peptide generation by stabilizing RanBP9 protein levels.

PubMed

Wang, Hongjie; Dey, Debleena; Carrera, Ivan; Minond, Dmitriy; Bianchi, Elisabetta; Xu, Shaohua; Lakshmana, Madepalli K

2013-09-13

Increased processing of amyloid precursor protein (APP) and accumulation of neurotoxic amyloid β peptide (Aβ) in the brain is central to the pathogenesis of Alzheimer's disease (AD). Therefore, the identification of molecules that regulate Aβ generation is crucial for future therapeutic approaches for AD. We demonstrated previously that RanBP9 regulates Aβ generation in a number of cell lines and primary neuronal cultures by forming tripartite protein complexes with APP, low-density lipoprotein-related protein, and BACE1, consequently leading to increased amyloid plaque burden in the brain. RanBP9 is a scaffold protein that exists and functions in multiprotein complexes. To identify other proteins that may bind RanBP9 and regulate Aβ levels, we used a two-hybrid analysis against a human brain cDNA library and identified COPS5 as a novel RanBP9-interacting protein. This interaction was confirmed by coimmunoprecipitation experiments in both neuronal and non-neuronal cells and mouse brain. Colocalization of COPS5 and RanBP9 in the same subcellular compartments further supported the interaction of both proteins. Furthermore, like RanBP9, COPS5 robustly increased Aβ generation, followed by increased soluble APP-β (sAPP-β) and decreased soluble-APP-α (sAPP-α) levels. Most importantly, down-regulation of COPS5 by siRNAs reduced Aβ generation, implying that endogenous COPS5 regulates Aβ generation. Finally, COPS5 levels were increased significantly in AD brains and APΔE9 transgenic mice, and overexpression of COPS5 strongly increased RanBP9 protein levels by increasing its half-life. Taken together, these results suggest that COPS5 increases Aβ generation by increasing RanBP9 levels. Thus, COPS5 is a novel RanBP9-binding protein that increases APP processing and Aβ generation by stabilizing RanBP9 protein levels.

Designing Health Apps to Support Dietetic Professional Practice and Their Patients: Qualitative Results From an International Survey

PubMed Central

Lieffers, Jessica; Bauman, Adrian; Hanning, Rhona; Allman-Farinelli, Margaret

2017-01-01

Background Dietitians are engaging with mobile health (mHealth) technologies, particularly with diet and nutrition apps in their patient care. Despite the plethora of apps available, the majority are not designed with a dietitian’s input. Objective The aim of this study was to identify the user preferences of dietitians in relation to tools, resources, and design features for smartphone health apps that would support their dietetic professional practice and their patients. Methods As part of a larger international Web-based survey of health-app use among dietitians, three open-ended responses were included for specific exploration of app design features and additional resources or tools that could guide the development of apps for use in dietetic practice and patient care. Inductive thematic analysis of responses was conducted using the qualitative data analysis program, NVivo version 11 (QSR International Pty Ltd), to understand the design preferences and features valued by dietitians. Results The responses from 381 dietitian respondents were analyzed. Five key themes were identified. Dietitians wanted access to credible apps, suggesting that dietetic associations should have greater involvement in reviewing and endorsing evidence-based apps for use in dietary counseling. Improvements to the usability of apps, relating to their ease of use and design, were also raised, as self-monitoring of dietary behaviors using existing nutrition apps was deemed to be burdensome. Furthermore, apps providing dietitian-oriented support were favored, for example, those with the ability to streamline the dietary assessment process, so that dietitians could spend more time on dietary counseling and negotiating patient goals for dietary and lifestyle behavior change. Provision of patient-oriented support, such as functionality to tailor apps to patient-specific needs, was also considered important. Finally, respondents valued apps that could integrate into their work systems to enhance the quality of the dietitian-patient relationship. Conclusions App developers should draw upon the features and characteristics valued by dietitians to guide their development of apps that support dietetic practice and enhance patient care. Moreover, to achieve better dietitian and patient-centered app design, it is imperative that app developers take a collaborative approach with dietitians, their professional associations, and their patients. PMID:28363882

Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes.

PubMed

Tang, Weihao; Tam, Joshua H K; Seah, Claudia; Chiu, Justin; Tyrer, Andrea; Cregan, Sean P; Meakin, Susan O; Pasternak, Stephen H

2015-07-14

Alzheimer's disease (AD) is characterized by the deposition of Beta-Amyloid (Aβ) peptides in the brain. Aβ peptides are generated by cleavage of the Amyloid Precursor Protein (APP) by the β - and γ - secretase enzymes. Although this process is tightly linked to the internalization of cell surface APP, the compartments responsible are not well defined. We have found that APP can be rapidly internalized from the cell surface to lysosomes, bypassing early and late endosomes. Here we show by confocal microscopy and electron microscopy that this pathway is mediated by macropinocytosis. APP internalization is enhanced by antibody binding/crosslinking of APP suggesting that APP may function as a receptor. Furthermore, a dominant negative mutant of Arf6 blocks direct transport of APP to lysosomes, but does not affect classical endocytosis to endosomes. Arf6 expression increases through the hippocampus with the development of Alzheimer's disease, being expressed mostly in the CA1 and CA2 regions in normal individuals but spreading through the CA3 and CA4 regions in individuals with pathologically diagnosed AD. Disruption of lysosomal transport of APP reduces both Aβ40 and Aβ42 production by more than 30 %. Our findings suggest that the lysosome is an important site for Aβ production and that altering APP trafficking represents a viable strategy to reduce Aβ production.

Women's experiences with using a smartphone app (the Pregnant+ app) to manage gestational diabetes mellitus in a randomised controlled trial.

PubMed

Skar, Jeanette B; Garnweidner-Holme, Lisa M; Lukasse, Mirjam; Terragni, Laura

2018-03-01

The purpose of this study was to explore the experiences of women with gestational diabetes mellitus (GDM) with controlling their blood glucose values and receiving health and nutrition information using a smartphone app (the Pregnant+ app). The study utilised the interpretative phenomenological analysis method. Semi-structured interviews were conducted with 17 participants among those participating to the randomised controlled trial. The women experienced sorrow and disappointment when they were diagnosed with GDM, but they all went through a process of learning to self-manage their condition that was strongly motivated by theirdesire to care for their unborn babies. The women found that the app increased their confidence in their self management of GDM and their motivation for behavioural change. For some women, the app contributed to feelings offrustration or obsession. In addition, some technological problems and a lack of support from health-care professionals limited several women from using the app. The findings suggest that asmartphone app may have potential for supporting women with GDM, particularly in their blood glucose management. However, it also highlights some of the potential challenges of using mHealth technologies. The findings indicate that a closer collaboration between health-care professionals and patients is of great importance in the implementation of apps for women with GDM. Copyright © 2018 Elsevier Ltd. All rights reserved.

Transforming paper-based assessment forms to a digital format: Exemplified by the Housing Enabler prototype app.

PubMed

Svarre, Tanja; Lunn, Tine Bieber Kirkegaard; Helle, Tina

2017-11-01

The aim of this paper is to provide the reader with an overall impression of the stepwise user-centred design approach including the specific methods used and lessons learned when transforming paper-based assessment forms into a prototype app, taking the Housing Enabler as an example. Four design iterations were performed, building on a domain study, workshops, expert evaluation and controlled and realistic usability tests. The user-centred design process involved purposefully selected participants with different Housing Enabler knowledge and housing adaptation experience. The design iterations resulted in the development of a Housing Enabler prototype app. The prototype app has several features and options that are new compared with the original paper-based Housing Enabler assessment form. These new features include a user friendly overview of the assessment form; easy navigation by swiping back and forth between items; onsite data analysis; and ranking of the accessibility score, photo documentation and a data export facility. Based on the presented stepwise approach, a high-fidelity Housing Enabler prototype app was successfully developed. The development process has emphasized the importance of combining design participants' knowledge and experiences, and has shown that methods should seem relevant to participants to increase their engagement.

Tyrosine Binding Protein Sites Regulate the Intracellular Trafficking and Processing of Amyloid Precursor Protein through a Novel Lysosome-Directed Pathway

PubMed Central

Tam, Joshua H. K.; Cobb, M. Rebecca; Seah, Claudia; Pasternak, Stephen H.

2016-01-01

The amyloid hypothesis posits that the production of β-amyloid (Aβ) aggregates leads to neurodegeneration and cognitive decline associated with AD. Aβ is produced by sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretase. While nascent APP is well known to transit to the endosomal/ lysosomal system via the cell surface, we have recently shown that APP can also traffic to lysosomes intracellularly via its interaction with AP-3. Because AP-3 interacts with cargo protein via interaction with tyrosine motifs, we mutated the three tyrosines motif in the cytoplasmic tail of APP. Here, we show that the YTSI motif interacts with AP-3, and phosphorylation of the serine in this motif disrupts the interaction and decreases APP trafficking to lysosomes. Furthermore, we show that phosphorylation at this motif can decrease the production of neurotoxic Aβ 42. This demonstrates that reducing APP trafficking to lysosomes may be a strategy to reduce Aβ 42 in Alzheimer’s disease. PMID:27776132

Direct Reading of Bona Fide Barcode Assays for Diagnostics with Smartphone Apps.

PubMed

Wong, Jessica X H; Li, Xiaochun; Liu, Frank S F; Yu, Hua-Zhong

2015-06-30

The desire to develop new point-of-care (POC) diagnostic tools has led to the adaptation of smartphones to tackle limitations in state-of-the-art instrumentation and centralized laboratory facilities. Today's smartphones possess the computer-like ability to image and process data using mobile apps; barcode scanners are one such type of apps. We demonstrate herein that a diagnostic assay can be performed by patterning immunoassay strips in a bona fide barcode format such that after target binding and signal enhancement, the linear barcode can be read directly with a standard smartphone app. Quantitative analysis can then be performed based on the grayscale intensities with a customized mobile app. This novel diagnostic concept has been validated for a real-world application, i.e., the detection of human chorionic gonadotropin, a pregnancy hormone. With the possibility of multiplex detection, the barcode assay protocol promises to boost POC diagnosis research by the direct adaptation of mobile devices and apps.

Direct Reading of Bona Fide Barcode Assays for Diagnostics with Smartphone Apps

PubMed Central

Wong, Jessica X. H.; Li, Xiaochun; Liu, Frank S. F.; Yu, Hua-Zhong

2015-01-01

The desire to develop new point-of-care (POC) diagnostic tools has led to the adaptation of smartphones to tackle limitations in state-of-the-art instrumentation and centralized laboratory facilities. Today’s smartphones possess the computer-like ability to image and process data using mobile apps; barcode scanners are one such type of apps. We demonstrate herein that a diagnostic assay can be performed by patterning immunoassay strips in a bona fide barcode format such that after target binding and signal enhancement, the linear barcode can be read directly with a standard smartphone app. Quantitative analysis can then be performed based on the grayscale intensities with a customized mobile app. This novel diagnostic concept has been validated for a real-world application, i.e., the detection of human chorionic gonadotropin, a pregnancy hormone. With the possibility of multiplex detection, the barcode assay protocol promises to boost POC diagnosis research by the direct adaptation of mobile devices and apps. PMID:26122608

Developing Smartphone Apps for Education, Outreach, Science, and Engineering

NASA Astrophysics Data System (ADS)

Weatherwax, A. T.; Fitzsimmons, Z.; Czajkowski, J.; Breimer, E.; Hellman, S. B.; Hunter, S.; Dematteo, J.; Savery, T.; Melsert, K.; Sneeringer, J.

2010-12-01

The increased popularity of mobile phone apps provide scientists with a new avenue for sharing and distributing data and knowledge with colleagues, while also providing meaningful education and outreach products for consumption by the general public. Our initial development of iPhone and Android apps centered on the distribution of exciting auroral images taken at the South Pole for education and outreach purposes. These portable platforms, with limited resources when compared to computers, presented a unique set of design and implementation challenges that we will discuss in this presentation. For example, the design must account for limited memory; screen size; processing power; battery life; and potentially high data transport costs. Some of these unique requirements created an environment that enabled undergraduate and high-school students to participate in the creation of these apps. Additionally, during development it became apparent that these apps could also serve as data analysis and engineering tools. Our presentation will further discuss our plans to use apps not only for Education and Public Outreach, but for teaching, science and engineering.

Tyrosine Binding Protein Sites Regulate the Intracellular Trafficking and Processing of Amyloid Precursor Protein through a Novel Lysosome-Directed Pathway.

PubMed

Tam, Joshua H K; Cobb, M Rebecca; Seah, Claudia; Pasternak, Stephen H

2016-01-01

The amyloid hypothesis posits that the production of β-amyloid (Aβ) aggregates leads to neurodegeneration and cognitive decline associated with AD. Aβ is produced by sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretase. While nascent APP is well known to transit to the endosomal/ lysosomal system via the cell surface, we have recently shown that APP can also traffic to lysosomes intracellularly via its interaction with AP-3. Because AP-3 interacts with cargo protein via interaction with tyrosine motifs, we mutated the three tyrosines motif in the cytoplasmic tail of APP. Here, we show that the YTSI motif interacts with AP-3, and phosphorylation of the serine in this motif disrupts the interaction and decreases APP trafficking to lysosomes. Furthermore, we show that phosphorylation at this motif can decrease the production of neurotoxic Aβ 42. This demonstrates that reducing APP trafficking to lysosomes may be a strategy to reduce Aβ 42 in Alzheimer's disease.

Direct Reading of Bona Fide Barcode Assays for Diagnostics with Smartphone Apps

NASA Astrophysics Data System (ADS)

Wong, Jessica X. H.; Li, Xiaochun; Liu, Frank S. F.; Yu, Hua-Zhong

2015-06-01

The desire to develop new point-of-care (POC) diagnostic tools has led to the adaptation of smartphones to tackle limitations in state-of-the-art instrumentation and centralized laboratory facilities. Today’s smartphones possess the computer-like ability to image and process data using mobile apps; barcode scanners are one such type of apps. We demonstrate herein that a diagnostic assay can be performed by patterning immunoassay strips in a bona fide barcode format such that after target binding and signal enhancement, the linear barcode can be read directly with a standard smartphone app. Quantitative analysis can then be performed based on the grayscale intensities with a customized mobile app. This novel diagnostic concept has been validated for a real-world application, i.e., the detection of human chorionic gonadotropin, a pregnancy hormone. With the possibility of multiplex detection, the barcode assay protocol promises to boost POC diagnosis research by the direct adaptation of mobile devices and apps.

Blood Culture Testing via a Mobile App That Uses a Mobile Phone Camera: A Feasibility Study

PubMed Central

Chong, Yong Pil; Jang, Seongsoo; Kim, Mi Na; Kim, Jeong Hoon; Kim, Woo Sung

2016-01-01

Background To evaluate patients with fever of unknown origin or those with suspected bacteremia, the precision of blood culture tests is critical. An inappropriate step in the test process or error in a parameter could lead to a false-positive result, which could then affect the direction of treatment in critical conditions. Mobile health apps can be used to resolve problems with blood culture tests, and such apps can hence ensure that point-of-care guidelines are followed and processes are monitored for blood culture tests. Objective In this pilot project, we aimed to investigate the feasibility of using a mobile blood culture app to manage blood culture test quality. We implemented the app at a university hospital in South Korea to assess the potential for its utilization in a clinical environment by reviewing the usage data among a small group of users and by assessing their feedback and the data related to blood culture sampling. Methods We used an iOS-based blood culture app that uses an embedded camera to scan the patient identification and sample number bar codes. A total of 4 medical interns working at 2 medical intensive care units (MICUs) participated in this project, which spanned 3 weeks. App usage and blood culture sampling parameters (including sampler, sampling site, sampling time, and sample volume) were analyzed. The compliance of sampling parameter entry was also measured. In addition, the participants’ opinions regarding patient safety, timeliness, efficiency, and usability were recorded. Results In total, 356/644 (55.3%) of all blood culture samples obtained at the MICUs were examined using the app, including 254/356 (71.3%) with blood collection volumes of 5-7 mL and 256/356 (71.9%) with blood collection from the peripheral veins. The sampling volume differed among the participants. Sampling parameters were completely entered in 354/356 cases (99.4%). All the participants agreed that the app ensured good patient safety, disagreed on its timeliness, and did not believe that it was efficient. Although the bar code scanning speed was acceptable, the Wi-Fi environment required improvement. Moreover, the participants requested feedback regarding their sampling quality. Conclusions Although this app could be used in the clinical setting, improvements in the app functions, environment network, and internal policy of blood culture testing are needed to ensure hospital-wide use. PMID:27784649

Blood Culture Testing via a Mobile App That Uses a Mobile Phone Camera: A Feasibility Study.

PubMed

Lee, Guna; Lee, Yura; Chong, Yong Pil; Jang, Seongsoo; Kim, Mi Na; Kim, Jeong Hoon; Kim, Woo Sung; Lee, Jae-Ho

2016-10-26

To evaluate patients with fever of unknown origin or those with suspected bacteremia, the precision of blood culture tests is critical. An inappropriate step in the test process or error in a parameter could lead to a false-positive result, which could then affect the direction of treatment in critical conditions. Mobile health apps can be used to resolve problems with blood culture tests, and such apps can hence ensure that point-of-care guidelines are followed and processes are monitored for blood culture tests. In this pilot project, we aimed to investigate the feasibility of using a mobile blood culture app to manage blood culture test quality. We implemented the app at a university hospital in South Korea to assess the potential for its utilization in a clinical environment by reviewing the usage data among a small group of users and by assessing their feedback and the data related to blood culture sampling. We used an iOS-based blood culture app that uses an embedded camera to scan the patient identification and sample number bar codes. A total of 4 medical interns working at 2 medical intensive care units (MICUs) participated in this project, which spanned 3 weeks. App usage and blood culture sampling parameters (including sampler, sampling site, sampling time, and sample volume) were analyzed. The compliance of sampling parameter entry was also measured. In addition, the participants' opinions regarding patient safety, timeliness, efficiency, and usability were recorded. In total, 356/644 (55.3%) of all blood culture samples obtained at the MICUs were examined using the app, including 254/356 (71.3%) with blood collection volumes of 5-7 mL and 256/356 (71.9%) with blood collection from the peripheral veins. The sampling volume differed among the participants. Sampling parameters were completely entered in 354/356 cases (99.4%). All the participants agreed that the app ensured good patient safety, disagreed on its timeliness, and did not believe that it was efficient. Although the bar code scanning speed was acceptable, the Wi-Fi environment required improvement. Moreover, the participants requested feedback regarding their sampling quality. Although this app could be used in the clinical setting, improvements in the app functions, environment network, and internal policy of blood culture testing are needed to ensure hospital-wide use.

Consent Processes for Mobile App Mediated Research: Systematic Review.

PubMed

Moore, Sarah; Tassé, Anne-Marie; Thorogood, Adrian; Winship, Ingrid; Zawati, Ma'n; Doerr, Megan

2017-08-30

Since the launch of ResearchKit on the iOS platform in March 2015 and ResearchStack on the Android platform in June 2016, many academic and commercial institutions around the world have adapted these frameworks to develop mobile app-based research studies. These studies cover a wide variety of subject areas including melanoma, cardiomyopathy, and autism. Additionally, these app-based studies target a variety of participant populations, including children and pregnant women. The aim of this review was to document the variety of self-administered remote informed consent processes used in app-based research studies available between May and September 2016. Remote consent is defined as any consenting process with zero in-person steps, when a participant is able to join a study without ever seeing a member of the research team. This type of review has not been previously conducted. The research community would benefit from a rigorous interrogation of the types of consent taken as part of the seismic shift to entirely mobile meditated research studies. This review examines both the process of information giving and specific content shared, with special attention to data privacy, aggregation, and sharing. Consistency across some elements of the app-based consent processes was found; for example, informing participants about how data will be curated from the phone. Variations in other elements were identified; for example, where specific information is shared and the level of detail disclosed. Additionally, several novel elements present in eConsent not typically seen in traditional consent for research were highlighted. This review advocates the importance of participant informedness in a novel and largely unregulated research setting. ©Sarah Moore, Anne-Marie Tassé, Adrian Thorogood, Ingrid Winship, Ma'n Zawati, Megan Doerr. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 30.08.2017.

The Large Hydrophilic Loop of Presenilin 1 Is Important for Regulating γ-Secretase Complex Assembly and Dictating the Amyloid β Peptide (Aβ) Profile without Affecting Notch Processing*

PubMed Central

Wanngren, Johanna; Frånberg, Jenny; Svensson, Annelie I.; Laudon, Hanna; Olsson, Fredrik; Winblad, Bengt; Liu, Frank; Näslund, Jan; Lundkvist, Johan; Karlström, Helena

2010-01-01

γ-Secretase is an enzyme complex that mediates both Notch signaling and β-amyloid precursor protein (APP) processing, resulting in the generation of Notch intracellular domain, APP intracellular domain, and the amyloid β peptide (Aβ), the latter playing a central role in Alzheimer disease (AD). By a hitherto undefined mechanism, the activity of γ-secretase gives rise to Aβ peptides of different lengths, where Aβ42 is considered to play a particular role in AD. In this study we have examined the role of the large hydrophilic loop (amino acids 320–374, encoded by exon 10) of presenilin 1 (PS1), the catalytic subunit of γ-secretase, for γ-secretase complex formation and activity on Notch and APP processing. Deletion of exon 10 resulted in impaired PS1 endoproteolysis, γ-secretase complex formation, and had a differential effect on Aβ-peptide production. Although the production of Aβ38, Aβ39, and Aβ40 was severely impaired, the effect on Aβ42 was affected to a lesser extent, implying that the production of the AD-related Aβ42 peptide is separate from the production of the Aβ38, Aβ39, and Aβ40 peptides. Interestingly, formation of the intracellular domains of both APP and Notch was intact, implying a differential cleavage activity between the ϵ/S3 and γ sites. The most C-terminal amino acids of the hydrophilic loop were important for regulating APP processing. In summary, the large hydrophilic loop of PS1 appears to differentially regulate the relative production of different Aβ peptides without affecting Notch processing, two parameters of significance when considering γ-secretase as a target for pharmaceutical intervention in AD. PMID:20106965

Consent Processes for Mobile App Mediated Research: Systematic Review

PubMed Central

Tassé, Anne-Marie; Thorogood, Adrian; Winship, Ingrid; Zawati, Ma'n; Doerr, Megan

2017-01-01

Background Since the launch of ResearchKit on the iOS platform in March 2015 and ResearchStack on the Android platform in June 2016, many academic and commercial institutions around the world have adapted these frameworks to develop mobile app-based research studies. These studies cover a wide variety of subject areas including melanoma, cardiomyopathy, and autism. Additionally, these app-based studies target a variety of participant populations, including children and pregnant women. Objective The aim of this review was to document the variety of self-administered remote informed consent processes used in app-based research studies available between May and September 2016. Remote consent is defined as any consenting process with zero in-person steps, when a participant is able to join a study without ever seeing a member of the research team. This type of review has not been previously conducted. The research community would benefit from a rigorous interrogation of the types of consent taken as part of the seismic shift to entirely mobile meditated research studies. Methods This review examines both the process of information giving and specific content shared, with special attention to data privacy, aggregation, and sharing. Results Consistency across some elements of the app-based consent processes was found; for example, informing participants about how data will be curated from the phone. Variations in other elements were identified; for example, where specific information is shared and the level of detail disclosed. Additionally, several novel elements present in eConsent not typically seen in traditional consent for research were highlighted. Conclusions This review advocates the importance of participant informedness in a novel and largely unregulated research setting. PMID:28855147

My Interventional Drug-Eluting Stent Educational App (MyIDEA): Patient-Centered Design Methodology

PubMed Central

Shroff, Adhir; Groo, Vicki; Dickens, Carolyn; Field, Jerry; Baumann, Matthew; Welland, Betty; Gutowski, Gerry; Flores Jr, Jose D; Zhao, Zhongsheng; Bahroos, Neil; Hynes, Denise M; Wilkie, Diana J

2015-01-01

Background Patient adherence to medication regimens is critical in most chronic disease treatment plans. This study uses a patient-centered tablet app, “My Interventional Drug-Eluting Stent Educational App (MyIDEA).” This is an educational program designed to improve patient medication adherence. Objective Our goal is to describe the design, methodology, limitations, and results of the MyIDEA tablet app. We created a mobile technology-based patient education app to improve dual antiplatelet therapy adherence in patients who underwent a percutaneous coronary intervention and received a drug-eluting stent. Methods Patient advisers were involved in the development process of MyIDEA from the initial wireframe to the final launch of the product. The program was restructured and redesigned based on the patient advisers’ suggestions as well as those from multidisciplinary team members. To accommodate those with low health literacy, we modified the language and employed attractive color schemes to improve ease of use. We assumed that the target patient population may have little to no experience with electronic tablets, and therefore, we designed the interface to be as intuitive as possible. Results The MyIDEA app has been successfully deployed to a low-health-literate elderly patient population in the hospital setting. A total of 6 patients have interacted with MyIDEA for an average of 17.6 minutes/session. Conclusions Including patient advisers in the early phases of a mobile patient education development process is critical. A number of changes in text order, language, and color schemes occurred to improve ease of use. The MyIDEA program has been successfully deployed to a low-health-literate elderly patient population. Leveraging patient advisers throughout the development process helps to ensure implementation success. PMID:26139587

Development and Testing of a Mobile Phone App for Self-Monitoring of Calcium Intake in Young Women

PubMed Central

Tay, Ilona

2017-01-01

Background Interventions to prevent osteoporosis by increasing dairy intake or physical activity in young women have been limited to increasing osteoporosis knowledge and awareness. However, findings have shown that this does not always lead to a change in behaviors. Self-monitoring using mobile devices in behavioral interventions has yielded significant and positive outcomes. Yet, to our knowledge, mobile self-monitoring has not been used as an intervention strategy to increase calcium intake, particularly in young women, for better bone health outcomes. Objective As development and testing of mobile app–based interventions requires a sequence of steps, our study focused on testing the acceptability and usability of Calci-app, a dietary app to self-monitor calcium consumption, before it is used in a behavioral change intervention in young women aged 18-25 years. Methods Calci-app development followed 4 steps: (1) conceptualization, (2) development and pretesting, (3) pilot testing, and (4) mixed methods evaluation. Results We present the development process of Calci-app and evaluation of the acceptability and usability of the app in young women. Overall, 78% (31/40) of study participants completed the 5-day food record with high compliance levels (defined as more than 3 days of full or partial completion). There was a significant reduction in the proportion of participants completing all meal entries over the 5 days (P=.01). Participants generally found Calci-app easy and convenient to use, but it was time-consuming and they expressed a lack of motivation to use the app. Conclusions We present a detailed description of the development process of Calci-app and an evaluation of its usability and acceptability to self-monitor dietary calcium intake. The findings from this preliminary study demonstrated acceptable use of Calci-app to self-monitor calcium consumption. However, for regular and long-term use the self-monitoring function in Calci-app could be expanded to allow participants to view their total daily calcium intake compared with the recommended daily intake. Additionally, to facilitate sustainable lifestyle behavior modifications, a combination of various behavior change techniques should be considered, such as education, goal setting, and advice to participants based on their stage of change. The feedback on barriers and facilitators from testing Calci-app will be used to design a bone health mHealth intervention to modify risky lifestyle behaviors in young women for better bone health outcomes. PMID:28270379

A Self-Regulation Theory–Based Asthma Management Mobile App for Adolescents: A Usability Assessment

PubMed Central

2017-01-01

Background Self-regulation theory suggests people learn to influence their own behavior through self-monitoring, goal-setting, feedback, self-reward, and self-instruction, all of which smartphones are now capable of facilitating. Several mobile apps exist to manage asthma; however, little evidence exists about whether these apps employ user-centered design processes that adhere to government usability guidelines for mobile apps. Objective Building upon a previous study that documented adolescent preferences for an asthma self-management app, we employed a user-centered approach to assess the usability of a high-fidelity wireframe for an asthma self-management app intended for use by adolescents with persistent asthma. Methods Individual interviews were conducted with adolescents (ages 11-18 years) with persistent asthma who owned a smartphone (N=8). Adolescents were asked to evaluate a PDF app wireframe consisting of 76 screen shots displaying app features, including log in and home screen, profile setup, settings and info, self-management features, and graphical displays for charting asthma control and medication. Preferences, comments, and suggestions for each set of screen shots were assessed using the audio-recorded interviews. Two coders reached consensus on adolescent evaluations of the following aspects of app features: (1) usability, (2) behavioral intentions to use, (3) confusing aspects, and (4) suggestions for improvement. Results The app wireframe was generally well received, and several suggestions for improvement were recorded. Suggestions included increased customization of charts and notifications, reminders, and alerts. Participants preferred longitudinal data about asthma control and medication use to be displayed using line graphs. All participants reported that they would find an asthma management app like the one depicted in the wireframe useful for managing their asthma. Conclusions Early stage usability tests guided by government usability guidelines (usability.gov) revealed areas for improvement for an asthma self-management app for adolescents. Addressing these areas will be critical to developing an engaging and effective asthma self-management app that is capable of improving adolescent asthma outcomes. PMID:28148471

Protection of primary neurons and mouse brain from Alzheimer’s pathology by molecular tweezers

PubMed Central

Attar, Aida; Ripoli, Cristian; Riccardi, Elisa; Maiti, Panchanan; Li Puma, Domenica D.; Liu, Tingyu; Hayes, Jane; Jones, Mychica R.; Lichti-Kaiser, Kristin; Yang, Fusheng; Gale, Greg D.; Tseng, Chi-hong; Tan, Miao; Xie, Cui-Wei; Straudinger, Jeffrey L.; Klärner, Frank-Gerrit; Schrader, Thomas; Frautschy, Sally A.; Grassi, Claudio

2012-01-01

Alzheimer’s disease is a devastating cureless neurodegenerative disorder affecting >35 million people worldwide. The disease is caused by toxic oligomers and aggregates of amyloid β protein and the microtubule-associated protein tau. Recently, the Lys-specific molecular tweezer CLR01 has been shown to inhibit aggregation and toxicity of multiple amyloidogenic proteins, including amyloid β protein and tau, by disrupting key interactions involved in the assembly process. Following up on these encouraging findings, here, we asked whether CLR01 could protect primary neurons from Alzheimer’s disease-associated synaptotoxicity and reduce Alzheimer’s disease–like pathology in vivo. Using cell culture and brain slices, we found that CLR01 effectively inhibited synaptotoxicity induced by the 42-residue isoform of amyloid β protein, including ∼80% inhibition of changes in dendritic spines density and long-term potentiation and complete inhibition of changes in basal synaptic activity. Using a radiolabelled version of the compound, we found that CLR01 crossed the mouse blood–brain barrier at ∼2% of blood levels. Treatment of 15-month-old triple-transgenic mice for 1 month with CLR01 resulted in a decrease in brain amyloid β protein aggregates, hyperphosphorylated tau and microglia load as observed by immunohistochemistry. Importantly, no signs of toxicity were observed in the treated mice, and CLR01 treatment did not affect the amyloidogenic processing of amyloid β protein precursor. Examining induction or inhibition of the cytochrome P450 metabolism system by CLR01 revealed minimal interaction. Together, these data suggest that CLR01 is safe for use at concentrations well above those showing efficacy in mice. The efficacy and toxicity results support a process-specific mechanism of action of molecular tweezers and suggest that these are promising compounds for developing disease-modifying therapy for Alzheimer’s disease and related disorders. PMID:23183235

LRP in amyloid-beta production and metabolism.

PubMed

Bu, Guojun; Cam, Judy; Zerbinatti, Celina

2006-11-01

Amyloid-beta peptide (Abeta) production and accumulation in the brain is a central event in the pathogenesis of Alzheimer's disease (AD). Recent studies have shown that apolipoprotein E (apoE) receptors, members of the low-density lipoprotein receptor (LDLR) family, modulate Abeta production as well as Abeta cellular uptake. Abeta is derived from proteolytic processing of the amyloid precursor protein (APP), which interacts with several members of the LDLR family. Studies from our laboratory have focused on two members of the LDLR family, the LDLR-related protein (LRP) and LRP1B. Our in vitro studies have shown that while LRP's rapid endocytosis facilitates APP endocytic trafficking and processing to Abeta, LRP1B's slow endocytosis inhibits these processes. In addition to modulating APP endocytic trafficking, LRP's rapid endocytosis also facilitates Abeta cellular uptake by binding to Abeta either directly or via LRP ligands such as apoE. Our in vivo studies using transgenic mice have shown that overexpression of LRP in central nervous system (CNS) neurons increases soluble brain Abeta and this increase correlates with deficits in memory. Together our studies demonstrate that members of the LDLR family modulate APP processing and Abeta metabolism by several independent mechanisms. Understanding the pathways that modulate brain Abeta metabolism may enable the rational design of molecular medicine to treat AD.

The Use of Communication Apps by Medical Staff in the Australian Health Care System: Survey Study on Prevalence and Use.

PubMed

Nikolic, Amanda; Wickramasinghe, Nilmini; Claydon-Platt, Damian; Balakrishnan, Vikram; Smart, Philip

2018-02-09

The use of communication apps on mobile phones offers an efficient, unobtrusive, and portable mode of communication for medical staff. The potential enhancements in patient care and education appear significant, with clinical details able to be shared quickly within multidisciplinary teams, supporting rapid integration of disparate information, and more efficient patient care. However, sharing patient data in this way also raises legal and ethical issues. No data is currently available demonstrating how widespread the use of these apps are, doctor's attitudes towards them, or what guides clinician choice of app. The objective of this study was to quantify and qualify the use of communication apps among medical staff in clinical situations, their role in patient care, and knowledge and attitudes towards safety, key benefits, potential disadvantages, and policy implications. Medical staff in hospitals across Victoria (Australia) were invited to participate in an anonymous 33-question survey. The survey collected data on respondent's demographics, their use of communication apps in clinical settings, attitudes towards communication apps, perceptions of data "safety," and why one communication app was chosen over others. Communication apps in Victorian hospitals are in widespread use from students to consultants, with WhatsApp being the primary app used. The median number of messages shared per day was 12, encompassing a range of patient information. All respondents viewed these apps positively in quickly communicating patient information in a clinical setting; however, all had concerns about the privacy implications arising from sharing patient information in this way. In total, 67% (60/90) considered patient data "moderately safe" on these apps, and 50% (46/90) were concerned the use of these apps was inconsistent with current legislation and policy. Apps were more likely to be used if they were fast, easy to use, had an easy login process, and were already in widespread use. Communication app use by medical personnel in Victorian hospitals is pervasive. These apps contribute to enhanced communication between medical staff, but their use raises compliance issues, most notably with Australian privacy legislation. Development of privacy-compliant apps such as MedX needs to prioritize a user-friendly interface and market the product as a privacy-compliant comparator to apps previously adapted to health care settings. ©Amanda Nikolic, Nilmini Wickramasinghe, Damian Claydon-Platt, Vikram Balakrishnan, Philip Smart. Originally published in JMIR Medical Informatics (http://medinform.jmir.org), 09.02.2018.

Spatially-Selective Membrane Permeabilization Induced by Cell-Solution Electrode Atmospheric Pressure Plasma Irradiation

NASA Astrophysics Data System (ADS)

Sasaki, Shota; Hokari, Yutaro; Kanzaki, Makoto; Kaneko, Toshiro

2015-09-01

Gene transfection, which is the process of deliberately introducing nucleic acids into cells, is expected to play an important role in medical treatment because the process is necessary for gene therapy and creation of induced pluripotent stem (iPS) cells. However, the conventional transfection methods have some problems, so we focus attention on promising transfection methods by atmospheric pressure plasma (APP). We have previously reported that the cell membrane permeability, which is closely related with gene transfection, is improved using a cell-solution electrode for generating He-APP. He-APP is irradiated to the solution containing the adherent cells and delivery materials such as fluorescent dyes (YOYO-1) and plasmid DNA (GFP). In case of YOYO-1 delivery, more than 80% of cells can be transferred only in the plasma-irradiated area and the spatially-selective membrane permeabilization is realized by the plasma irradiation. In addition, it is confirmed that plasmid DNA is transfected and the GFP genes are expressed using same APP irradiation system with no obvious cellular damage.

Mindfulness-Based Symptom and Stress Management Apps for Adults With Chronic Lung Disease: Systematic Search in App Stores

PubMed Central

2018-01-01

Background Up to 70% of lung cancer survivors are affected by chronic obstructive pulmonary disease (COPD), a common, debilitating, comorbid disease. Lung cancer and COPD are both characterized by symptoms such as breathlessness, fatigue, and psychological distress. These distressing chronic symptoms are exacerbated by stress and detract from an individual’s quality of life. Objective The aim of this study was to identify and evaluate evidence-based, commercially available apps for promoting mindfulness-based strategies among adults with a COPD or lung cancer history (ie, chronic lung disease). Methods For this review, an interdisciplinary research team used 19 keyword combinations in the search engines of Google and iOS app stores in May 2017. Evaluations were conducted on the apps’ (1) content, (2) usability heuristics, (3) grade-level readability, and (4) cultural sensitivity. Results The search resulted in 768 apps (508 in iOS and 260 in Google stores). A total of 9 apps met the inclusion criteria and received further evaluation. Only 1 app had below an eighth-grade reading level; the ninth one did not have enough text to calculate a readability score. None of the 9 apps met the cultural sensitivity evaluation criteria. Conclusions This systematic review identified critical design flaws that may affect the ease of using the apps in this study. Few mobile apps promote mindfulness-based strategies among adults with chronic lung disease (ie, COPD or lung cancer or both), but those that exist, overall, do not meet the latest scientific evidence. Recommendations include more stringent regulation of health-related apps, use of evidence-based frameworks and participatory design processes, following evidence-based usability practices, use of culturally sensitive language and images, and ensuring that content is written in plain language. PMID:29764800

Impact of an iDevice application on student learning in an occupational therapy kinesiology course.

PubMed

Hughes, Jason K; Kearney, Pamalyn

2017-01-01

As technology continues to evolve, and information is increasingly accessed through smartphones and tablets, it is essential for university faculty to reassess teaching methodologies. This study explored how use of an iDevice application (app) by participants enrolled in an entry-level occupational therapy kinesiology course affected student learning in the course. This iDevice app was developed through a collaboration between the lead author and the Department of Technology Enhanced Learning and Innovation at Augusta University. The iDevice app was released to the public via the Apple ® App Store at the midpoint of the kinesiology course. All students were invited to use the app. Focus groups were conducted with 19 students recruited from the first year cohort of occupational therapy graduate students. These focus groups were conducted at the end of the semester once grades had been submitted. Thematic analysis of focus group transcripts revealed three themes reflecting how participants perceived app use impacting their learning. Participants report the app facilitated learning through provision of visual content, serving as a reliable source of information, and generally supporting the learning process. The Kinesiology Pro Consult App provided on demand learning, allowing students to be more autonomous with their learning and take advantage of opportunities to learn anywhere and anytime. Finally, participants reported the app allowed them to be more efficient in their learning, possibly allowing more time for other courses. Mobile device apps that support student learning in specific content areas may provide positive benefits to student learning both in the specific course related to the app but also in other courses as a result of increased efficiency in learning.

Impact of an iDevice application on student learning in an occupational therapy kinesiology course

PubMed Central

Kearney, Pamalyn

2017-01-01

Background As technology continues to evolve, and information is increasingly accessed through smartphones and tablets, it is essential for university faculty to reassess teaching methodologies. This study explored how use of an iDevice application (app) by participants enrolled in an entry-level occupational therapy kinesiology course affected student learning in the course. This iDevice app was developed through a collaboration between the lead author and the Department of Technology Enhanced Learning and Innovation at Augusta University. Methods The iDevice app was released to the public via the Apple® App Store at the midpoint of the kinesiology course. All students were invited to use the app. Focus groups were conducted with 19 students recruited from the first year cohort of occupational therapy graduate students. These focus groups were conducted at the end of the semester once grades had been submitted. Results Thematic analysis of focus group transcripts revealed three themes reflecting how participants perceived app use impacting their learning. Participants report the app facilitated learning through provision of visual content, serving as a reliable source of information, and generally supporting the learning process. The Kinesiology Pro Consult App provided on demand learning, allowing students to be more autonomous with their learning and take advantage of opportunities to learn anywhere and anytime. Finally, participants reported the app allowed them to be more efficient in their learning, possibly allowing more time for other courses. Conclusions Mobile device apps that support student learning in specific content areas may provide positive benefits to student learning both in the specific course related to the app but also in other courses as a result of increased efficiency in learning. PMID:29184895

Quality of Mobile Phone and Tablet Mobile Apps for Speech Sound Disorders: Protocol for an Evidence-Based Appraisal.

PubMed

Furlong, Lisa M; Morris, Meg E; Erickson, Shane; Serry, Tanya A

2016-11-29

Although mobile apps are readily available for speech sound disorders (SSD), their validity has not been systematically evaluated. This evidence-based appraisal will critically review and synthesize current evidence on available therapy apps for use by children with SSD. The main aims are to (1) identify the types of apps currently available for Android and iOS mobile phones and tablets, and (2) to critique their design features and content using a structured quality appraisal tool. This protocol paper presents and justifies the methods used for a systematic review of mobile apps that provide intervention for use by children with SSD. The primary outcomes of interest are (1) engagement, (2) functionality, (3) aesthetics, (4) information quality, (5) subjective quality, and (6) perceived impact. Quality will be assessed by 2 certified practicing speech-language pathologists using a structured quality appraisal tool. Two app stores will be searched from the 2 largest operating platforms, Android and iOS. Systematic methods of knowledge synthesis shall include searching the app stores using a defined procedure, data extraction, and quality analysis. This search strategy shall enable us to determine how many SSD apps are available for Android and for iOS compatible mobile phones and tablets. It shall also identify the regions of the world responsible for the apps' development, the content and the quality of offerings. Recommendations will be made for speech-language pathologists seeking to use mobile apps in their clinical practice. This protocol provides a structured process for locating apps and appraising the quality, as the basis for evaluating their use in speech pathology for children in English-speaking nations. ©Lisa M Furlong, Meg E Morris, Shane Erickson, Tanya A Serry. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 29.11.2016.

Understanding the Relationships between mHealth Apps' Characteristics, Trialability, and mHealth Literacy.

PubMed

Lin, Trisha T C; Bautista, John Robert

2017-04-01

The widespread adoption of mobile phones has increased the potential of mHealth to improve health communication and health outcomes because these devices could serve as a ubiquitous and affordable means to disseminate health information to large populations. Given that mHealth apps offer free or limited trials as part of promotional strategies, potential users' trialability is a critical step of the preadoption process. Drawing from Rogers' diffusion of innovation theory, this study examines the relationships of adopters' perceived characteristics of mHealth apps (i.e., relative advantage, complexity, compatibility, and observability) with their trialability. It further investigates how the perceived control of mobile devices and trialability of mHealth apps influence two dimensions of mHealth literacy, namely seeking and appraisal of health information. This web survey recruited 295 young mHealth app users from a Singaporean university. Results of partial least squares regression show that the observability of mHealth apps is the only factor positively related to mHealth trialability. Perceived control of mobile devices and trialability of mHealth apps are positively associated with seeking and appraisal of health information. Practical and theoretical implications to mHealth are discussed.

Barriers to Expanding Advanced Pharmacy Practice Experience Site Availability in an Experiential Education Consortium

PubMed Central

Byrd, Debbie C.; Duke, Lori J.; Fetterman, James W.; Unterwagner, Whitney L.; Staton, April G.; Miller, Mindi S.; Sheffield, Melody C.; Kennedy, William K.; McDuffie, Charles H.; Stevenson, T. Lynn; Thompson, Paula A.; McCullough, Elizabeth S.

2009-01-01

Objectives To compare 2006-2007 and projected 2010-2011 advanced pharmacy practice experience (APPE) availability and needs for 4 colleges and schools of pharmacy in Georgia and Alabama and to examine barriers and offer potential solutions to increase APPE site and preceptor availability. Methods Data on APPE needs and availability were gathered prospectively and evaluated relative to current and projected enrollment and planned programmatic changes. Results Combined 2006-2007 non-community APPE needs and availabilities were 3,590 and 4,427, respectively, with a surplus availability of 837. Combined projected 2010-2011 non-community APPEs were estimated at 4,309. Assuming 2006-2007 non-community availability remained unchanged, the surplus availability declined to 118. Conclusions The need for quality experiential education represents a significant barrier and rate-limiting step to the matriculation of the increased numbers of pharmacists. Barriers to expanding APPE availability include: introductory pharmacy practice experience (IPPE) and APPE expansion, growth of new and existing pharmacy programs, financial instability of acute care facilities, and lack of preceptor development resources. Regional experiential education consortiums can provide a constructive approach to improve access to quality sites and preceptors through standardizing processes and leveraging resources. PMID:19777097

Exploring the Usability of Mobile Apps Supporting Radiologists' Training in Diagnostic Decision Making.

PubMed

Kim, Min Soon; Aro, Michael R; Lage, Kraig J; Ingalls, Kevin L; Sindhwani, Vivek; Markey, Mia K

2016-03-01

The objective of this study was to conduct a usability evaluation of mobile apps for supporting education and training in radiologic diagnostic decision-making processes. Of 381 mobile apps available at two major stores (Google Play and iTunes), eight iOS apps were selected for laboratory-based usability tests. Six staff radiologists completed eight app-specific task sets, using a think-aloud strategy. The triangular methods approach included quantitative performance measures, System Usability Scale (SUS), and qualitative thematic analysis using heuristic usability principles of usability issues. Overall, radiologists achieved higher than 70% success, with favorable SUS scores, in completing the tasks for seven of the eight apps. However, task success rate and SUS score had a weak relation (r = 0.23), indicating that the perceived usability may not reflect the holistic usability of the app. Task analysis and self-report revealed 108 usability issues, which were condensed to 55 unique issues and categorized by nine usability themes and mapped to ten usability heuristics. Nonintuitive functionality (eg, nonintuitive or misleading labels) was the most frequent theme observed, leading to inefficient navigation. These usability findings were consistent with the 13 improvements the radiologists suggested. This study demonstrates the feasibility of usability evaluation of radiology mobile apps and suggests potential improvements in the development of radiology mobile apps. This study also suggests that proficiency with mobile devices may not be equivalent to being an expert user, proficient in using the apps. Copyright © 2016 American College of Radiology. Published by Elsevier Inc. All rights reserved.

Mobile applications for diabetics: a systematic review and expert-based usability evaluation considering the special requirements of diabetes patients age 50 years or older.

PubMed

Arnhold, Madlen; Quade, Mandy; Kirch, Wilhelm

2014-04-09

A multitude of mhealth (mobile health) apps have been developed in recent years to support effective self-management of patients with diabetes mellitus type 1 or 2. We carried out a systematic review of all currently available diabetes apps for the operating systems iOS and Android. We considered the number of newly released diabetes apps, range of functions, target user groups, languages, acquisition costs, user ratings, available interfaces, and the connection between acquisition costs and user ratings. Additionally, we examined whether the available applications serve the special needs of diabetes patients aged 50 or older by performing an expert-based usability evaluation. We identified relevant keywords, comparative categories, and their specifications. Subsequently, we performed the app review based on the information given in the Google Play Store, the Apple App Store, and the apps themselves. In addition, we carried out an expert-based usability evaluation based on a representative 10% sample of diabetes apps. In total, we analyzed 656 apps finding that 355 (54.1%) offered just one function and 348 (53.0%) provided a documentation function. The dominating app language was English (85.4%, 560/656), patients represented the main user group (96.0%, 630/656), and the analysis of the costs revealed a trend toward free apps (53.7%, 352/656). The median price of paid apps was €1.90. The average user rating was 3.6 stars (maximum 5). Our analyses indicated no clear differences in the user rating between free and paid apps. Only 30 (4.6%) of the 656 available diabetes apps offered an interface to a measurement device. We evaluated 66 apps within the usability evaluation. On average, apps were rated best regarding the criterion "comprehensibility" (4.0 out of 5.0), while showing a lack of "fault tolerance" (2.8 out of 5.0). Of the 66 apps, 48 (72.7%) offered the ability to read the screen content aloud. The number of functions was significantly negative correlated with usability. The presence of documentation and analysis functions reduced the usability score significantly by 0.36 and 0.21 points. A vast number of diabetes apps already exist, but the majority offer similar functionalities and combine only one to two functions in one app. Patients and physicians alike should be involved in the app development process to a greater extent. We expect that the data transmission of health parameters to physicians will gain more importance in future applications. The usability of diabetes apps for patients aged 50 or older was moderate to good. But this result applied mainly to apps offering a small range of functions. Multifunctional apps performed considerably worse in terms of usability. Moreover, the presence of a documentation or analysis function resulted in significantly lower usability scores. The operability of accessibility features for diabetes apps was quite limited, except for the feature "screen reader".

Intracellular trafficking of the β-secretase and processing of amyloid precursor protein.

PubMed

Zhi, Pei; Chia, Pei Zhi Cheryl; Chia, Cheryl; Gleeson, Paul A

2011-09-01

The main component of the amyloid plaques found in the brains of those with Alzheimer's disease (AD) is a polymerized form of the β-amyloid peptide (Aβ) and is considered to play a central role in the pathogenesis of this neurodegenerative disorder. Aβ is derived from the proteolytic processing of the amyloid precursor protein (APP). Beta site APP-cleaving enzyme, BACE1 (also known as β-secretase) is a membrane-bound aspartyl protease responsible for the initial step in the generation of Aβ peptide and is thus a prime target for therapeutic intervention. Substantive evidence now indicates that the processing of APP by BACE1 is regulated by the intracellular sorting of the enzyme and, moreover, perturbations in these intracellular trafficking pathways have been linked to late-onset AD. In this review, we highlight the recent advances in the understanding of the regulation of the intracellular sorting of BACE1 and APP and illustrate why the trafficking of these cargos represent a key issue for understanding the membrane-mediated events associated with the generation of the neurotoxic Aβ products in AD. Copyright © 2011 International Union of Biochemistry and Molecular Biology, Inc.

Specific Inhibition of β-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein.

PubMed

Ben Halima, Saoussen; Mishra, Sabyashachi; Raja, K Muruga Poopathi; Willem, Michael; Baici, Antonio; Simons, Kai; Brüstle, Oliver; Koch, Philipp; Haass, Christian; Caflisch, Amedeo; Rajendran, Lawrence

2016-03-08

Development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD). AD is characterized by toxic β-amyloid (Aβ) peptides produced by β- and γ-secretase-mediated cleavage of the amyloid precursor protein (APP). β-secretase inhibitors reduce Aβ levels, but mechanism-based side effects arise because they also inhibit β-cleavage of non-amyloid substrates like Neuregulin. We report that β-secretase has a higher affinity for Neuregulin than it does for APP. Kinetic studies demonstrate that the affinities and catalytic efficiencies of β-secretase are higher toward non-amyloid substrates than toward APP. We show that non-amyloid substrates are processed by β-secretase in an endocytosis-independent manner. Exploiting this compartmentalization of substrates, we specifically target the endosomal β-secretase by an endosomally targeted β-secretase inhibitor, which blocked cleavage of APP but not non-amyloid substrates in many cell systems, including induced pluripotent stem cell (iPSC)-derived neurons. β-secretase inhibitors can be designed to specifically inhibit the Alzheimer process, enhancing their potential as AD therapeutics without undesired side effects. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Interferon-γ and Tumor Necrosis Factor-α Regulate Amyloid-β Plaque Deposition and β-Secretase Expression in Swedish Mutant APP Transgenic Mice

PubMed Central

Yamamoto, Masaru; Kiyota, Tomomi; Horiba, Masahide; Buescher, James L.; Walsh, Shannon M.; Gendelman, Howard E.; Ikezu, Tsuneya

2007-01-01

Reactive astrocytes and microglia in Alzheimer’s disease surround amyloid plaques and secrete proinflammatory cytokines that affect neuronal function. Relationship between cytokine signaling and amyloid-β peptide (Aβ) accumulation is poorly understood. Thus, we generated a novel Swedish β-amyloid precursor protein mutant (APP) transgenic mouse in which the interferon (IFN)-γ receptor type I was knocked out (APP/GRKO). IFN-γ signaling loss in the APP/GRKO mice reduced gliosis and amyloid plaques at 14 months of age. Aggregated Aβ induced IFN-γ production from co-culture of astrocytes and microglia, and IFN-γ elicited tumor necrosis factor (TNF)-α secretion in wild type (WT) but not GRKO microglia co-cultured with astrocytes. Both IFN-γ and TNF-α enhanced Aβ production from APP-expressing astrocytes and cortical neurons. TNF-α directly stimulated β-site APP-cleaving enzyme (BACE1) expression and enhanced β-processing of APP in astrocytes. The numbers of reactive astrocytes expressing BACE1 were increased in APP compared with APP/GRKO mice in both cortex and hippocampus. IFN-γ and TNF-α activation of WT microglia suppressed Aβ degradation, whereas GRKO microglia had no changes. These results support the idea that glial IFN-γ and TNF-α enhance Aβ deposition through BACE1 expression and suppression of Aβ clearance. Taken together, these observations suggest that proinflammatory cytokines are directly linked to Alzheimer’s disease pathogenesis. PMID:17255335

Development of Smartphone Applications for Nutrition and Physical Activity Behavior Change

PubMed Central

Cook, Amelia; van der Ploeg, Hidde P; Allman-Farinelli, Margaret

2012-01-01

Background Young adults (aged 18 to 35) are a population group at high risk for weight gain, yet we know little about how to intervene in this group. Easy access to treatment and support with self-monitoring of their behaviors may be important. Smartphones are gaining in popularity with this population group and software applications (“apps”) used on these mobile devices are a novel technology that can be used to deliver brief health behavior change interventions directly to individuals en masse, with potentially favorable cost-utility. However, existing apps for modifying nutrition or physical activity behaviors may not always reflect best practice guidelines for weight management. Objective This paper describes the process of developing four apps aimed at modifying key lifestyle behaviors associated with weight gain during young adulthood, including physical activity, and consumption of take-out foods (fast food), fruit and vegetables, and sugar-sweetened drinks. Methods The development process involved: (1) deciding on the behavior change strategies, relevant guidelines, graphic design, and potential data collection; (2) selecting the platform (Web-based versus native); (3) creating the design, which required decisions about the user interface, architecture of the relational database, and programming code; and (4) testing the prototype versions with the target audience (young adults aged 18 to 35). Results The four apps took 18 months to develop, involving the fields of marketing, nutrition and dietetics, physical activity, and information technology. Ten subjects provided qualitative feedback about using the apps. The slow running speed of the apps (due to a reliance on an active Internet connection) was the primary issue identified by this group, as well as the requirement to log in to the apps. Conclusions Smartphone apps may be an innovative medium for delivering individual health behavior change intervention en masse, but researchers must give consideration to the target population, available technologies, existing commercial apps, and the possibility that their use will be irregular and short-lived. PMID:23611892

Smoking cessation apps for smartphones: content analysis with the self-determination theory.

PubMed

Choi, Jounghwa; Noh, Ghee-Young; Park, Dong-Jin

2014-02-12

Smartphones are increasingly receiving attention from public health scholars and practitioners as a means to assist individuals' health management. A number of smartphone apps for smoking cessation are also available; however, little effort has been made to evaluate the content and functions of these apps employing a theoretical framework. The present study aims to analyze and evaluate the contents of smoking cessation apps available in South Korea employing the self-determination theory (SDT) as a theoretical framework for analysis. This study analyzes the extent to which smoking cessation apps have features that satisfy the basic needs identified in the SDT, which stimulate autonomous motivation. The type of motivational goal content manifested in the apps and how the goal content was framed are also explored. By assessing the features of smoking cessation apps based on the SDT, this study aims to offer direction for improvement for these apps. Out of 309 apps identified from the iTunes store and Google Play (excluding 27 duplications), 175 apps were randomly drawn and analyzed. The coding scheme was drafted by the authors based on the SDT and gain/loss framing theory and was further finely tuned through the process of coder training and by establishing intercoder reliability. Once the intercoder reliability was established, the coders divided up the rest of the sample and coded them independently. The analysis revealed that most apps (94.3%, 165/175) had at least one feature that tapped at least 1 of the 3 basic needs. Only 18 of 175 apps (10.3%) addressed all 3 basic needs. For goal content, money (53.7%, 94/175) showed the highest frequency, followed by health (32.0%, 56/175), time (7.4%, 13/175), and appearance (1.1%, 2/175), suggesting that extrinsic goals are more dominantly presented in smoking cessation apps. For the framing of goal content, gain framing appeared more frequently (41.7%, 73/175). The results suggest that these smoking cessation apps may not sufficiently stimulate autonomous motivation; a small number of apps addressed all 3 basic needs suggested by the SDT (ie, autonomy, competence, and relatedness). The apps also tended to present extrinsic goal content (primarily in terms of money) over intrinsic ones (ie, health) by primarily adopting gain framing. Implications of these findings for public health practitioners and consumers are discussed.

Smoking Cessation Apps for Smartphones: Content Analysis With the Self-Determination Theory

PubMed Central

Noh, Ghee-Young; Park, Dong-Jin

2014-01-01

Background Smartphones are increasingly receiving attention from public health scholars and practitioners as a means to assist individuals’ health management. A number of smartphone apps for smoking cessation are also available; however, little effort has been made to evaluate the content and functions of these apps employing a theoretical framework. Objective The present study aims to analyze and evaluate the contents of smoking cessation apps available in South Korea employing the self-determination theory (SDT) as a theoretical framework for analysis. This study analyzes the extent to which smoking cessation apps have features that satisfy the basic needs identified in the SDT, which stimulate autonomous motivation. The type of motivational goal content manifested in the apps and how the goal content was framed are also explored. By assessing the features of smoking cessation apps based on the SDT, this study aims to offer direction for improvement for these apps. Methods Out of 309 apps identified from the iTunes store and Google Play (excluding 27 duplications), 175 apps were randomly drawn and analyzed. The coding scheme was drafted by the authors based on the SDT and gain/loss framing theory and was further finely tuned through the process of coder training and by establishing intercoder reliability. Once the intercoder reliability was established, the coders divided up the rest of the sample and coded them independently. Results The analysis revealed that most apps (94.3%, 165/175) had at least one feature that tapped at least 1 of the 3 basic needs. Only 18 of 175 apps (10.3%) addressed all 3 basic needs. For goal content, money (53.7%, 94/175) showed the highest frequency, followed by health (32.0%, 56/175), time (7.4%, 13/175), and appearance (1.1%, 2/175), suggesting that extrinsic goals are more dominantly presented in smoking cessation apps. For the framing of goal content, gain framing appeared more frequently (41.7%, 73/175). Conclusions The results suggest that these smoking cessation apps may not sufficiently stimulate autonomous motivation; a small number of apps addressed all 3 basic needs suggested by the SDT (ie, autonomy, competence, and relatedness). The apps also tended to present extrinsic goal content (primarily in terms of money) over intrinsic ones (ie, health) by primarily adopting gain framing. Implications of these findings for public health practitioners and consumers are discussed. PMID:24521881

Protection of Radial Glial-Like Cells in the Hippocampus of APP/PS1 Mice: a Novel Mechanism of Memantine in the Treatment of Alzheimer's Disease.

PubMed

Sun, Dayu; Chen, Junhua; Bao, Xiaohang; Cai, Yulong; Zhao, Jinghui; Huang, Jing; Huang, Wei; Fan, Xiaotang; Xu, Haiwei

2015-08-01

The failure of adult neurogenesis in the hippocampal dentate gyrus (DG) is closely correlated with memory decline in Alzheimer's disease (AD). Radial glial-like cells (RGLs) localized to the adult DG generate intermediate progenitor cells and immature neurons and thus contribute to adult hippocampus neurogenesis. Memantine (MEM) has been indicated to dramatically increase hippocampal neurogenesis by promoting the proliferation of RGLs. In this study, we examined the effect of MEM on the capacity for hippocampal cell proliferation and the amount of RGLs in APPswe/PS1∆E9 transgenic (APP/PS1) mice between 9 and 13 months of age. MEM could enhance hippocampal neurogenesis and increase the number of RGLs in the DG subgranular zone (DG-SGZ) of APP/PS1 mice of both ages. Moreover, MEM decreased amyloidogenesis in 13-month-old APP/PS1 mice and protected cultured radial glia cells (RGCs, L2.3 cells) from apoptosis induced by the β amyloid peptide (Aβ). Additionally, MEM inhibited microglial activation in a vertical process in DG-SGZ of APP/PS1 mice and decreased interacting with RGL processes. Reelin is involved in the proliferation of RGLs in the hippocampus, which was typically upregulated in the hippocampus of APP/PS1 mice by MEM and thought to be an active signaling pathway associated with the MEM-induced increase in RGLs. Our data suggest a previously uncharacterized role for MEM in treating AD.

Amyloid-β Peptide Induces Prion Protein Amyloid Formation: Evidence for Its Widespread Amyloidogenic Effect.

PubMed

Honda, Ryo

2018-04-12

Transmissible spongiform encephalopathy is associated with misfolding of prion protein (PrP) into an amyloid β-rich aggregate. Previous studies have indicated that PrP interacts with Alzheimer's disease amyloid-β peptide (Aβ), but it remains elusive how this interaction impacts on the misfolding of PrP. This study presents the first in vitro evidence that Aβ induces PrP-amyloid formation at submicromolar concentrations. Interestingly, systematic mutagenesis of PrP revealed that Aβ requires no specific amino acid sequences in PrP, and induces the misfolding of other unrelated proteins (insulin and lysozyme) into amyloid fibrils in a manner analogous to PrP. This unanticipated nonspecific amyloidogenic effect of Aβ indicates that this peptide might be involved in widespread protein aggregation, regardless of the amino acid sequences of target proteins, and exacerbate the pathology of many neurodegenerative diseases. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Sequence Complexity of Amyloidogenic Regions in Intrinsically Disordered Human Proteins

PubMed Central

Das, Swagata; Pal, Uttam; Das, Supriya; Bagga, Khyati; Roy, Anupam; Mrigwani, Arpita; Maiti, Nakul C.

2014-01-01

An amyloidogenic region (AR) in a protein sequence plays a significant role in protein aggregation and amyloid formation. We have investigated the sequence complexity of AR that is present in intrinsically disordered human proteins. More than 80% human proteins in the disordered protein databases (DisProt+IDEAL) contained one or more ARs. With decrease of protein disorder, AR content in the protein sequence was decreased. A probability density distribution analysis and discrete analysis of AR sequences showed that ∼8% residue in a protein sequence was in AR and the region was in average 8 residues long. The residues in the AR were high in sequence complexity and it seldom overlapped with low complexity regions (LCR), which was largely abundant in disorder proteins. The sequences in the AR showed mixed conformational adaptability towards α-helix, β-sheet/strand and coil conformations. PMID:24594841

Epigallocatechin-3-gallate preferentially induces aggregation of amyloidogenic immunoglobulin light chains

PubMed Central

Hora, Manuel; Carballo-Pacheco, Martin; Weber, Benedikt; Morris, Vanessa K.; Wittkopf, Antje; Buchner, Johannes; Strodel, Birgit; Reif, Bernd

2017-01-01

Antibody light chain amyloidosis is a rare disease caused by fibril formation of secreted immunoglobulin light chains (LCs). The huge variety of antibody sequences puts a serious challenge to drug discovery. The green tea polyphenol epigallocatechin-3-gallate (EGCG) is known to interfere with fibril formation in general. Here we present solution- and solid-state NMR studies as well as MD simulations to characterise the interaction of EGCG with LC variable domains. We identified two distinct EGCG binding sites, both of which include a proline as an important recognition element. The binding sites were confirmed by site-directed mutagenesis and solid-state NMR analysis. The EGCG-induced protein complexes are unstructured. We propose a general mechanistic model for EGCG binding to a conserved site in LCs. We find that EGCG reacts selectively with amyloidogenic mutants. This makes this compound a promising lead structure, that can handle the immense sequence variability of antibody LCs. PMID:28128355

A Smartphone App to Promote an Active Lifestyle in Lower-Educated Working Young Adults: Development, Usability, Acceptability, and Feasibility Study

PubMed Central

De Bourdeaudhuij, Ilse; Clarys, Peter; De Cocker, Katrien; Vandelanotte, Corneel; Deforche, Benedicte

2018-01-01

Background Physical activity (PA) levels are problematic in lower-educated working young adults (18-26 years). To promote PA, smartphone apps have great potential, but there is no evidence for their effectiveness in this population. To increase the likelihood that a newly developed app will be effective, formative research and user testing are required. Objective The aim of this study was to describe the development, usability, acceptability, and feasibility of a new theory- and evidence-based smartphone app to promote an active lifestyle in lower-educated working young adults. Methods The new app was developed by applying 4 steps. First, determinants important to promote an active lifestyle in this population were selected. Second, evidence-based behavior change techniques were selected to convert the determinants into practical applications. Third, a new smartphone app was developed. Fourth, volunteers (n=11, both lower and higher educated) tested the app on usability, and lower-educated working young adults (n=16) tested its acceptability and feasibility via (think aloud) interviews, a questionnaire, and Google Analytics. The app was accordingly adapted for the final version. Results A new Android app, Active Coach, was developed that focused on knowledge, attitude, social support, and self-efficacy (based on outcomes from step 1), and that applied self-regulation techniques (based on outcomes from step 2). The app consists of a 9-week program with personal goals, practical tips, and scientific facts to encourage an active lifestyle. To ensure all-day and automatic self-monitoring of the activity behavior, the Active Coach app works in combination with a wearable activity tracker, the Fitbit Charge. Issues detected by the usability test (eg, text errors, wrong messages) were all fixed. The acceptability and feasibility test showed that participants found the app clear, understandable, and motivating, although some aspects needed to be more personal. Conclusions By applying a stepwise, user-centered approach that regularly consulted the target group, the new app is adapted to their specific needs and preferences. The Active Coach app was overall positively evaluated by the lower-educated working young adults at the end of the development process. PMID:29463491

Chinese Cardiovascular Disease Mobile Apps' Information Types, Information Quality, and Interactive Functions for Self-Management: Systematic Review.

PubMed

Xie, Bo; Su, Zhaohui; Zhang, Wenhui; Cai, Run

2017-12-14

China has a large population with cardiovascular disease (CVD) that requires extensive self-management. Mobile health (mHealth) apps may be a useful tool for CVD self-management. Little is currently known about the types and quality of health information provided in Chinese CVD mobile apps and whether app functions are conducive to promoting CVD self-management. We undertook a systematic review to evaluate the types and quality of health information provided in Chinese CVD mobile apps and interactive app functions for promoting CVD self-management. Mobile apps targeting end users in China with CVD conditions were selected in February 2017 through a multi-stage process. Three frameworks were used to evaluate the selected apps: (1) types of health information offered were assessed using our Health Information Wants framework, which encompasses 7 types of information; (2) quality of information provided in the apps was assessed using the 11 guidelines recommended by the National Library of Medicine of the National Institutes of Health; and (3) types of interactive app functions for CVD self-management were assessed using a 15-item framework adapted from the literature, including our own prior work. Of 578 apps identified, 82 were eligible for final review. Among these, information about self-care (67/82, 82%) and information specifically regarding CVD (63/82, 77%) were the most common types of information provided, while information about health care providers (22/82, 27%) and laboratory tests (5/82, 6%) were least common. The most common indicators of information quality were the revealing of apps' providers (82/82, 100%) and purpose (82/82, 100%), while the least common quality indicators were the revealing of how apps' information was selected (1/82, 1%) and app sponsorship (0/82, 0%). The most common interactive functions for CVD self-management were those that enabled user interaction with the app provider (57/82, 70%) and with health care providers (36/82, 44%), while the least common interactive functions were those that enabled lifestyle management (13/82, 16%) and psychological health management (6/82, 7%). None of the apps covered all 7 types of health information, all 11 indicators of information quality, or all 15 interactive functions for CVD self-management. Chinese CVD apps are insufficient in providing comprehensive health information, high-quality information, and interactive functions to facilitate CVD self-management. End users should exercise caution when using existing apps. Health care professionals and app developers should collaborate to better understand end users' preferences and follow evidence-based guidelines to develop mHealth apps conducive to CVD self-management. ©Bo Xie, Zhaohui Su, Wenhui Zhang, Run Cai. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 14.12.2017.

Amyloid Precursor Protein (APP) Mediated Regulation of Ganglioside Homeostasis Linking Alzheimer's Disease Pathology with Ganglioside Metabolism

PubMed Central

Grimm, Marcus O. W.; Zinser, Eva G.; Grösgen, Sven; Hundsdörfer, Benjamin; Rothhaar, Tatjana L.; Burg, Verena K.; Kaestner, Lars; Bayer, Thomas A.; Lipp, Peter; Müller, Ulrike; Grimm, Heike S.; Hartmann, Tobias

2012-01-01

Gangliosides are important players for controlling neuronal function and are directly involved in AD pathology. They are among the most potent stimulators of Aβ production, are enriched in amyloid plaques and bind amyloid beta (Aβ). However, the molecular mechanisms linking gangliosides with AD are unknown. Here we identified the previously unknown function of the amyloid precursor protein (APP), specifically its cleavage products Aβ and the APP intracellular domain (AICD), of regulating GD3-synthase (GD3S). Since GD3S is the key enzyme converting a- to b-series gangliosides, it therefore plays a major role in controlling the levels of major brain gangliosides. This regulation occurs by two separate and additive mechanisms. The first mechanism directly targets the enzymatic activity of GD3S: Upon binding of Aβ to the ganglioside GM3, the immediate substrate of the GD3S, enzymatic turnover of GM3 by GD3S was strongly reduced. The second mechanism targets GD3S expression. APP cleavage results, in addition to Aβ release, in the release of AICD, a known candidate for gene transcriptional regulation. AICD strongly down regulated GD3S transcription and knock-in of an AICD deletion mutant of APP in vivo, or knock-down of Fe65 in neuroblastoma cells, was sufficient to abrogate normal GD3S functionality. Equally, knock-out of the presenilin genes, presenilin 1 and presenilin 2, essential for Aβ and AICD production, or of APP itself, increased GD3S activity and expression and consequently resulted in a major shift of a- to b-series gangliosides. In addition to GD3S regulation by APP processing, gangliosides in turn altered APP cleavage. GM3 decreased, whereas the ganglioside GD3, the GD3S product, increased Aβ production, resulting in a regulatory feedback cycle, directly linking ganglioside metabolism with APP processing and Aβ generation. A central aspect of this homeostatic control is the reduction of GD3S activity via an Aβ-GM3 complex and AICD-mediated repression of GD3S transcription. PMID:22470521

Identification of Key Amino Acid Residues Modulating Intracellular and In vitro Microcin E492 Amyloid Formation

PubMed Central

Aguilera, Paulina; Marcoleta, Andrés; Lobos-Ruiz, Pablo; Arranz, Rocío; Valpuesta, José M.; Monasterio, Octavio; Lagos, Rosalba

2016-01-01

Microcin E492 (MccE492) is a pore-forming bacteriocin produced and exported by Klebsiella pneumoniae RYC492. Besides its antibacterial activity, excreted MccE492 can form amyloid fibrils in vivo as well as in vitro. It has been proposed that bacterial amyloids can be functional playing a biological role, and in the particular case of MccE492 it would control the antibacterial activity. MccE492 amyloid fibril’s morphology and formation kinetics in vitro have been well-characterized, however, it is not known which amino acid residues determine its amyloidogenic propensity, nor if it forms intracellular amyloid inclusions as has been reported for other bacterial amyloids. In this work we found the conditions in which MccE492 forms intracellular amyloids in Escherichia coli cells, that were visualized as round-shaped inclusion bodies recognized by two amyloidophilic probes, 2-4′-methylaminophenyl benzothiazole and thioflavin-S. We used this property to perform a flow cytometry-based assay to evaluate the aggregation propensity of MccE492 mutants, that were designed using an in silico prediction of putative aggregation hotspots. We established that the predicted amino acid residues 54–63, effectively act as a pro-amyloidogenic stretch. As in the case of other amyloidogenic proteins, this region presented two gatekeeper residues (P57 and P59), which disfavor both intracellular and in vitro MccE492 amyloid formation, preventing an uncontrolled aggregation. Mutants in each of these gatekeeper residues showed faster in vitro aggregation and bactericidal inactivation kinetics, and the two mutants were accumulated as dense amyloid inclusions in more than 80% of E. coli cells expressing these variants. In contrast, the MccE492 mutant lacking residues 54–63 showed a significantly lower intracellular aggregation propensity and slower in vitro polymerization kinetics. Electron microscopy analysis of the amyloids formed in vitro by these mutants revealed that, although with different efficiency, all formed fibrils morphologically similar to wild-type MccE492. The physiological implication of MccE492 intracellular amyloid formation is probably similar to the inactivation process observed for extracellular amyloids, and could be used as a mean of sequestering potentially toxic species inside the cell when this bacteriocin is produced in large amounts. PMID:26858708

A Classification Scheme for Analyzing Mobile Apps Used to Prevent and Manage Disease in Late Life

PubMed Central

Wang, Aiguo; Lu, Xin; Chen, Hongtu; Li, Changqun; Levkoff, Sue

2014-01-01

Background There are several mobile apps that offer tools for disease prevention and management among older adults, and promote health behaviors that could potentially reduce or delay the onset of disease. A classification scheme that categorizes apps could be useful to both older adult app users and app developers. Objective The objective of our study was to build and evaluate the effectiveness of a classification scheme that classifies mobile apps available for older adults in the “Health & Fitness” category of the iTunes App Store. Methods We constructed a classification scheme for mobile apps according to three dimensions: (1) the Precede-Proceed Model (PPM), which classifies mobile apps in terms of predisposing, enabling, and reinforcing factors for behavior change; (2) health care process, specifically prevention versus management of disease; and (3) health conditions, including physical health and mental health. Content analysis was conducted by the research team on health and fitness apps designed specifically for older adults, as well as those applicable to older adults, released during the months of June and August 2011 and August 2012. Face validity was assessed by a different group of individuals, who were not related to the study. A reliability analysis was conducted to confirm the accuracy of the coding scheme of the sample apps in this study. Results After applying sample inclusion and exclusion criteria, a total of 119 apps were included in the study sample, of which 26/119 (21.8%) were released in June 2011, 45/119 (37.8%) in August 2011, and 48/119 (40.3%) in August 2012. Face validity was determined by interviewing 11 people, who agreed that this scheme accurately reflected the nature of this application. The entire study sample was successfully coded, demonstrating satisfactory inter-rater reliability by two independent coders (95.8% initial concordance and 100% concordance after consensus was reached). The apps included in the study sample were more likely to be used for the management of disease than prevention of disease (109/119, 91.6% vs 15/119, 12.6%). More apps contributed to physical health rather than mental health (81/119, 68.1% vs 47/119, 39.5%). Enabling apps (114/119, 95.8%) were more common than reinforcing (20/119, 16.8%) or predisposing apps (10/119, 8.4%). Conclusions The findings, including face validity and inter-rater reliability, support the integrity of the proposed classification scheme for categorizing mobile apps for older adults in the “Health and Fitness” category available in the iTunes App Store. Using the proposed classification system, older adult app users would be better positioned to identify apps appropriate for their needs, and app developers would be able to obtain the distributions of available mobile apps for health-related concerns of older adults more easily. PMID:25098687

Mindfulness-Based Symptom and Stress Management Apps for Adults With Chronic Lung Disease: Systematic Search in App Stores.

PubMed

Owens, Otis L; Beer, Jenay M; Reyes, Ligia I; Gallerani, David G; Myhren-Bennett, Amanda R; McDonnell, Karen K

2018-05-15

Up to 70% of lung cancer survivors are affected by chronic obstructive pulmonary disease (COPD), a common, debilitating, comorbid disease. Lung cancer and COPD are both characterized by symptoms such as breathlessness, fatigue, and psychological distress. These distressing chronic symptoms are exacerbated by stress and detract from an individual's quality of life. The aim of this study was to identify and evaluate evidence-based, commercially available apps for promoting mindfulness-based strategies among adults with a COPD or lung cancer history (ie, chronic lung disease). For this review, an interdisciplinary research team used 19 keyword combinations in the search engines of Google and iOS app stores in May 2017. Evaluations were conducted on the apps' (1) content, (2) usability heuristics, (3) grade-level readability, and (4) cultural sensitivity. The search resulted in 768 apps (508 in iOS and 260 in Google stores). A total of 9 apps met the inclusion criteria and received further evaluation. Only 1 app had below an eighth-grade reading level; the ninth one did not have enough text to calculate a readability score. None of the 9 apps met the cultural sensitivity evaluation criteria. This systematic review identified critical design flaws that may affect the ease of using the apps in this study. Few mobile apps promote mindfulness-based strategies among adults with chronic lung disease (ie, COPD or lung cancer or both), but those that exist, overall, do not meet the latest scientific evidence. Recommendations include more stringent regulation of health-related apps, use of evidence-based frameworks and participatory design processes, following evidence-based usability practices, use of culturally sensitive language and images, and ensuring that content is written in plain language. ©Otis L Owens, Jenay M Beer, Ligia I Reyes, David G Gallerani, Amanda R Myhren-Bennett, Karen K McDonnell. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 15.05.2018.

Usability Testing of the BRANCH Smartphone App Designed to Reduce Harmful Drinking in Young Adults.

PubMed

Milward, Joanna; Deluca, Paolo; Drummond, Colin; Watson, Rod; Dunne, Jacklyn; Kimergård, Andreas

2017-08-08

Electronic screening and brief intervention (eSBI) apps demonstrate potential to reduce harmful drinking. However, low user engagement rates with eSBI reduce overall effectiveness of interventions. As "Digital Natives," young adults have high expectations of app quality. Ensuring that the design, content, and functionality of an eSBI app are acceptable to young adults is an integral stage to the development process. The objective of this study was to identify usability barriers and enablers for an app, BRANCH, targeting harmful drinking in young adults. The BRANCH app contains a drinking diary, alcohol reduction goal setting functions, normative drinking feedback, and information on risks and advice for cutting down. The app includes a social feature personalized to motivate cutting down and to promote engagement with a point-based system for usage. Three focus groups were conducted with 20 users who had tested the app for 1 week. A detailed thematic analysis was undertaken. The first theme, "Functionality" referred to how users wanted an easy-to-use interface, with minimum required user-input. Poor functionality was considered a major usability barrier. The second theme, "Design" described how an aesthetic with minimum text, clearly distinguishable tabs and buttons and appealing infographics was integral to the level of usability. The final theme, "Content" described how participants wanted all aspects of the app to be automatically personalized to them, as well as providing them with opportunities to personalize the app themselves, with increased options for social connectivity. There are high demands for apps such as BRANCH that target skilled technology users including young adults. Key areas to optimize eSBI app development that emerged from testing BRANCH with representative users include high-quality functionality, appealing aesthetics, and improved personalization. ©Joanna Milward, Paolo Deluca, Colin Drummond, Rod Watson, Jacklyn Dunne, Andreas Kimergård. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 08.08.2017.

Usability Testing of the BRANCH Smartphone App Designed to Reduce Harmful Drinking in Young Adults

PubMed Central

Deluca, Paolo; Drummond, Colin; Watson, Rod; Dunne, Jacklyn; Kimergård, Andreas

2017-01-01

Background Electronic screening and brief intervention (eSBI) apps demonstrate potential to reduce harmful drinking. However, low user engagement rates with eSBI reduce overall effectiveness of interventions. As “Digital Natives,” young adults have high expectations of app quality. Ensuring that the design, content, and functionality of an eSBI app are acceptable to young adults is an integral stage to the development process. Objective The objective of this study was to identify usability barriers and enablers for an app, BRANCH, targeting harmful drinking in young adults. Methods The BRANCH app contains a drinking diary, alcohol reduction goal setting functions, normative drinking feedback, and information on risks and advice for cutting down. The app includes a social feature personalized to motivate cutting down and to promote engagement with a point-based system for usage. Three focus groups were conducted with 20 users who had tested the app for 1 week. A detailed thematic analysis was undertaken. Results The first theme, “Functionality” referred to how users wanted an easy-to-use interface, with minimum required user-input. Poor functionality was considered a major usability barrier. The second theme, “Design” described how an aesthetic with minimum text, clearly distinguishable tabs and buttons and appealing infographics was integral to the level of usability. The final theme, “Content” described how participants wanted all aspects of the app to be automatically personalized to them, as well as providing them with opportunities to personalize the app themselves, with increased options for social connectivity. Conclusions There are high demands for apps such as BRANCH that target skilled technology users including young adults. Key areas to optimize eSBI app development that emerged from testing BRANCH with representative users include high-quality functionality, appealing aesthetics, and improved personalization. PMID:28790022

Tetrahydrohyperforin Inhibits the Proteolytic Processing of Amyloid Precursor Protein and Enhances Its Degradation by Atg5-Dependent Autophagy

PubMed Central

Muñoz, Vanessa C.; Yefi, Claudia P.; Bustamante, Hianara A.; Barraza, Rafael R.; Tapia-Rojas, Cheril; Otth, Carola; Barrera, María José; González, Carlos; Mardones, Gonzalo A.; Inestrosa, Nibaldo C.; Burgos, Patricia V.

2015-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) peptide. We have previously shown that the compound tetrahydrohyperforin (IDN5706) prevents accumulation of Aβ species in an in vivo model of AD, however the mechanism that explains this reduction is not well understood. We show herein that IDN5706 decreases the levels of ER degradation enhancer, mannosidase alpha-like 1 (EDEM1), a key chaperone related to endoplasmic-reticulum-associated degradation (ERAD). Moreover, we observed that low levels of EDEM1 correlated with a strong activation of autophagy, suggesting a crosstalk between these two pathways. We observed that IDN5706 perturbs the glycosylation and proteolytic processing of the amyloid precursor protein (APP), resulting in the accumulation of immature APP (iAPP) in the endoplasmic reticulum. To investigate the contribution of autophagy, we tested the effect of IDN5706 in Atg5-depleted cells. We found that depletion of Atg5 enhanced the accumulation of iAPP in response to IDN5706 by slowing down its degradation. Our findings reveal that IDN5706 promotes degradation of iAPP via the activation of Atg5-dependent autophagy, shedding light on the mechanism that may contribute to the reduction of Aβ production in vivo. PMID:26308941

Adaptor protein 2–mediated endocytosis of the β-secretase BACE1 is dispensable for amyloid precursor protein processing

PubMed Central

Prabhu, Yogikala; Burgos, Patricia V.; Schindler, Christina; Farías, Ginny G.; Magadár, Javier G.; Bonifacino, Juan S.

2012-01-01

The β-site amyloid precursor protein (APP)–cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease that catalyzes the proteolytic processing of APP and other plasma membrane protein precursors. BACE1 cycles between the trans-Golgi network (TGN), the plasma membrane, and endosomes by virtue of signals contained within its cytosolic C-terminal domain. One of these signals is the DXXLL-motif sequence DISLL, which controls transport between the TGN and endosomes via interaction with GGA proteins. Here we show that the DISLL sequence is embedded within a longer [DE]XXXL[LI]-motif sequence, DDISLL, which mediates internalization from the plasma membrane by interaction with the clathrin-associated, heterotetrameric adaptor protein 2 (AP-2) complex. Mutation of this signal or knockdown of either AP-2 or clathrin decreases endosomal localization and increases plasma membrane localization of BACE1. Remarkably, internalization-defective BACE1 is able to cleave an APP mutant that itself cannot be delivered to endosomes. The drug brefeldin A reversibly prevents BACE1-catalyzed APP cleavage, ruling out that this reaction occurs in the endoplasmic reticulum (ER) or ER–Golgi intermediate compartment. Taken together, these observations support the notion that BACE1 is capable of cleaving APP in late compartments of the secretory pathway. PMID:22553349

Tetrahydrohyperforin Inhibits the Proteolytic Processing of Amyloid Precursor Protein and Enhances Its Degradation by Atg5-Dependent Autophagy.

PubMed

Cavieres, Viviana A; González, Alexis; Muñoz, Vanessa C; Yefi, Claudia P; Bustamante, Hianara A; Barraza, Rafael R; Tapia-Rojas, Cheril; Otth, Carola; Barrera, María José; González, Carlos; Mardones, Gonzalo A; Inestrosa, Nibaldo C; Burgos, Patricia V

2015-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) peptide. We have previously shown that the compound tetrahydrohyperforin (IDN5706) prevents accumulation of Aβ species in an in vivo model of AD, however the mechanism that explains this reduction is not well understood. We show herein that IDN5706 decreases the levels of ER degradation enhancer, mannosidase alpha-like 1 (EDEM1), a key chaperone related to endoplasmic-reticulum-associated degradation (ERAD). Moreover, we observed that low levels of EDEM1 correlated with a strong activation of autophagy, suggesting a crosstalk between these two pathways. We observed that IDN5706 perturbs the glycosylation and proteolytic processing of the amyloid precursor protein (APP), resulting in the accumulation of immature APP (iAPP) in the endoplasmic reticulum. To investigate the contribution of autophagy, we tested the effect of IDN5706 in Atg5-depleted cells. We found that depletion of Atg5 enhanced the accumulation of iAPP in response to IDN5706 by slowing down its degradation. Our findings reveal that IDN5706 promotes degradation of iAPP via the activation of Atg5-dependent autophagy, shedding light on the mechanism that may contribute to the reduction of Aβ production in vivo.

Molecular Origin of Gerstmann-Sträussler-Scheinker Syndrome: Insight from Computer Simulation of an Amyloidogenic Prion Peptide

PubMed Central

Daidone, Isabella; Di Nola, Alfredo; Smith, Jeremy C.

2011-01-01

Prion proteins become pathogenic through misfolding. Here, we characterize the folding of a peptide consisting of residues 109–122 of the Syrian hamster prion protein (the H1 peptide) and of a more amyloidogenic A117V point mutant that leads in humans to an inheritable form of the Gerstmann-Sträussler-Scheinker syndrome. Atomistic molecular dynamics simulations are performed for 2.5 μs. Both peptides lose their α-helical starting conformations and assume a β-hairpin that is structurally similar in both systems. In each simulation several unfolding/refolding events occur, leading to convergence of the thermodynamics of the conformational states to within 1 kJ/mol. The similar stability of the β-hairpin relative to the unfolded state is observed in the two peptides. However, substantial differences are found between the two unfolded states. A local minimum is found within the free energy unfolded basin of the A117V mutant populated by misfolded collapsed conformations of comparable stability to the β-hairpin state, consistent with increased amyloidogenicity. This population, in which V117 stabilizes a hydrophobic core, is absent in the wild-type peptide. These results are supported by simulations of oligomers showing a slightly higher stability of the associated structures and a lower barrier to association for the mutated peptide. Hence, a single point mutation carrying only two additional methyl groups is here shown to be responsible for rather dramatic differences of structuring within the unfolded (misfolded) state. PMID:21689534

Inhibition of TTR Aggregation-Induced Cell Death – A New Role for Serum Amyloid P Component

PubMed Central

Dacklin, Ingrid; Lundgren, Erik

2013-01-01

Background Serum amyloid P component (SAP) is a glycoprotein that is universally found associated with different types of amyloid deposits. It has been suggested that it stabilizes amyloid fibrils and therefore protects them from proteolytic degradation. Methodology/Principal Findings In this paper, we show that SAP binds not only to mature amyloid fibrils but also to early aggregates of amyloidogenic mutants of the plasma protein transthyretin (TTR). It does not inhibit fibril formation of TTR mutants, which spontaneously form amyloid in vitro at physiological pH. We found that SAP prevents cell death induced by mutant TTR, while several other molecules that are also known to decorate amyloid fibrils do not have such effect. Using a Drosophila model for TTR-associated amyloidosis, we found a new role for SAP as a protective factor in inhibition of TTR-induced toxicity. Overexpression of mutated TTR leads to a neurological phenotype with changes in wing posture. SAP-transgenic flies were crossed with mutated TTR-expressing flies and the results clearly confirmed a protective effect of SAP on TTR-induced phenotype, with an almost complete reduction in abnormal wing posture. Furthermore, we found in vivo that binding of SAP to mutated TTR counteracts the otherwise detrimental effects of aggregation of amyloidogenic TTR on retinal structure. Conclusions/Significance Together, these two approaches firmly establish the protective effect of SAP on TTR-induced cell death and degenerative phenotypes, and suggest a novel role for SAP through which the toxicity of early amyloidogenic aggregates is attenuated. PMID:23390551

Hsp70 and Antifibrillogenic Peptides Promote Degradation and Inhibit Intracellular Aggregation of Amyloidogenic Light Chains

PubMed Central

Dul, Jeanne L.; Davis, David P.; Williamson, Edward K.; Stevens, Fred J.; Argon, Yair

2001-01-01

In light chain (LC) amyloidosis an immunoglobulin LC assembles into fibrils that are deposited in various tissues. Little is known about how these fibrils form in vivo. We previously showed that a known amyloidogenic LC, SMA, can give rise to amyloid fibrils in vitro when a segment of one of its β sheets undergoes a conformational change, exposing an Hsp70 binding site. To examine SMA aggregation in vivo, we expressed it and its wild-type counterpart, LEN, in COS cells. While LEN is rapidly oxidized and subsequently secreted, newly synthesized SMA remains in the reduced state. Most SMA molecules are dislocated out of the ER into the cytosol, where they are ubiquitinylated and degraded by proteasomes. A parallel pathway for molecules that are not degraded is condensation into perinuclear aggresomes that are surrounded by vimentin-containing intermediate filaments and are dependent upon intact microtubules. Inhibition of proteasome activity shifts the balance toward aggresome formation. Intracellular aggregation is decreased and targeting to proteasomes improved by overexpression of the cytosolic chaperone Hsp70. Importantly, transduction into the cell of an Hsp70 target peptide, derived from the LC sequence, also reduces aggresome formation and increases SMA degradation. These results demonstrate that an amyloidogenic LC can aggregate intracellularly despite the common presentation of extracellular aggregates, and that a similar molecular surface mediates both in vitro fibril formation and in vivo aggregation. Furthermore, rationally designed peptides can be used to suppress this aggregation and may provide a feasible therapeutic approach. PMID:11266462

Hsp70 and antifibrillogenic peptides promote degradation and inhibit intracellular aggregation of amyloidogenic light chains.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dul, J. L.; Davis, D. P.; Williamson, E. K.

2001-02-19

In light chain (LC) amyloidosis an immunoglobulin LC assembles into fibrils that are deposited in various tissues. Little is known about how these fibrils form in vivo. We previously showed that a known amyloidogenic LC, SMA, can give rise to amyloid fibrils in vitro when a segment of one of its {beta} sheets undergoes a conformational change, exposing an Hsp70 binding site. To examine SMA aggregation in vivo, we expressed it and its wild-type counterpart, LEN, in COS cells. While LEN is rapidly oxidized and subsequently secreted, newly synthesized SMA remains in the reduced state. Most SMA molecules are dislocatedmore » out of the ER into the cytosol, where they are ubiquitinylated and degraded by proteasomes. A parallel pathway for molecules that are not degraded is condensation into perinuclear aggresomes that are surrounded by vimentin-containing intermediate filaments and are dependent upon intact microtubules. Inhibition of proteasome activity shifts the balance toward aggresome formation. Intracellular aggregation is decreased and targeting to proteasomes improved by overexpression of the cytosolic chaperone Hsp70. Importantly, transduction into the cell of an Hsp70 target peptide, derived from the LC sequence, also reduces aggresome formation and increases SMA degradation. These results demonstrate that an amyloidogenic LC can aggregate intracellularly despite the common presentation of extracellular aggregates, and that a similar molecular surface mediates both in vitro fibril formation and in vivo aggregation. Furthermore, rationally designed peptides can be used to suppress this aggregation and may provide a feasible therapeutic approach.« less

Quality of Mobile Phone and Tablet Mobile Apps for Speech Sound Disorders: Protocol for an Evidence-Based Appraisal

PubMed Central

Morris, Meg E; Erickson, Shane; Serry, Tanya A

2016-01-01

Background Although mobile apps are readily available for speech sound disorders (SSD), their validity has not been systematically evaluated. This evidence-based appraisal will critically review and synthesize current evidence on available therapy apps for use by children with SSD. Objective The main aims are to (1) identify the types of apps currently available for Android and iOS mobile phones and tablets, and (2) to critique their design features and content using a structured quality appraisal tool. Methods This protocol paper presents and justifies the methods used for a systematic review of mobile apps that provide intervention for use by children with SSD. The primary outcomes of interest are (1) engagement, (2) functionality, (3) aesthetics, (4) information quality, (5) subjective quality, and (6) perceived impact. Quality will be assessed by 2 certified practicing speech-language pathologists using a structured quality appraisal tool. Two app stores will be searched from the 2 largest operating platforms, Android and iOS. Systematic methods of knowledge synthesis shall include searching the app stores using a defined procedure, data extraction, and quality analysis. Results This search strategy shall enable us to determine how many SSD apps are available for Android and for iOS compatible mobile phones and tablets. It shall also identify the regions of the world responsible for the apps’ development, the content and the quality of offerings. Recommendations will be made for speech-language pathologists seeking to use mobile apps in their clinical practice. Conclusions This protocol provides a structured process for locating apps and appraising the quality, as the basis for evaluating their use in speech pathology for children in English-speaking nations. PMID:27899341

Machine learning methods can replace 3D profile method in classification of amyloidogenic hexapeptides.

PubMed

Stanislawski, Jerzy; Kotulska, Malgorzata; Unold, Olgierd

2013-01-17

Amyloids are proteins capable of forming fibrils. Many of them underlie serious diseases, like Alzheimer disease. The number of amyloid-associated diseases is constantly increasing. Recent studies indicate that amyloidogenic properties can be associated with short segments of aminoacids, which transform the structure when exposed. A few hundreds of such peptides have been experimentally found. Experimental testing of all possible aminoacid combinations is currently not feasible. Instead, they can be predicted by computational methods. 3D profile is a physicochemical-based method that has generated the most numerous dataset - ZipperDB. However, it is computationally very demanding. Here, we show that dataset generation can be accelerated. Two methods to increase the classification efficiency of amyloidogenic candidates are presented and tested: simplified 3D profile generation and machine learning methods. We generated a new dataset of hexapeptides, using more economical 3D profile algorithm, which showed very good classification overlap with ZipperDB (93.5%). The new part of our dataset contains 1779 segments, with 204 classified as amyloidogenic. The dataset of 6-residue sequences with their binary classification, based on the energy of the segment, was applied for training machine learning methods. A separate set of sequences from ZipperDB was used as a test set. The most effective methods were Alternating Decision Tree and Multilayer Perceptron. Both methods obtained area under ROC curve of 0.96, accuracy 91%, true positive rate ca. 78%, and true negative rate 95%. A few other machine learning methods also achieved a good performance. The computational time was reduced from 18-20 CPU-hours (full 3D profile) to 0.5 CPU-hours (simplified 3D profile) to seconds (machine learning). We showed that the simplified profile generation method does not introduce an error with regard to the original method, while increasing the computational efficiency. Our new dataset proved representative enough to use simple statistical methods for testing the amylogenicity based only on six letter sequences. Statistical machine learning methods such as Alternating Decision Tree and Multilayer Perceptron can replace the energy based classifier, with advantage of very significantly reduced computational time and simplicity to perform the analysis. Additionally, a decision tree provides a set of very easily interpretable rules.

Tuning the conformational properties of the prion peptide.

PubMed

Ho, Chai-Chi; Lee, Lily Y-L; Huang, Kuo-Ting; Lin, Chun-Cheng; Ku, Mei-Yun; Yang, Chien-Chih; Chan, Sunney I; Hsu, Ruei-Lin; Chen, Rita P-Y

2009-07-01

Previously, we disclosed that O-linked glycosylation of Ser-132 or Ser-135 could dramatically change the amyloidogenic property of the hamster prion peptide (sequence 108-144). This peptide, which corresponds to the flexible loop and the first beta-strand in the structure of the prion protein, is a random coil when it is initially dissolved in buffer, but amyloid fibrils are formed with time. Thus, it offers a convenient model system to observe and compare how different chemical modifications and sequence mutations alter the amyloidogenic property of the peptide within a reasonable experimental time frame. In our earlier study, aside from uncovering a site-specificity of the glycosylation on the fibrillogenesis, different effects of alpha-GalNAc and beta-GlcNAc were observed. In this work, we explore further how different sugar configurations affect the conformational property of the polypeptide chain. We compare the effects of O-linked glycosylation by the common sugars alpha-GalNAc, beta-GlcNAc with their non-native analogs beta-GalNAc, alpha-GlcNAc in an effort to uncover the origin of the sugar-specificity on the fibril formation. We find that the anomeric configuration of the sugar is the most important factor affecting the fibrillogenesis. Sugars with the glycosidic bond in the alpha-configuration at Ser-135 have a dramatic inhibitory effect on the structural conversion of the glycosylated peptide. Because O-glycosylation of Ser-135 with alpha-linked sugars also promote the formation of three slowly converting conformations at the site of glycosylation, we surmise that the amyloidogenic property of the peptide is related to its conformational flexibility, and the proclivity of this region of the peptide to undergo the structural conversion from the random coil to form the beta-structure. Upon O-glycosylation with an alpha-linked sugar, this conversion is inhibited and the nucleation of fibril formation is largely retarded. Consistent with this scenario, Arg-136 is the residue most affected in the TOCSY NMR spectra of the glycosylated peptides, other than the serine site modified. In addition, when Arg-136 is substituted by Gly, a mutation that should provide higher structural flexibility in this part of the peptide, the amyloidogenic property of the peptide is greatly enhanced, and the inhibition effect of glycosylation is largely diminished. These results are consistent with Ser-135 and Arg-136 being part of the kink region involved in the structural conversion.

Mobile Applications for Diabetics: A Systematic Review and Expert-Based Usability Evaluation Considering the Special Requirements of Diabetes Patients Age 50 Years or Older

PubMed Central

Quade, Mandy; Kirch, Wilhelm

2014-01-01

Background A multitude of mhealth (mobile health) apps have been developed in recent years to support effective self-management of patients with diabetes mellitus type 1 or 2. Objective We carried out a systematic review of all currently available diabetes apps for the operating systems iOS and Android. We considered the number of newly released diabetes apps, range of functions, target user groups, languages, acquisition costs, user ratings, available interfaces, and the connection between acquisition costs and user ratings. Additionally, we examined whether the available applications serve the special needs of diabetes patients aged 50 or older by performing an expert-based usability evaluation. Methods We identified relevant keywords, comparative categories, and their specifications. Subsequently, we performed the app review based on the information given in the Google Play Store, the Apple App Store, and the apps themselves. In addition, we carried out an expert-based usability evaluation based on a representative 10% sample of diabetes apps. Results In total, we analyzed 656 apps finding that 355 (54.1%) offered just one function and 348 (53.0%) provided a documentation function. The dominating app language was English (85.4%, 560/656), patients represented the main user group (96.0%, 630/656), and the analysis of the costs revealed a trend toward free apps (53.7%, 352/656). The median price of paid apps was €1.90. The average user rating was 3.6 stars (maximum 5). Our analyses indicated no clear differences in the user rating between free and paid apps. Only 30 (4.6%) of the 656 available diabetes apps offered an interface to a measurement device. We evaluated 66 apps within the usability evaluation. On average, apps were rated best regarding the criterion “comprehensibility” (4.0 out of 5.0), while showing a lack of “fault tolerance” (2.8 out of 5.0). Of the 66 apps, 48 (72.7%) offered the ability to read the screen content aloud. The number of functions was significantly negative correlated with usability. The presence of documentation and analysis functions reduced the usability score significantly by 0.36 and 0.21 points. Conclusions A vast number of diabetes apps already exist, but the majority offer similar functionalities and combine only one to two functions in one app. Patients and physicians alike should be involved in the app development process to a greater extent. We expect that the data transmission of health parameters to physicians will gain more importance in future applications. The usability of diabetes apps for patients aged 50 or older was moderate to good. But this result applied mainly to apps offering a small range of functions. Multifunctional apps performed considerably worse in terms of usability. Moreover, the presence of a documentation or analysis function resulted in significantly lower usability scores. The operability of accessibility features for diabetes apps was quite limited, except for the feature “screen reader”. PMID:24718852

Development and Application of a Stepwise Assessment Process for Rational Redesign of Sequential Skills-Based Courses.

PubMed

Gallimore, Casey E; Porter, Andrea L; Barnett, Susanne G

2016-10-25

Objective. To develop and apply a stepwise process to assess achievement of course learning objectives related to advanced pharmacy practice experiences (APPEs) preparedness and inform redesign of sequential skills-based courses. Design. Four steps comprised the assessment and redesign process: (1) identify skills critical for APPE preparedness; (2) utilize focus groups and course evaluations to determine student competence in skill performance; (3) apply course mapping to identify course deficits contributing to suboptimal skill performance; and (4) initiate course redesign to target exposed deficits. Assessment. Focus group participants perceived students were least prepared for skills within the Accreditation Council for Pharmacy Education's pre-APPE core domains of Identification and Assessment of Drug-related Problems and General Communication Abilities. Course mapping identified gaps in instruction, performance, and assessment of skills within aforementioned domains. Conclusions. A stepwise process that identified strengths and weaknesses of a course, was used to facilitate structured course redesign. Strengths of the process included input and corroboration from both preceptors and students. Limitations included feedback from a small number of pharmacy preceptors and increased workload on course coordinators.

Herpes Simplex Virus Dances with Amyloid Precursor Protein while Exiting the Cell

PubMed Central

Cheng, Shi-Bin; Ferland, Paulette; Webster, Paul; Bearer, Elaine L.

2011-01-01

Herpes simplex type 1 (HSV1) replicates in epithelial cells and secondarily enters local sensory neuronal processes, traveling retrograde to the neuronal nucleus to enter latency. Upon reawakening newly synthesized viral particles travel anterograde back to the epithelial cells of the lip, causing the recurrent cold sore. HSV1 co-purifies with amyloid precursor protein (APP), a cellular transmembrane glycoprotein and receptor for anterograde transport machinery that when proteolyzed produces A-beta, the major component of senile plaques. Here we focus on transport inside epithelial cells of newly synthesized virus during its transit to the cell surface. We hypothesize that HSV1 recruits cellular APP during transport. We explore this with quantitative immuno-fluorescence, immuno-gold electron-microscopy and live cell confocal imaging. After synchronous infection most nascent VP26-GFP-labeled viral particles in the cytoplasm co-localize with APP (72.8+/−6.7%) and travel together with APP inside living cells (81.1+/−28.9%). This interaction has functional consequences: HSV1 infection decreases the average velocity of APP particles (from 1.1+/−0.2 to 0.3+/−0.1 µm/s) and results in APP mal-distribution in infected cells, while interplay with APP-particles increases the frequency (from 10% to 81% motile) and velocity (from 0.3+/−0.1 to 0.4+/−0.1 µm/s) of VP26-GFP transport. In cells infected with HSV1 lacking the viral Fc receptor, gE, an envelope glycoprotein also involved in viral axonal transport, APP-capsid interactions are preserved while the distribution and dynamics of dual-label particles differ from wild-type by both immuno-fluorescence and live imaging. Knock-down of APP with siRNA eliminates APP staining, confirming specificity. Our results indicate that most intracellular HSV1 particles undergo frequent dynamic interplay with APP in a manner that facilitates viral transport and interferes with normal APP transport and distribution. Such dynamic interactions between APP and HSV1 suggest a mechanistic basis for the observed clinical relationship between HSV1 seropositivity and risk of Alzheimer's disease. PMID:21483850

A Self-Regulation Theory-Based Asthma Management Mobile App for Adolescents: A Usability Assessment.

PubMed

Sage, Adam; Roberts, Courtney; Geryk, Lorie; Sleath, Betsy; Tate, Deborah; Carpenter, Delesha

2017-02-01

Self-regulation theory suggests people learn to influence their own behavior through self-monitoring, goal-setting, feedback, self-reward, and self-instruction, all of which smartphones are now capable of facilitating. Several mobile apps exist to manage asthma; however, little evidence exists about whether these apps employ user-centered design processes that adhere to government usability guidelines for mobile apps. Building upon a previous study that documented adolescent preferences for an asthma self-management app, we employed a user-centered approach to assess the usability of a high-fidelity wireframe for an asthma self-management app intended for use by adolescents with persistent asthma. Individual interviews were conducted with adolescents (ages 11-18 years) with persistent asthma who owned a smartphone (N=8). Adolescents were asked to evaluate a PDF app wireframe consisting of 76 screen shots displaying app features, including log in and home screen, profile setup, settings and info, self-management features, and graphical displays for charting asthma control and medication. Preferences, comments, and suggestions for each set of screen shots were assessed using the audio-recorded interviews. Two coders reached consensus on adolescent evaluations of the following aspects of app features: (1) usability, (2) behavioral intentions to use, (3) confusing aspects, and (4) suggestions for improvement. The app wireframe was generally well received, and several suggestions for improvement were recorded. Suggestions included increased customization of charts and notifications, reminders, and alerts. Participants preferred longitudinal data about asthma control and medication use to be displayed using line graphs. All participants reported that they would find an asthma management app like the one depicted in the wireframe useful for managing their asthma. Early stage usability tests guided by government usability guidelines (usability.gov) revealed areas for improvement for an asthma self-management app for adolescents. Addressing these areas will be critical to developing an engaging and effective asthma self-management app that is capable of improving adolescent asthma outcomes. ©Adam Sage, Courtney Roberts, Lorie Geryk, Betsy Sleath, Deborah Tate, Delesha Carpenter. Originally published in JMIR Human Factors (http://humanfactors.jmir.org), 01.02.2017.

Ear2 deletion causes early memory and learning deficits in APP/PS1 mice.

PubMed

Kummer, Markus P; Hammerschmidt, Thea; Martinez, Ana; Terwel, Dick; Eichele, Gregor; Witten, Anika; Figura, Stefanie; Stoll, Monika; Schwartz, Stephanie; Pape, Hans-Christian; Schultze, Joachim L; Weinshenker, David; Heneka, Michael T; Urban, Inga

2014-06-25

To assess the consequences of locus ceruleus (LC) degeneration and subsequent noradrenaline (NA) deficiency in early Alzheimer's disease (AD), mice overexpressing mutant amyloid precursor protein and presenilin-1 (APP/PS1) were crossed with Ear2(-/-) mice that have a severe loss of LC neurons projecting to the hippocampus and neocortex. Testing spatial memory and hippocampal long-term potentiation revealed an impairment in APP/PS1 Ear2(-/-) mice, whereas APP/PS1 or Ear2(-/-) mice showed only minor changes. These deficits were associated with distinct synaptic changes including reduced expression of the NMDA 2A subunit and increased levels of NMDA receptor 2B in APP/PS1 Ear2(-/-) mice. Acute pharmacological replacement of NA by L-threo-DOPS partially restored phosphorylation of β-CaMKII and spatial memory performance in APP/PS1 Ear2(-/-) mice. These changes were not accompanied by altered APP processing or amyloid β peptide (Aβ) deposition. Thus, early LC degeneration and subsequent NA reduction may contribute to cognitive deficits via CaMKII and NMDA receptor dysfunction independent of Aβ and suggests that NA supplementation could be beneficial in treating AD. Copyright © 2014 the authors 0270-6474/14/348845-10$15.00/0.

[Possibilities of mobile applications for managing obesity according to professionals].

PubMed

Aguilar-Martínez, Alicia; Tort, Elena; Medina, F Xavier; Saigí-Rubió, Francesc

2015-01-01

Given the increasing use and importance of mobile telephone applications (apps) in the health setting, this study aimed to ascertain the views of health professionals involved in the treatment of obesity about their current needs and gaps in their requirements, their willingness to use mobile apps, and the features these devices should have for the treatment of obesity. A qualitative study was conducted through semi-structured interviews with experts treating obesity. The experts believed that apps could be useful to interact or deal with patients. However, their willingness to use apps contrasts with the current limited use of these devices. Practitioners felt that apps could partly compensate for the lack of daily contact between patients and professionals and could increase interaction with patients, achieving more favourable weight control results, especially with regard to improved adherence and motivation. In terms of the functionality and requirements of such apps, the main elements to be included were records of weight, physical activity and food consumption. Adding apps to the existing treatment of overweight and obesity still requires further definition of its functions. Additionally, further investigation is needed into both the role and involvement of professionals in the design process and during treatment. Copyright © 2015 SESPAS. Published by Elsevier Espana. All rights reserved.

A phonology-free mobile communication app.

PubMed

Kondapalli, Ananya; Zhang, Lee R; Patel, Shreya; Han, Xiao; Kim, Hee Jin; Li, Xintong; Altschuler, Eric L

2016-11-01

Aphasia - loss of comprehension or expression of language - is a devastating functional sequela of stroke. There are as yet no effective methods for rehabilitation of aphasia. An assistive device that allows aphasia patients to communicate and interact at speeds approaching real time is urgently needed. Behavioral and linguistic studies of aphasia patients show that they retain normal thinking processes and most aspects of language. They lack only phonology: the ability to translate (input) and/or output sounds (or written words) such as "ta-ble" into the image of a four-legged object with a top at which one works or eats. We have made a phonology-free communication mobile app that may be useful for patients with aphasia and other communication disorders. Particular innovations of our app include calling Google Images as a "subroutine" to allow a near-infinite number of choices (e.g. food or clothing items) for patients without having to make countless images, and by the use of animation for words, phrases or concepts that cannot be represented by a single image. We have tested our app successfully in one patient. The app may be of great benefit to patients with aphasia and other communication disorders. Implications for Rehabilitation We have made a phonology-free mobile communication app. This app may facilitate communication for patients with aphasia and other communication disorders.

Role of Liver X Receptor in AD Pathophysiology

PubMed Central

Sandoval-Hernández, Adrián G.; Buitrago, Luna; Moreno, Herman; Cardona-Gómez, Gloria Patricia; Arboleda, Gonzalo

2015-01-01

Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment). The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD. PMID:26720273

More Stamina, a Gamified mHealth Solution for Persons with Multiple Sclerosis: Research Through Design.

PubMed

Giunti, Guido; Mylonopoulou, Vasiliki; Rivera Romero, Octavio

2018-03-02

Multiple sclerosis (MS) is one of the world's most common neurologic disorders. Fatigue is one of most common symptoms that persons with MS experience, having significant impact on their quality of life and limiting their activity levels. Self-management strategies are used to support them in the care of their health. Mobile health (mHealth) solutions are a way to offer persons with chronic conditions tools to successfully manage their symptoms and problems. Gamification is a current trend among mHealth apps used to create engaging user experiences and is suggested to be effective for behavioral change. To be effective, mHealth solutions need to be designed to specifically meet the intended audience needs. User-centered design (UCD) is a design philosophy that proposes placing end users' needs and characteristics in the center of design and development, involving users early in the different phases of the software life cycle. There is a current gap in mHealth apps for persons with MS, which presents an interesting area to explore. The purpose of this study was to describe the design and evaluation process of a gamified mHealth solution for behavioral change in persons with MS using UCD. Building on previous work of our team where we identified needs, barriers, and facilitators for mHealth apps for persons with MS, we followed UCD to design and evaluate a mobile app prototype aimed to help persons with MS self-manage their fatigue. Design decisions were evidence-driven and guided by behavioral change models (BCM). Usability was assessed through inspection methods using Nielsen's heuristic evaluation. The mHealth solution More Stamina was designed. It is a task organization tool designed to help persons with MS manage their energy to minimize the impact of fatigue in their day-to-day life. The tool acts as a to-do list where users can input tasks in a simple manner and assign Stamina Credits, a representation of perceived effort, to the task to help energy management and energy profiling. The app also features personalization and positive feedback. The design process gave way to relevant lessons to the design of a gamified behavioral change mHealth app such as the importance of metaphors in concept design, negotiate requirements with the BCM constructs, and tailoring of gamified experiences among others. Several usability problems were discovered during heuristic evaluation and guided the iterative design of our solution. In this paper, we designed an app targeted for helping persons with MS in their fatigue management needs. We illustrate how UCD can help in designing mHealth apps and the benefits and challenges that designers might face when using this approach. This paper provides insight into the design process of gamified behavioral change mHealth apps and the negotiation process implied in it. ©Guido Giunti, Vasiliki Mylonopoulou, Octavio Rivera Romero. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 02.03.2018.

More Stamina, a Gamified mHealth Solution for Persons with Multiple Sclerosis: Research Through Design

PubMed Central

Mylonopoulou, Vasiliki; Rivera Romero, Octavio

2018-01-01

Background Multiple sclerosis (MS) is one of the world’s most common neurologic disorders. Fatigue is one of most common symptoms that persons with MS experience, having significant impact on their quality of life and limiting their activity levels. Self-management strategies are used to support them in the care of their health. Mobile health (mHealth) solutions are a way to offer persons with chronic conditions tools to successfully manage their symptoms and problems. Gamification is a current trend among mHealth apps used to create engaging user experiences and is suggested to be effective for behavioral change. To be effective, mHealth solutions need to be designed to specifically meet the intended audience needs. User-centered design (UCD) is a design philosophy that proposes placing end users’ needs and characteristics in the center of design and development, involving users early in the different phases of the software life cycle. There is a current gap in mHealth apps for persons with MS, which presents an interesting area to explore. Objective The purpose of this study was to describe the design and evaluation process of a gamified mHealth solution for behavioral change in persons with MS using UCD. Methods Building on previous work of our team where we identified needs, barriers, and facilitators for mHealth apps for persons with MS, we followed UCD to design and evaluate a mobile app prototype aimed to help persons with MS self-manage their fatigue. Design decisions were evidence-driven and guided by behavioral change models (BCM). Usability was assessed through inspection methods using Nielsen’s heuristic evaluation. Results The mHealth solution More Stamina was designed. It is a task organization tool designed to help persons with MS manage their energy to minimize the impact of fatigue in their day-to-day life. The tool acts as a to-do list where users can input tasks in a simple manner and assign Stamina Credits, a representation of perceived effort, to the task to help energy management and energy profiling. The app also features personalization and positive feedback. The design process gave way to relevant lessons to the design of a gamified behavioral change mHealth app such as the importance of metaphors in concept design, negotiate requirements with the BCM constructs, and tailoring of gamified experiences among others. Several usability problems were discovered during heuristic evaluation and guided the iterative design of our solution. Conclusions In this paper, we designed an app targeted for helping persons with MS in their fatigue management needs. We illustrate how UCD can help in designing mHealth apps and the benefits and challenges that designers might face when using this approach. This paper provides insight into the design process of gamified behavioral change mHealth apps and the negotiation process implied in it. PMID:29500159

An App for the Cathedral in Freiberg--An Interdisciplinary Project Seminar

ERIC Educational Resources Information Center

Kröber, Cindy; Münster, Sander

2014-01-01

This project seminar aims at creating and evaluating a manual for interdisciplinary projects as part of a learning process. Working together, pedagogies and students from different disciplines assess tools and recommendations for successful collaborations while developing an app for the cathedral in Freiberg. As part of the project the students…

Mobile Apps for Weight Management: A Scoping Review.

PubMed

Rivera, Jordan; McPherson, Amy; Hamilton, Jill; Birken, Catherine; Coons, Michael; Iyer, Sindoora; Agarwal, Arnav; Lalloo, Chitra; Stinson, Jennifer

2016-07-26

Obesity remains a major public health concern. Mobile apps for weight loss/management are found to be effective for improving health outcomes in adults and adolescents, and are pursued as a cost-effective and scalable intervention for combating overweight and obesity. In recent years, the commercial market for 'weight loss apps' has expanded at rapid pace, yet little is known regarding the evidence-based quality of these tools for weight control. To characterize the inclusion of evidence-based strategies, health care expert involvement, and scientific evaluation of commercial mobile apps for weight loss/management. An electronic search was conducted between July 2014 and July 2015 of the official app stores for four major mobile operating systems. Three raters independently identified apps with a stated goal of weight loss/management, as well as weight loss/management apps targeted to pediatric users. All discrepancies regarding selection were resolved through discussion with a fourth rater. Metadata from all included apps were abstracted into a standard assessment criteria form and the evidence-based strategies, health care expert involvement, and scientific evaluation of included apps was assessed. Evidence-based strategies included: self-monitoring, goal-setting, physical activity support, healthy eating support, weight and/or health assessment, personalized feedback, motivational strategies, and social support. A total of 393 apps were included in this review. Self-monitoring was most common (139/393, 35.3%), followed by physical activity support (108/393, 27.5%), weight assessment (100/393, 25.4%), healthy eating support (91/393, 23.2%), goal-setting (84/393, 21.4%), motivational strategies (28/393, 7.1%), social support (21/393, 5.3%), and personalized feedback (7/393, 1.8%). Of apps, 0.8% (3/393) underwent scientific evaluation and 0.3% (1/393) reported health care expert involvement. No apps were comprehensive in the assessment criteria, with the majority of apps meeting less than two criteria. Commercial mobile apps for weight loss/management lack important evidence-based features, do not involve health care experts in their development process, and have not undergone rigorous scientific testing. This calls into question the validity of apps' claims regarding their effectiveness and safety, at a time when the availability and growth in adoption of these tools is rapidly increasing. Collaborative efforts between developers, researchers, clinicians, and patients are needed to develop and test high-quality, evidence-based mobile apps for weight loss/management before they are widely disseminated in commercial markets.

APP with Kunitz type protease inhibitor domain (KPI) correlates with neuritic plaque density but not with cortical synaptophysin immunoreactivity in Alzheimer's disease and non-demented aged subjects: a multifactorial analysis.

PubMed

Zhan, S S; Sandbrink, R; Beyreuther, K; Schmitt, H P

1995-01-01

The formation of beta A4 amyloid protein in neuritic plaques in Alzheimer's disease (AD) and advanced age is a complex process that involves a number of both cellular and molecular mechanisms, the interrelations of which are not yet completely understood. We have examined quantitatively, in AD and aged controls an extended spectrum of amyloid plaque-related cellular and molecular factors and the cortical synaptophysin immunoreactivity (synaptic density) in order to check for interrelations between them by multifactorial analysis. In 3 cases of senile dementia of the Alzheimer type (SDAT) aged 72, 80 and 82 years, and 9 controls aged 43-88 (mean age 65) years, the cortical synaptophysin immunoreactivity was assessed, together with the numbers of neurons, astrocytes and microglial cells, senile plaques, of tangle-bearing neurons, and the amount of beta A4 amyloid precursor protein (APP) with and without the Kunitz type serine protease inhibitor (KPI) domain. The main results were: APP including the KPI domain (KPI-APP) correlated with the number of neuritic plaques, regardless of whether they occurred in SDAT or non-demented controls. There was no significant difference in the amount of KPI-APP between SDAT and controls. Conversely, APP695 (without KPI) was significantly reduced in SDAT. KPI-APP did not correlate with the synaptophysin immunoreactivity (RGVA), while APP695 showed a significant correlation with the latter in all evaluations. It also correlated with the neuron counts, which was not true for KPI-APP. These results support previous findings indicating that KPI-APP is an important local factor for amyloid deposition in the neuritic plaques, both in AD and in non-demented aged people. On the contrary, KPI-APP does not seem to be significantly involved in the mechanisms of synaptic change outside of the plaques.

Development and testing of a mobile application to support diabetes self-management for people with newly diagnosed type 2 diabetes: a design thinking case study.

PubMed

Petersen, Mira; Hempler, Nana F

2017-06-26

Numerous mobile applications have been developed to support diabetes-self-management. However, the majority of these applications lack a theoretical foundation and the involvement of people with diabetes during development. The aim of this study was to develop and test a mobile application (app) supporting diabetes self-management among people with newly diagnosed type 2 diabetes using design thinking. The app was developed and tested in 2015 using a design-based research approach involving target users (individuals newly diagnosed with type 2 diabetes), research scientists, healthcare professionals, designers, and app developers. The research approach comprised three major phases: inspiration, ideation, and implementation. The first phase included observations of diabetes education and 12 in-depth interviews with users regarding challenges and needs related to living with diabetes. The ideation phrase consisted of four interactive workshops with users focusing on app needs, in which ideas were developed and prioritized. Finally, 14 users tested the app over 4 weeks; they were interviewed about usability and perceptions about the app as a support tool. A multifunctional app was useful for people with newly diagnosed type 2 diabetes. The final app comprised five major functions: overview of diabetes activities after diagnosis, recording of health data, reflection games and goal setting, knowledge games and recording of psychological data such as sleep, fatigue, and well-being. Users found the app to be a valuable tool for support, particularly for raising their awareness about their psychological health and for informing and guiding them through the healthcare system after diagnosis. The design thinking processes used in the development and implementation of the mobile health app were crucial to creating value for users. More attention should be paid to the training of professionals who introduce health apps. Danish Data Protection Agency: 2012-58-0004. Registered 6 February 2016.

Functionalization of nanomaterials by non-thermal large area atmospheric pressure plasmas: application to flexible dye-sensitized solar cells.

PubMed

Jung, Heesoo; Park, Jaeyoung; Yoo, Eun Sang; Han, Gill-Sang; Jung, Hyun Suk; Ko, Min Jae; Park, Sanghoo; Choe, Wonho

2013-09-07

A key challenge to the industrial application of nanotechnology is the development of fabrication processes for functional devices based on nanomaterials which can be scaled up for mass production. In this report, we disclose the results of non-thermal radio-frequency (rf) atmospheric pressure plasma (APP) based deposition of TiO2 nanoparticles on a flexible substrate for the fabrication of dye-sensitized solar cells (DSSCs). Operating at 190 °C without a vacuum enclosure, the APP method can avoid thermal damage and vacuum compatibility restrictions and utilize roll-to-roll processing over a large area. The various analyses of the TiO2 films demonstrate that superior film properties can be obtained by the non-thermal APP method when compared with the thermal sintering process operating at 450 °C. The crystallinity of the anatase TiO2 nanoparticles is significantly improved without thermal agglomeration, while the surface defects such as Ti(3+) ions are eliminated, thus providing efficient charge collecting properties for solar cells. Finally, we successfully fabricated a flexible DSSC with an energy conversion efficiency of 4.2% using a transparent plastic substrate. This work demonstrates the potential of non-thermal APP technology in the area of device-level, nano-enabled material manufacturing.

Aβ-Induced Inflammatory Processes in Microglia Cells of APP23 Transgenic Mice

PubMed Central

Bornemann, Klaus D.; Wiederhold, Karl-Heinz; Pauli, Chantal; Ermini, Florian; Stalder, Martina; Schnell, Lisa; Sommer, Bernd; Jucker, Mathias; Staufenbiel, Matthias

2001-01-01

A microglial response is part of the inflammatory processes in Alzheimer’s disease (AD). We have used APP23 transgenic mice overexpressing human amyloid precursor protein with the Swedish mutation to characterize this microglia response to amyloid deposits in aged mice. Analyses with MAC-1 and F4/80 antibodies as well as in vivo labeling with bromodeoxyuridine demonstrate that microglia in the plaque vicinity are in an activated state and that proliferation contributes to their accumulation at the plaque periphery. The amyloid-induced microglia activation may be mediated by scavenger receptor A, which is generally elevated, whereas the increased immunostaining of the receptor for advanced glycation end products is more restricted. Although components of the phagocytic machinery such as macrosialin and Fc receptors are increased in activated microglia, efficient clearance of amyloid is missing seemingly because of the lack of amyloid-bound autoantibodies. Similarly, although up-regulation of major histocompatibility complex class II (IA) points toward an intact antigen-presenting function of microglia, lack of T and B lymphocytes does not indicate a cell-mediated immune response in the brains of APP23 mice. The similar characteristics of microglia in the APP23 mice and in AD render the mouse model suitable to study the role of inflammatory processes during AD pathogenesis. PMID:11141480

Long-Term Mangiferin Extract Treatment Improves Central Pathology and Cognitive Deficits in APP/PS1 Mice.

PubMed

Infante-Garcia, Carmen; Ramos-Rodriguez, Juan Jose; Delgado-Olmos, Irene; Gamero-Carrasco, Carlos; Fernandez-Ponce, Maria Teresa; Casas, Lourdes; Mantell, Casimiro; Garcia-Alloza, Monica

2017-08-01

Alzheimer's disease (AD) is the most common cause of dementia; however, available treatments have had limited success. Therefore AD patients are in tremendous need of new pharmacological approaches that may delay or slow the progression of the disease. In addition to the classical neuropathological features, immunological and inflammatory processes are also involved in AD pathogenesis. Naturally occurring compounds, such as Mangifera indica Linn (MGF) extracts have previously been shown to significantly reduce peripheral inflammatory processes. In order to explore the role of MGF in AD central pathology, we have orally treated APP/PS1 mice for 22 weeks. While MGF did not affect amyloid pathology, tau hyperphosphorylation was significantly reduced in the cortex and hippocampus. Also, inflammatory processes, measured by microglia and astrocyte burdens, were diminished in MGF-treated mice. Moreover, neuronal morphological alterations, such as abnormal neurite curvature and dystrophies, highly increased in APP/PS1 mice, were significantly ameliorated by long-term MGF treatment. Reduction of all these pathological features were accompanied by compelling improvements of episodic and spatial memory in APP/PS1 mice treated with MGF. Altogether our data suggest that MGF may provide a useful tool to target different aspects of AD pathology and could lead to more effective future therapeutic or preventive strategies.

Ubiquilin-1 and protein quality control in Alzheimer disease.

PubMed

El Ayadi, Amina; Stieren, Emily S; Barral, José M; Boehning, Darren

2013-01-01

Single nucleotide polymorphisms in the ubiquilin-1 gene may confer risk for late-onset Alzheimer disease (AD). We have shown previously that ubiquilin-1 functions as a molecular chaperone for the amyloid precursor protein (APP) and that protein levels of ubiquilin-1 are decreased in the brains of AD patients. We have recently found that ubiquilin-1 regulates APP trafficking and subsequent secretase processing by stimulating non-degradative ubiquitination of a single lysine residue in the cytosolic domain of APP. Thus, ubiquilin-1 plays a central role in regulating APP biosynthesis, trafficking and ultimately toxicity. As ubiquilin-1 and other ubiquilin family members have now been implicated in the pathogenesis of numerous neurodegenerative diseases, these findings provide mechanistic insights into the central role of ubiquilin proteins in maintaining neuronal proteostasis.

The pattern of trabecular bone microarchitecture in the distal femur of typically developing children and its effect on processing of magnetic resonance images.

PubMed

Modlesky, Christopher M; Whitney, Daniel G; Carter, Patrick T; Allerton, Brianne M; Kirby, Joshua T; Miller, Freeman

2014-03-01

Magnetic resonance imaging (MRI) is used to assess trabecular bone microarchitecture in humans; however, image processing can be labor intensive and time consuming. One aim of this study was to determine the pattern of trabecular bone microarchitecture in the distal femur of typically developing children. A second aim was to determine the proportion and location of magnetic resonance images that need to be processed to yield representative estimates of trabecular bone microarchitecture. Twenty-six high resolution magnetic resonance images were collected immediately above the growth plate in the distal femur of 6-12year-old typically developing children (n=40). Measures of trabecular bone microarchitecture [i.e., apparent trabecular bone volume to total volume (appBV/TV), trabecular number (appTb.N), trabecular thickness (appTb.Th) and trabecular separation (appTb.Sp)] in the lateral aspect of the distal femur were determined using the twenty most central images (20IM). The average values for appBV/TV, appTb.N, appTb.Th and appTb.Sp from 20IM were compared to the average values from 10 images (10IM), 5 images (5IM) and 3 images (3IM) equally dispersed throughout the total image set and one image (1IM) from the center of the total image set using linear regression analysis. The resulting mathematical models were cross-validated using the leave-one-out technique. Distance from the growth plate was strongly and inversely related to appBV/TV (r(2)=0.68, p<0.001) and appTb.N (r(2)=0.92, p<0.001) and was strongly and positively related to appTb.Sp (r(2)=0.86, p<0.001). The relationship between distance from the growth plate and appTb.Th was not linear (r(2)=0.06, p=0.28), but instead it was quadratic and statistically significant (r(2)=0.54, p<0.001). Trabecular bone microarchitecture estimates from 10IM, 5IM, 3IM and 1IM were not different from estimates from 20IM (p>0.05). However, there was a progressive decrease in the strength of the relationships as a smaller proportion of images were used to predict estimates from 20IM (r(2)=0.98 to 0.99 using 10IM, 0.94 to 0.96 using 5IM, 0.87 to 0.90 using 3IM and 0.66 to 0.72 using 1IM; all p<0.001). Using the resulting mathematical models and the leave-one-out cross-validation analysis, measures of trabecular bone microarchitecture estimated from the 10IM and 5IM partial image sets agreed extremely well with estimates from 20IM. The findings indicate that partial magnetic resonance image sets can be used to provide reasonable estimates of trabecular bone microarchitecture status in the distal femur of typically developing children. However, because the relative amount of trabecular bone in the distal femur decreases with distance from the growth plate due to a decrease in trabecular number, careful positioning of the region of interest and sampling from throughout the region of interest is necessary. Copyright © 2013 Elsevier Inc. All rights reserved.

Smartphone Applications for Educating and Helping Non-motivating Patients Adhere to Medication That Treats Mental Health Conditions: Aims and Functioning.

PubMed

Kassianos, Angelos P; Georgiou, Giorgos; Papaconstantinou, Electra P; Detzortzi, Angeliki; Horne, Rob

2017-01-01

Background: Patients prescribed with medication that treats mental health conditions benefit the most compared to those prescribed with other types of medication. However, they are also the most difficult to adhere. The development of mobile health (mHealth) applications ("apps") to help patients monitor their adherence is fast growing but with limited evidence on their efficacy. There is no evidence on the content of these apps for patients taking psychotropic medication. The aim of this study is to identify and evaluate the aims and functioning of available apps that are aiming to help and educate patients to adhere to medication that treats mental health conditions. Method: Three platform descriptions (Apple, Google, and Microsoft) were searched between October 2015 and February 2016. Included apps need to focus on adherence to medication that treats mental health conditions and use at least a reinforcement strategy. Descriptive information was extracted and apps evaluated on a number of assessment criteria using content analysis. Results: Sixteen apps were identified. All apps included self-monitoring properties like reminders and psycho-educational properties like mood logs. It was unclear how the latter were used or how adherence was measured. Major barriers to medication adherence like patients' illness and medication beliefs and attitudes were not considered nor where information to patients about mediation side effects. Very few apps were tailored and none was developed based on established theories explaining the processes for successful medication adherence like cognitions and beliefs. Reported information on app development and validation was poor. Discussion: A variety of apps with different properties that tackle both intentional and unintentional non-adherence from a different perspective are identified. An evidence-based approach and co-creation with patients is needed. This will ensure that the apps increase the possibility to impact on non-adherence. Theories like social cognition models can be useful in ensuring that patients' education, motivation, skills, beliefs, and type of adherence are taken into consideration when developing the apps. Findings from this study can help clinicians and patients make informed choices and pursue policy-makers to integrate evidence when developing future apps. Quality-assurance tools are needed to ensure the apps are systematically evaluated.

A Smartphone App to Promote an Active Lifestyle in Lower-Educated Working Young Adults: Development, Usability, Acceptability, and Feasibility Study.

PubMed

Simons, Dorien; De Bourdeaudhuij, Ilse; Clarys, Peter; De Cocker, Katrien; Vandelanotte, Corneel; Deforche, Benedicte

2018-02-20

Physical activity (PA) levels are problematic in lower-educated working young adults (18-26 years). To promote PA, smartphone apps have great potential, but there is no evidence for their effectiveness in this population. To increase the likelihood that a newly developed app will be effective, formative research and user testing are required. The aim of this study was to describe the development, usability, acceptability, and feasibility of a new theory- and evidence-based smartphone app to promote an active lifestyle in lower-educated working young adults. The new app was developed by applying 4 steps. First, determinants important to promote an active lifestyle in this population were selected. Second, evidence-based behavior change techniques were selected to convert the determinants into practical applications. Third, a new smartphone app was developed. Fourth, volunteers (n=11, both lower and higher educated) tested the app on usability, and lower-educated working young adults (n=16) tested its acceptability and feasibility via (think aloud) interviews, a questionnaire, and Google Analytics. The app was accordingly adapted for the final version. A new Android app, Active Coach, was developed that focused on knowledge, attitude, social support, and self-efficacy (based on outcomes from step 1), and that applied self-regulation techniques (based on outcomes from step 2). The app consists of a 9-week program with personal goals, practical tips, and scientific facts to encourage an active lifestyle. To ensure all-day and automatic self-monitoring of the activity behavior, the Active Coach app works in combination with a wearable activity tracker, the Fitbit Charge. Issues detected by the usability test (eg, text errors, wrong messages) were all fixed. The acceptability and feasibility test showed that participants found the app clear, understandable, and motivating, although some aspects needed to be more personal. By applying a stepwise, user-centered approach that regularly consulted the target group, the new app is adapted to their specific needs and preferences. The Active Coach app was overall positively evaluated by the lower-educated working young adults at the end of the development process. ©Dorien Simons, Ilse De Bourdeaudhuij, Peter Clarys, Katrien De Cocker, Corneel Vandelanotte, Benedicte Deforche. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 20.02.2018.

Genetically Augmenting Aβ42 Levels in Skeletal Muscle Exacerbates Inclusion Body Myositis-Like Pathology and Motor Deficits in Transgenic Mice

PubMed Central

Kitazawa, Masashi; Green, Kim N.; Caccamo, Antonella; LaFerla, Frank M.

2006-01-01

The pathogenic basis of inclusion body myositis (IBM), the leading muscle degenerative disease afflicting the elderly, is unknown, although the histopathological features are remarkably similar to those observed in Alzheimer’s disease. One leading hypothesis is that the buildup of amyloid-β (Aβ) peptide within selective skeletal muscle fibers contributes to the degenerative phenotype. Aβ is a small peptide derived via endoproteolysis of the amyloid precursor protein (APP). To determine the pathogenic effect of augmenting Aβ42 levels in skeletal muscle, we used a genetic approach to replace the endogenous wild-type presenilin-1 (PS1) allele with the PS1M146V allele in MCK-APP mice. Although APP transgene expression was unaltered, Aβ levels, particularly Aβ42, were elevated in skeletal muscle of the double transgenic (MCK-APP/PS1) mice compared to the parental MCK-APP line. Elevated phospho-tau accumulation was found in the MCK-APP/PS1 mice, and the greater activation of GSK-3β and cdk5 were observed. Other IBM-like pathological features, such as inclusion bodies and inflammatory infiltrates, were more severe and prominent in the MCK-APP/PS1 mice. Motor coordination and balance were more adversely affected and manifested at an earlier age in the MCK-APP/PS1 mice. The data presented here provide experimental evidence that Aβ42 plays a proximal and critical role in the muscle degenerative process. PMID:16723713

Cocreated Smartphone App to Improve the Quality of Life of Adolescents and Young Adults with Cancer (Kræftværket): Protocol for a Quantitative and Qualitative Evaluation

PubMed Central

Elsbernd, Abbey; Hjerming, Maiken; Visler, Camilla; Hjalgrim, Lisa Lyngsie; Niemann, Carsten Utoft; Boisen, Kirsten

2018-01-01

Background Adolescents and young adults with cancer face significant challenges during the course of their medical treatment and recovery from illness. Many adolescents and young adults struggle with long-term complications in the physical, psychosocial, economic, and academic domains. Mobile health (mHealth) interventions provide an innovative platform for delivering supportive care, particularly through the utilization of apps on smartphones and tablets. To create a successful mHealth intervention for adolescents and young adults, youth input and feedback is essential. The process of cocreation, in which the target app user has a direct role in dictating design and function, was utilized to create the prototype smartphone app for adolescents and young adults with cancer, “Kræftværket.” Objective The objective of this paper is to describe the protocol for the evaluation of the Kræftværket app, a prototype app designed via cocreation, to support and improve health-related quality of life for adolescents and young adults with cancer. Methods The Kræftværket app has three primary features, (1) a symptom and activity diary, (2) a supportive communication network between app users, and (3) a “one-stop shop” information bank with practical information as well as links to patient organizations and other resources. The app will be evaluated in two phases, a pilot test and an implementation test. In the pilot test, the app will be launched to a test group of 20 adolescents and young adults aged 15 to 29 years, selected for equal representation amongst age group and treatment status. Patients will be allowed to utilize the app over the course of six weeks and will complete a baseline and follow-up European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) health-related quality of life inventory. In addition, participant focus group interviews will be conducted according to a semistructured interview guide. Resulting data will be analyzed using thematic analysis. Results and appropriate analysis from both the qualitative and quantitative branches of the pilot test will be discussed amongst the research group, and appropriate changes based on user feedback will be made to the app before the final project phase. In the implementation test, the app will be provided and utilized by a sample of 50 adolescents and young adults aged 15-29 years selected for equal representation amongst gender, age group, diagnosis, and treatment status over the course of 3 months. Participants will be asked to complete a baseline and follow-up EORTC QLQ-C30 HRQoL inventory. Results Pilot testing is expected to take place in February 2018, and implementation testing is expected to begin May 2018. Conclusions It is the hope that Kræftværket app will serve as a beneficial and easily utilized product. The process of evaluating the app and its effect on quality of life will address the absence of evidence-based mHealth interventions, and attempt to validate new approaches to benefitting adolescents and young adult oncology patients in the digital world. Registered Report Identifier RR1-10.2196/10098 PMID:29748162

Cocreated Smartphone App to Improve the Quality of Life of Adolescents and Young Adults with Cancer (Kræftværket): Protocol for a Quantitative and Qualitative Evaluation.

PubMed

Elsbernd, Abbey; Hjerming, Maiken; Visler, Camilla; Hjalgrim, Lisa Lyngsie; Niemann, Carsten Utoft; Boisen, Kirsten; Pappot, Helle

2018-05-10

Adolescents and young adults with cancer face significant challenges during the course of their medical treatment and recovery from illness. Many adolescents and young adults struggle with long-term complications in the physical, psychosocial, economic, and academic domains. Mobile health (mHealth) interventions provide an innovative platform for delivering supportive care, particularly through the utilization of apps on smartphones and tablets. To create a successful mHealth intervention for adolescents and young adults, youth input and feedback is essential. The process of cocreation, in which the target app user has a direct role in dictating design and function, was utilized to create the prototype smartphone app for adolescents and young adults with cancer, "Kræftværket." The objective of this paper is to describe the protocol for the evaluation of the Kræftværket app, a prototype app designed via cocreation, to support and improve health-related quality of life for adolescents and young adults with cancer. The Kræftværket app has three primary features, (1) a symptom and activity diary, (2) a supportive communication network between app users, and (3) a "one-stop shop" information bank with practical information as well as links to patient organizations and other resources. The app will be evaluated in two phases, a pilot test and an implementation test. In the pilot test, the app will be launched to a test group of 20 adolescents and young adults aged 15 to 29 years, selected for equal representation amongst age group and treatment status. Patients will be allowed to utilize the app over the course of six weeks and will complete a baseline and follow-up European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) health-related quality of life inventory. In addition, participant focus group interviews will be conducted according to a semistructured interview guide. Resulting data will be analyzed using thematic analysis. Results and appropriate analysis from both the qualitative and quantitative branches of the pilot test will be discussed amongst the research group, and appropriate changes based on user feedback will be made to the app before the final project phase. In the implementation test, the app will be provided and utilized by a sample of 50 adolescents and young adults aged 15-29 years selected for equal representation amongst gender, age group, diagnosis, and treatment status over the course of 3 months. Participants will be asked to complete a baseline and follow-up EORTC QLQ-C30 HRQoL inventory. Pilot testing is expected to take place in February 2018, and implementation testing is expected to begin May 2018. It is the hope that Kræftværket app will serve as a beneficial and easily utilized product. The process of evaluating the app and its effect on quality of life will address the absence of evidence-based mHealth interventions, and attempt to validate new approaches to benefitting adolescents and young adult oncology patients in the digital world. RR1-10.2196/10098. ©Abbey Elsbernd, Maiken Hjerming, Camilla Visler, Lisa Lyngsie Hjalgrim, Carsten Utoft Niemann, Kirsten Boisen, Helle Pappot. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 10.05.2018.

Effect of Time-Dependent Sorption on the Dissipation of Water-Extractable Pesticides in Soils.

PubMed

Motoki, Yutaka; Iwafune, Takashi; Seike, Nobuyasu; Inao, Keiya; Otani, Takashi

2016-06-08

The dissipation behavior of water-extractable pesticides in soils is important when assessing the phytoavailability of pesticides in soils. This process is less understood than pesticide extraction with organic solvents. To elucidate the dissipation behavior of water-extractable pesticides in soils, we conducted an incubation study using 27 pesticides and five Japanese soils. The rate of decrease of the level of pesticides in water extracts was faster in soils than that of total extracts (water extracts and acetone extracts). This suggests that time-dependent sorption contributed to the difference in the dissipation between the pesticides in water and total extracts from soils. Increased apparent sorption coefficients (Kd,app) with time were positively and significantly correlated with Kd,app values of a 0 day incubation [Kd,app(t0)]. This empirical relationship suggests that Kd,app(t0) values can predict the time-dependent increase in Kd,app and the dissipation of water-extractable pesticides in soils.

Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer's Disease

PubMed Central

Grimm, Marcus O. W.; Grösgen, Sven; Rothhaar, Tatjana L.; Burg, Verena K.; Hundsdörfer, Benjamin; Haupenthal, Viola J.; Friess, Petra; Müller, Ulrike; Fassbender, Klaus; Riemenschneider, Matthias; Grimm, Heike S.; Hartmann, Tobias

2011-01-01

Lipids play an important role as risk or protective factors in Alzheimer's disease (AD), a disease biochemically characterized by the accumulation of amyloid beta peptides (Aβ), released by proteolytic processing of the amyloid precursor protein (APP). Changes in sphingolipid metabolism have been associated to the development of AD. The key enzyme in sphingolipid de novo synthesis is serine-palmitoyl-CoA transferase (SPT). In the present study we identified a new physiological function of APP in sphingolipid synthesis. The APP intracellular domain (AICD) was found to decrease the expression of the SPT subunit SPTLC2, the catalytic subunit of the SPT heterodimer, resulting in that decreased SPT activity. AICD function was dependent on Fe65 and SPTLC2 levels are increased in APP knock-in mice missing a functional AICD domain. SPTLC2 levels are also increased in familial and sporadic AD postmortem brains, suggesting that SPT is involved in AD pathology. PMID:21660213

Chinese Cardiovascular Disease Mobile Apps’ Information Types, Information Quality, and Interactive Functions for Self-Management: Systematic Review

PubMed Central

Xie, Bo; Su, Zhaohui; Zhang, Wenhui

2017-01-01

Background China has a large population with cardiovascular disease (CVD) that requires extensive self-management. Mobile health (mHealth) apps may be a useful tool for CVD self-management. Little is currently known about the types and quality of health information provided in Chinese CVD mobile apps and whether app functions are conducive to promoting CVD self-management. Objective We undertook a systematic review to evaluate the types and quality of health information provided in Chinese CVD mobile apps and interactive app functions for promoting CVD self-management. Methods Mobile apps targeting end users in China with CVD conditions were selected in February 2017 through a multi-stage process. Three frameworks were used to evaluate the selected apps: (1) types of health information offered were assessed using our Health Information Wants framework, which encompasses 7 types of information; (2) quality of information provided in the apps was assessed using the 11 guidelines recommended by the National Library of Medicine of the National Institutes of Health; and (3) types of interactive app functions for CVD self-management were assessed using a 15-item framework adapted from the literature, including our own prior work. Results Of 578 apps identified, 82 were eligible for final review. Among these, information about self-care (67/82, 82%) and information specifically regarding CVD (63/82, 77%) were the most common types of information provided, while information about health care providers (22/82, 27%) and laboratory tests (5/82, 6%) were least common. The most common indicators of information quality were the revealing of apps’ providers (82/82, 100%) and purpose (82/82, 100%), while the least common quality indicators were the revealing of how apps’ information was selected (1/82, 1%) and app sponsorship (0/82, 0%). The most common interactive functions for CVD self-management were those that enabled user interaction with the app provider (57/82, 70%) and with health care providers (36/82, 44%), while the least common interactive functions were those that enabled lifestyle management (13/82, 16%) and psychological health management (6/82, 7%). None of the apps covered all 7 types of health information, all 11 indicators of information quality, or all 15 interactive functions for CVD self-management. Conclusions Chinese CVD apps are insufficient in providing comprehensive health information, high-quality information, and interactive functions to facilitate CVD self-management. End users should exercise caution when using existing apps. Health care professionals and app developers should collaborate to better understand end users’ preferences and follow evidence-based guidelines to develop mHealth apps conducive to CVD self-management. PMID:29242176

The Possible Mechanism of Advanced Glycation End Products (AGEs) for Alzheimer’s Disease

PubMed Central

Ko, Shun-Yao; Ko, Hshin-An; Chu, Kuo-Hsiung; Shieh, Tzong-Ming; Chi, Tzong-Cherng; Chen, Hong-I; Chang, Weng-Cheng; Chang, Shu-Shing

2015-01-01

Amyloid precursor protein (APP) has been modified by β and γ-secretase that cause amyloid deposits (plaques) in neuronal cells. Glyceraldhyde-derived AGEs has been identified as a major source of neurotoxicity in Alzheimer’s disease (AD). In a previous study, we demonstrated that glyceraldehyde-derived AGEs increase APP and Aβ via ROS. Furthermore, the combination of AGEs and Aβ has been shown to enhance neurotoxicity. In mice, APP expression is increased by tail vein injection of AGEs. This evidence suggests a correlation between AGEs and the development of AD. However, the role played by AGEs in the pathogenesis of AD remains unclear. In this report, we demonstrate that AGEs up-regulate APP processing protein (BACE and PS1) and Sirt1 expression via ROS, but do not affect the expression of downstream antioxidant genes HO-1 and NQO-1. Moreover, we found that AGEs increase GRP78 expression and enhance the cell death-related pathway p53, bcl-2/bax ratio, caspase 3. These results indicate that AGEs impair the neuroprotective effects of Sirt1 and lead to neuronal cell death via ER stress. Our findings suggest that AGEs increase ROS production, which stimulates downstream pathways related to APP processing, Aβ production, Sirt1, and GRP78, resulting in the up-regulation of cell death related pathway. This in-turn enhances neuronal cell death, which leads to the development of AD. PMID:26587989

The Possible Mechanism of Advanced Glycation End Products (AGEs) for Alzheimer's Disease.

PubMed

Ko, Shun-Yao; Ko, Hshin-An; Chu, Kuo-Hsiung; Shieh, Tzong-Ming; Chi, Tzong-Cherng; Chen, Hong-I; Chang, Weng-Cheng; Chang, Shu-Shing

2015-01-01

Amyloid precursor protein (APP) has been modified by β and γ-secretase that cause amyloid deposits (plaques) in neuronal cells. Glyceraldhyde-derived AGEs has been identified as a major source of neurotoxicity in Alzheimer's disease (AD). In a previous study, we demonstrated that glyceraldehyde-derived AGEs increase APP and Aβ via ROS. Furthermore, the combination of AGEs and Aβ has been shown to enhance neurotoxicity. In mice, APP expression is increased by tail vein injection of AGEs. This evidence suggests a correlation between AGEs and the development of AD. However, the role played by AGEs in the pathogenesis of AD remains unclear. In this report, we demonstrate that AGEs up-regulate APP processing protein (BACE and PS1) and Sirt1 expression via ROS, but do not affect the expression of downstream antioxidant genes HO-1 and NQO-1. Moreover, we found that AGEs increase GRP78 expression and enhance the cell death-related pathway p53, bcl-2/bax ratio, caspase 3. These results indicate that AGEs impair the neuroprotective effects of Sirt1 and lead to neuronal cell death via ER stress. Our findings suggest that AGEs increase ROS production, which stimulates downstream pathways related to APP processing, Aβ production, Sirt1, and GRP78, resulting in the up-regulation of cell death related pathway. This in-turn enhances neuronal cell death, which leads to the development of AD.

Enhance wound healing monitoring through a thermal imaging based smartphone app

NASA Astrophysics Data System (ADS)

Yi, Steven; Lu, Minta; Yee, Adam; Harmon, John; Meng, Frank; Hinduja, Saurabh

2018-03-01

In this paper, we present a thermal imaging based app to augment traditional appearance based wound growth monitoring. Accurate diagnose and track of wound healing enables physicians to effectively assess, document, and individualize the treatment plan given to each wound patient. Currently, wounds are primarily examined by physicians through visual appearance and wound area. However, visual information alone cannot present a complete picture on a wound's condition. In this paper, we use a smartphone attached thermal imager and evaluate its effectiveness on augmenting visual appearance based wound diagnosis. Instead of only monitoring wound temperature changes on a wound, our app presents physicians a comprehensive measurements including relative temperature, wound healing thermal index, and wound blood flow. Through the rat wound experiments and by monitoring the integrated thermal measurements over 3 weeks of time frame, our app is able to show the underlying healing process through the blood flow. The implied significance of our app design and experiment includes: (a) It is possible to use a low cost smartphone attached thermal imager for added value on wound assessment, tracking, and treatment; and (b) Thermal mobile app can be used for remote wound healing assessment for mobile health based solution.

Organizing a Community Advanced Pharmacy Practice Experience

PubMed Central

Koenigsfeld, Carrie Foust; Tice, Angela L

2006-01-01

Setting up a community advanced pharmacy practice experience can be an overwhelming task for many pharmacy preceptors. This article provides guidance to pharmacist preceptors in developing a complete and effective community advanced pharmacy practice experience (APPE). When preparing for the APPE, initial discussions with the college or school of pharmacy are key. Benefits, training, and requirements should be addressed. Site preparation, including staff education, will assist in the development process. The preceptor should plan orientation day activities and determine appropriate evaluation and feedback methods. With thorough preparation, the APPE will be rewarding for both the student and the pharmacy site. PMID:17136163

Organizing a community advanced pharmacy practice experience.

PubMed

Koenigsfeld, Carrie Foust; Tice, Angela L

2006-02-15

Setting up a community advanced pharmacy practice experience can be an overwhelming task for many pharmacy preceptors. This article provides guidance to pharmacist preceptors in developing a complete and effective community advanced pharmacy practice experience (APPE). When preparing for the APPE, initial discussions with the college or school of pharmacy are key. Benefits, training, and requirements should be addressed. Site preparation, including staff education, will assist in the development process. The preceptor should plan orientation day activities and determine appropriate evaluation and feedback methods. With thorough preparation, the APPE will be rewarding for both the student and the pharmacy site.

Suppression of amyloid beta A11 antibody immunoreactivity by vitamin C: possible role of heparan sulfate oligosaccharides derived from glypican-1 by ascorbate-induced, nitric oxide (NO)-catalyzed degradation.

PubMed

Cheng, Fang; Cappai, Roberto; Ciccotosto, Giuseppe D; Svensson, Gabriel; Multhaup, Gerd; Fransson, Lars-Åke; Mani, Katrin

2011-08-05

Amyloid β (Aβ) is generated from the copper- and heparan sulfate (HS)-binding amyloid precursor protein (APP) by proteolytic processing. APP supports S-nitrosylation of the HS proteoglycan glypican-1 (Gpc-1). In the presence of ascorbate, there is NO-catalyzed release of anhydromannose (anMan)-containing oligosaccharides from Gpc-1-nitrosothiol. We investigated whether these oligosaccharides interact with Aβ during APP processing and plaque formation. anMan immunoreactivity was detected in amyloid plaques of Alzheimer (AD) and APP transgenic (Tg2576) mouse brains by immunofluorescence microscopy. APP/APP degradation products detected by antibodies to the C terminus of APP, but not Aβ oligomers detected by the anti-Aβ A11 antibody, colocalized with anMan immunoreactivity in Tg2576 fibroblasts. A 50-55-kDa anionic, sodium dodecyl sulfate-stable, anMan- and Aβ-immunoreactive species was obtained from Tg2576 fibroblasts using immunoprecipitation with anti-APP (C terminus). anMan-containing HS oligo- and disaccharide preparations modulated or suppressed A11 immunoreactivity and oligomerization of Aβ42 peptide in an in vitro assay. A11 immunoreactivity increased in Tg2576 fibroblasts when Gpc-1 autoprocessing was inhibited by 3-β[2(diethylamino)ethoxy]androst-5-en-17-one (U18666A) and decreased when Gpc-1 autoprocessing was stimulated by ascorbate. Neither overexpression of Gpc-1 in Tg2576 fibroblasts nor addition of copper ion and NO donor to hippocampal slices from 3xTg-AD mice affected A11 immunoreactivity levels. However, A11 immunoreactivity was greatly suppressed by the subsequent addition of ascorbate. We speculate that temporary interaction between the Aβ domain and small, anMan-containing oligosaccharides may preclude formation of toxic Aβ oligomers. A portion of the oligosaccharides are co-secreted with the Aβ peptides and deposited in plaques. These results support the notion that an inadequate supply of vitamin C could contribute to late onset AD in humans.

Antifouling paint particles: Sources, occurrence, composition and dynamics.

PubMed

Soroldoni, Sanye; Castro, Ítalo Braga; Abreu, Fiamma; Duarte, Fabio Andrei; Choueri, Rodrigo Brasil; Möller, Osmar Olinto; Fillmann, Gilberto; Pinho, Grasiela Lopes Leães

2018-06-15

Sources, occurrence, composition and dynamics of antifouling paint particles (APPs) were assessed in Patos Lagoon estuary (PLE), Southern Brazil. Ten areas including boatyards, a marina and artisanal fishing harbors were identified in the estuarine system as potential sources of APPs. The APPs generated in these areas were highly heterogeneous considering the size, shape and composition. Based on an estimate of antifouling paint usage and amount of boats in each studied area, artisanal fishing harbors could be the main source of particles to PLE. However, relatively high amounts of APPs, which ranged from 130 to 40,300 μg g -1 , were detected in sediments collected in front of boatyards and a marina. The uneven distribution of APPs levels among the sediment samples were probably due to the presence of diffuse sources (fishing harbors) associated to "hotspots" (boatyards and marina) along the study area. Additionally, data of settling experiment indicate that size, shape and density of APPs, combined to local hydrodynamics, appears to contribute to the mobility of these residues within the estuary. In the main channel of PLE, smaller particles tend to be transported to adjacent coastal zone while particles tend to be deposited in the sediment surface of sheltered areas. Since different trace metals, and booster biocides were detected in APPs that were not correctly disposed, these particles can be considered as an important source of contamination to aquatic environments. The present data suggest that APPs represent an environmental problem for aquatic systems in Brazil, since the country lacks legislation in addition to inefficient control mechanisms. An improvement in boat maintenance processes are urgently needed to avoid this continuous release of APPs into the aquatic systems. Copyright © 2018 Elsevier Ltd. All rights reserved.

Using WhatsApp to Create a Space of Language and Content for Students of International Relations

ERIC Educational Resources Information Center

Keogh, Conor

2017-01-01

For language learners of this generation, the smart phone represents a key cultural artefact that complements the learning process. Instant messaging applications such as WhatsApp are widely used in personal, professional and, increasingly, academic circles to maintain constant contact among friends, colleagues, or classmates. This study seeks to…

Development and use of the Cytoscape app GFD-Net for measuring semantic dissimilarity of gene networks

PubMed Central

Diaz-Montana, Juan J.; Diaz-Diaz, Norberto

2014-01-01

Gene networks are one of the main computational models used to study the interaction between different elements during biological processes being widely used to represent gene–gene, or protein–protein interaction complexes. We present GFD-Net, a Cytoscape app for visualizing and analyzing the functional dissimilarity of gene networks. PMID:25400907

Development of a Mobile Clinical Prediction Tool to Estimate Future Depression Severity and Guide Treatment in Primary Care: User-Centered Design

PubMed Central

2018-01-01

Background Around the world, depression is both under- and overtreated. The diamond clinical prediction tool was developed to assist with appropriate treatment allocation by estimating the 3-month prognosis among people with current depressive symptoms. Delivering clinical prediction tools in a way that will enhance their uptake in routine clinical practice remains challenging; however, mobile apps show promise in this respect. To increase the likelihood that an app-delivered clinical prediction tool can be successfully incorporated into clinical practice, it is important to involve end users in the app design process. Objective The aim of the study was to maximize patient engagement in an app designed to improve treatment allocation for depression. Methods An iterative, user-centered design process was employed. Qualitative data were collected via 2 focus groups with a community sample (n=17) and 7 semistructured interviews with people with depressive symptoms. The results of the focus groups and interviews were used by the computer engineering team to modify subsequent protoypes of the app. Results Iterative development resulted in 3 prototypes and a final app. The areas requiring the most substantial changes following end-user input were related to the iconography used and the way that feedback was provided. In particular, communicating risk of future depressive symptoms proved difficult; these messages were consistently misinterpreted and negatively viewed and were ultimately removed. All participants felt positively about seeing their results summarized after completion of the clinical prediction tool, but there was a need for a personalized treatment recommendation made in conjunction with a consultation with a health professional. Conclusions User-centered design led to valuable improvements in the content and design of an app designed to improve allocation of and engagement in depression treatment. Iterative design allowed us to develop a tool that allows users to feel hope, engage in self-reflection, and motivate them to treatment. The tool is currently being evaluated in a randomized controlled trial. PMID:29685864

Differential recruitment efficacy of patient-derived amyloidogenic and myeloma light chain proteins by synthetic fibrils-A metric for predicting amyloid propensity.

PubMed

Martin, Emily B; Williams, Angela; Wooliver, Craig; Heidel, R Eric; Adams, Sarah; Dunlap, John; Ramirez-Alvarado, Marina; Blancas-Mejia, Luis M; Lands, Ronald H; Kennel, Stephen J; Wall, Jonathan S

2017-01-01

Monoclonal free light chain (LC) proteins are present in the circulation of patients with immunoproliferative disorders such as light chain (AL) amyloidosis and multiple myeloma (MM). Light chain-associated amyloid is a complex pathology composed of proteinaceous fibrils and extracellular matrix proteins found in all patients with AL and in ~10-30% of patients who presented with MM. Amyloid deposits systemically in multiple organs and tissues leading to dysfunction and ultimately death. The overall survival of patients with amyloidosis is worse than for those with early stage MM. We have developed a sensitive binding assay quantifying the recruitment of full length, patient-derived LC proteins by synthetic amyloid fibrils, as a method for studying their amyloidogenic potential. In a survey of eight urinary LC, both AL and MM-associated proteins were recruited by synthetic amyloid fibrils; however, AL-associated LC bound significantly more efficiently (p < 0.05) than did MM LCs. The LC proteins used in this study were isolated from urine and presumed to represent a surrogate of serum free light chains. The binding of LC to synthetic fibrils in this assay accurately differentiated LC with amyloidogenic propensity from MM LC that were not associated with clinical amyloid disease. Notably, the LC from a MM patient who subsequently developed amyloid behaved as an AL-associated protein in the assay, indicating the possibility for identifying MM patients at risk for developing amyloidosis based on the light chain recruitment efficacy. With this information, at risk patients can be monitored more closely for the development of amyloidosis, allowing timely administration of novel, amyloid-directed immunotherapies-this approach may improve the prognosis for these patients.

Systemic amyloidosis: novel therapies and role of biomarkers.

PubMed

Nuvolone, Mario; Merlini, Giampaolo

2017-05-01

Systemic amyloidosis is caused by misfolding and extracellular deposition of one of an ever-growing list of circulating proteins, resulting in vital organ dysfunction and eventually death. Despite different predisposing conditions, including plasma cell dyscrasias [immunoglobulin light chain (AL) amyloidosis], long-lasting inflammation [reactive (AA) amyloidosis] or mutations (hereditary amyloidoses), clinical manifestations are conspicuously overlapping and mimic more prevalent conditions, significantly complicating and often delaying the recognition of these rare, complex diseases. However, refined diagnostic and imaging approaches and the increasing role of biomarkers, which help in establishing the diagnosis, assessing the prognosis and evaluating the response to therapy, have considerably improved the management of these conditions. The pillar of anti-amyloid therapy remains the prompt reduction or elimination of the amyloidogenic precursor. This is accomplished by targeting the underlying condition, and recent improvements in the treatment of plasma cell disorders and chronic inflammatory conditions have positively reverberated onto the management of AL and AA amyloidosis, respectively. Moreover, recent, substantial improvements in the understanding of the molecular underpinnings of systemic amyloidosis have unveiled different key steps in the amyloidogenic cascade which can be valid therapeutic targets. These include stabilizers of the native conformation of the amyloidogenic precursor, inhibitors of fibrillogenesis, amyloid fibril disruptors and promoters of amyloid clearance. Innovative pharmacological strategies, including rational, structure-based drug design, gene knockdown and immunotherapy, but also repurposing of old, safe drugs with newly recognized anti-amyloid properties, are currently being pursued already in the clinical setting, holding the promise of dramatically improving the outcome of these dismal conditions in the near future. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Amyloidosis in transgenic mice expressing murine amyloidogenic apolipoprotein A-II (Apoa2c).

PubMed

Ge, Fengxia; Yao, Junjie; Fu, Xiaoying; Guo, Zhanjun; Yan, Jingmin; Zhang, Beiru; Zhang, Huanyu; Tomozawa, Hiroshi; Miyazaki, Junichi; Sawashita, Jinko; Mori, Masayuki; Higuchi, Keiichi

2007-07-01

In mice, apolipoprotein A-II (apoA-II) self-associates to form amyloid fibrils (AApoAII) in an age-associated manner. We postulated that the two most important factors in apoA-II amyloidosis are the Apoa2(c) allele, which codes for the amyloidogenic protein APOA2C (Gln5, Ala38) and transmission of amyloid fibrils. To characterize further the contribution of the Apoa2(c) allele to amyloidogenesis and improve detection of amyloidogenic materials, we established transgenic mice that overexpress APOA2C protein under the cytomegalovirus (CMV) immediate early gene (CMV-IE) enhancer/chicken beta promoter. Compared to transgene negative (Tg(-/-)) mice that express apoA-II protein mainly in the liver, mice homozygous (Tg(+/+)) and heterozygous (Tg(+/-)) for the transgene express a high level of apoA-II protein in many tissues. They also have higher plasma concentrations of apoA-II, higher ratios of ApoA-II/apolipoprotein A-I (ApoA-I) and higher concentrations of high-density lipoprotein (HDL) cholesterol. Following injection of AApoAII fibrils into Tg(+/+) mice, amyloid deposition was observed in the testis, liver, kidney, heart, lungs, spleen, tongue, stomach and intestine but not in the brain. In Tg(+/+) mice, but not in Tg(-/-) mice, amyloid deposition was induced by injection of less than 10(-8) mug AApoAII fibrils. Furthermore, deposition in Tg(+/+) mice occurred more rapidly and to a greater extent than in Tg(-/-) mice. These studies indicate that increased levels of APOA2C protein lead to earlier and greater amyloid deposition and enhanced sensitivity to the transmission of amyloid fibrils in transgenic mice. This transgenic mouse model should prove valuable for studies of amyloidosis.

Localized conformational changes trigger the pH-induced fibrillogenesis of an amyloidogenic λ light chain protein.

PubMed

Velázquez-López, Isabel; Valdés-García, Gilberto; Romero Romero, Sergio; Maya Martínez, Roberto; Leal-Cervantes, Ana I; Costas, Miguel; Sánchez-López, Rosana; Amero, Carlos; Pastor, Nina; Fernández Velasco, D Alejandro

2018-07-01

Solvent conditions modulate the expression of the amyloidogenic potential of proteins. In this work the effect of pH on the fibrillogenic behavior and the conformational properties of 6aJL2, a model protein of the highly amyloidogenic variable light chain λ6a gene segment, was examined. Ordered aggregates showing the ultrastructural and spectroscopic properties observed in amyloid fibrils were formed in the 2.0-8.0 pH range. At pH <3.0 a drastic decrease in lag time and an increase in fibril formation rate were found. In the 4.0-8.0 pH range there was no spectroscopic evidence for significant conformational changes in the native state. Likewise, heat capacity measurements showed no evidence for residual structure in the unfolded state. However, at pH <3.0 stability is severely decreased and the protein suffers conformational changes as detected by circular dichroism, tryptophan and ANS fluorescence, as well as by NMR spectroscopy. Molecular dynamics simulations indicate that acid-induced conformational changes involve the exposure of the loop connecting strands E and F. These results are compatible with pH-induced changes in the NMR spectra. Overall, the results indicate that the mechanism involved in the acid-induced increase in the fibrillogenic potential of 6aJL2 is profoundly different to that observed in κ light chains, and is promoted by localized conformational changes in a region of the protein that was previously not known to be involved in acid-induced light chain fibril formation. The identification of this region opens the potential for the design of specific inhibitors. Copyright © 2018 Elsevier B.V. All rights reserved.

Mobile Application to Promote Adherence to Oral Chemotherapy and Symptom Management: A Protocol for Design and Development

PubMed Central

MacDonald, James John; Amoyal Pensak, Nicole; Jacobs, Jamie Michele; Flanagan, Clare; Jethwani, Kamal

2017-01-01

Background Oral chemotherapy is increasingly used in place of traditional intravenous chemotherapy to treat patients with cancer. While oral chemotherapy includes benefits such as ease of administration, convenience, and minimization of invasive infusions, patients receive less oversight, support, and symptom monitoring from clinicians. Additionally, adherence is a well-documented challenge for patients with cancer prescribed oral chemotherapy regimens. With the ever-growing presence of smartphones and potential for efficacious behavioral intervention technology, we created a mobile health intervention for medication and symptom management. Objective The objective of this study was to develop and evaluate the usability and acceptability of a smartphone app to support adherence to oral chemotherapy and symptom management in patients with cancer. Methods We used a 5-step development model to create a comprehensive mobile app with theoretically informed content. The research and technical development team worked together to develop and iteratively test the app. In addition to the research team, key stakeholders including patients and family members, oncology clinicians, health care representatives, and practice administrators contributed to the content refinement of the intervention. Patient and family members also participated in alpha and beta testing of the final prototype to assess usability and acceptability before we began the randomized controlled trial. Results We incorporated app components based on the stakeholder feedback we received in focus groups and alpha and beta testing. App components included medication reminders, self-reporting of medication adherence and symptoms, an education library including nutritional information, Fitbit integration, social networking resources, and individually tailored symptom management feedback. We are conducting a randomized controlled trial to determine the effectiveness of the app in improving adherence to oral chemotherapy, quality of life, and burden of symptoms and side effects. At every stage in this trial, we are engaging stakeholders to solicit feedback on our progress and next steps. Conclusions To our knowledge, we are the first to describe the development of an app designed for people taking oral chemotherapy. The app addresses many concerns with oral chemotherapy, such as medication adherence and symptom management. Soliciting feedback from stakeholders with broad perspectives and expertise ensured that the app was acceptable and potentially beneficial for patients, caregivers, and clinicians. In our development process, we instantiated 7 of the 8 best practices proposed in a recent review of mobile health app development. Our process demonstrated the importance of effective communication between research groups and technical teams, as well as meticulous planning of technical specifications before development begins. Future efforts should consider incorporating other proven strategies in software, such as gamification, to bolster the impact of mobile health apps. Forthcoming results from our randomized controlled trial will provide key data on the effectiveness of this app in improving medication adherence and symptom management. Trial Registration ClinicalTrials.gov NCT02157519; https://clinicaltrials.gov/ct2/show/NCT02157519 (Archived by WebCite at http://www.webcitation.org/6prj3xfKA) PMID:28428158

A Smartphone App for Increasing Live Organ Donation.

PubMed

Kumar, K; King, E A; Muzaale, A D; Konel, J M; Bramstedt, K A; Massie, A B; Segev, D L; Cameron, A M

2016-12-01

The incidence of live donor transplantation has declined over the past decade, and waitlisted candidates report substantial barriers to identifying a live donor. Since asking someone to donate feels awkward and unfamiliar, candidates are hesitant to ask directly and may be more comfortable with a passive approach. In collaboration with Facebook leadership (Facebook Inc., Menlo Park, CA), we developed a mobile application-an app-that enables waitlisted candidates to create a Facebook post about their experience with organ failure and their need for a live donor. We conducted a single-center prospective cohort study of 54 adult kidney-only and liver-only waitlisted candidates using the Facebook app. Cox proportional hazards models were used to describe donor referral on behalf of candidates using the app compared with matched controls. The majority of candidates who used the app reported it to be "good" or "excellent" with regard to the installation process (82.9%), readability (88.6%), simplicity (70.6%), clarity (87.5%) and the information provided (85.3%). Compared with controls, candidates using the Facebook app were 2.43 6.61 17.98 times more likely to have a donor come forward on their behalf (p < 0.001). The Facebook app is an easy-to-use instrument that enables waitlisted candidates to passively communicate with their social network about their need for a live donor. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

The E2 Domains of APP and APLP1 Share a Conserved Mode of Dimerization

DOE Office of Scientific and Technical Information (OSTI.GOV)

S Lee; Y Xue; J Hulbert

2011-12-31

Amyloid precursor protein (APP) is genetically linked to Alzheimer's disease. APP is a type I membrane protein, and its oligomeric structure is potentially important because this property may play a role in its function or affect the processing of the precursor by the secretases to generate amyloid {beta}-peptide. Several independent studies have shown that APP can form dimers in the cell, but how it dimerizes remains controversial. At least three regions of the precursor, including a centrally located and conserved domain called E2, have been proposed to contribute to dimerization. Here we report two new crystal structures of E2, onemore » from APP and the other from APLP1, a mammalian APP homologue. Comparison with an earlier APP structure, which was determined in a different space group, shows that the E2 domains share a conserved and antiparallel mode of dimerization. Biophysical measurements in solution show that heparin binding induces E2 dimerization. The 2.1 {angstrom} resolution electron density map also reveals phosphate ions that are bound to the protein surface. Mutational analysis shows that protein residues interacting with the phosphate ions are also involved in heparin binding. The locations of two of these residues, Arg-369 and His-433, at the dimeric interface suggest a mechanism for heparin-induced protein dimerization.« less

Smartphone Applications for Educating and Helping Non-motivating Patients Adhere to Medication That Treats Mental Health Conditions: Aims and Functioning

PubMed Central

Kassianos, Angelos P.; Georgiou, Giorgos; Papaconstantinou, Electra P.; Detzortzi, Angeliki; Horne, Rob

2017-01-01

Background: Patients prescribed with medication that treats mental health conditions benefit the most compared to those prescribed with other types of medication. However, they are also the most difficult to adhere. The development of mobile health (mHealth) applications (“apps”) to help patients monitor their adherence is fast growing but with limited evidence on their efficacy. There is no evidence on the content of these apps for patients taking psychotropic medication. The aim of this study is to identify and evaluate the aims and functioning of available apps that are aiming to help and educate patients to adhere to medication that treats mental health conditions. Method: Three platform descriptions (Apple, Google, and Microsoft) were searched between October 2015 and February 2016. Included apps need to focus on adherence to medication that treats mental health conditions and use at least a reinforcement strategy. Descriptive information was extracted and apps evaluated on a number of assessment criteria using content analysis. Results: Sixteen apps were identified. All apps included self-monitoring properties like reminders and psycho-educational properties like mood logs. It was unclear how the latter were used or how adherence was measured. Major barriers to medication adherence like patients' illness and medication beliefs and attitudes were not considered nor where information to patients about mediation side effects. Very few apps were tailored and none was developed based on established theories explaining the processes for successful medication adherence like cognitions and beliefs. Reported information on app development and validation was poor. Discussion: A variety of apps with different properties that tackle both intentional and unintentional non-adherence from a different perspective are identified. An evidence-based approach and co-creation with patients is needed. This will ensure that the apps increase the possibility to impact on non-adherence. Theories like social cognition models can be useful in ensuring that patients' education, motivation, skills, beliefs, and type of adherence are taken into consideration when developing the apps. Findings from this study can help clinicians and patients make informed choices and pursue policy-makers to integrate evidence when developing future apps. Quality-assurance tools are needed to ensure the apps are systematically evaluated. PMID:29075216

Management of the General Process of Parenteral Nutrition Using mHealth Technologies: Evaluation and Validation Study

PubMed Central

2018-01-01

Background Any system applied to the control of parenteral nutrition (PN) ought to prove that the process meets the established requirements and include a repository of records to allow evaluation of the information about PN processes at any time. Objective The goal of the research was to evaluate the mobile health (mHealth) app and validate its effectiveness in monitoring the management of the PN process. Methods We studied the evaluation and validation of the general process of PN using an mHealth app. The units of analysis were the PN bags prepared and administered at the Son Espases University Hospital, Palma, Spain, from June 1 to September 6, 2016. For the evaluation of the app, we used the Poststudy System Usability Questionnaire and subsequent analysis with the Cronbach alpha coefficient. Validation was performed by checking the compliance of control for all operations on each of the stages (validation and transcription of the prescription, preparation, conservation, and administration) and by monitoring the operative control points and critical control points. Results The results obtained from 387 bags were analyzed, with 30 interruptions of administration. The fulfillment of stages was 100%, including noncritical nonconformities in the storage control. The average deviation in the weight of the bags was less than 5%, and the infusion time did not present deviations greater than 1 hour. Conclusions The developed app successfully passed the evaluation and validation tests and was implemented to perform the monitoring procedures for the overall PN process. A new mobile solution to manage the quality and traceability of sensitive medicines such as blood-derivative drugs and hazardous drugs derived from this project is currently being deployed. PMID:29615389

iOS and OS X Apps for Exploring Earthquake Activity

NASA Astrophysics Data System (ADS)

Ammon, C. J.

2015-12-01

The U.S. Geological Survey and many other agencies rapidly provide information following earthquakes. This timely information garners great public interest and provides a rich opportunity to engage students in discussion and analysis of earthquakes and tectonics. In this presentation I will describe a suite of iOS and Mac OS X apps that I use for teaching and that Penn State employs in outreach efforts in a small museum run by the College of Earth and Mineral Sciences. The iOS apps include a simple, global overview of earthquake activity, epicentral, designed for a quick review or event lookup. A more full-featured iPad app, epicentral-plus, includes a simple global overview along with views that allow a more detailed exploration of geographic regions of interest. In addition, epicentral-plus allows the user to monitor ground motions using seismic channel lists compatible with the IRIS web services. Some limited seismogram processing features are included to allow focus on appropriate signal bandwidths. A companion web site, which includes background material on earthquakes, and a blog that includes sample images and channel lists appropriate for monitoring earthquakes in regions of recent earthquake activity can be accessed through the a third panel in the app. I use epicentral-plus at the beginning of each earthquake seismology class to review recent earthquake activity and to stimulate students to formulate and to ask questions that lead to discussions of earthquake and tectonic processes. Less interactive OS X versions of the apps are used to display a global map of earthquake activity and seismograms in near real time in a small museum on the ground floor of the building hosting Penn State's Geoscience Department.

Screening for Small Molecule Inhibitors of Statin-Induced APP C-terminal Toxic Fragment Production

PubMed Central

Poksay, Karen S.; Sheffler, Douglas J.; Spilman, Patricia; Campagna, Jesus; Jagodzinska, Barbara; Descamps, Olivier; Gorostiza, Olivia; Matalis, Alex; Mullenix, Michael; Bredesen, Dale E.; Cosford, Nicholas D. P.; John, Varghese

2017-01-01

Alzheimer’s disease (AD) is characterized by neuronal and synaptic loss. One process that could contribute to this loss is the intracellular caspase cleavage of the amyloid precursor protein (APP) resulting in release of the toxic C-terminal 31-amino acid peptide APP-C31 along with the production of APPΔC31, full-length APP minus the C-terminal 31 amino acids. We previously found that a mutation in APP that prevents this caspase cleavage ameliorated synaptic loss and cognitive impairment in a murine AD model. Thus, inhibition of this cleavage is a reasonable target for new therapeutic development. In order to identify small molecules that inhibit the generation of APP-C31, we first used an APPΔC31 cleavage site-specific antibody to develop an AlphaLISA to screen several chemical compound libraries for the level of N-terminal fragment production. This antibody was also used to develop an ELISA for validation studies. In both high throughput screening (HTS) and validation testing, the ability of compounds to inhibit simvastatin- (HTS) or cerivastatin- (validation studies) induced caspase cleavage at the APP-D720 cleavage site was determined in Chinese hamster ovary (CHO) cells stably transfected with wildtype (wt) human APP (CHO-7W). Several compounds, as well as control pan-caspase inhibitor Q-VD-OPh, inhibited APPΔC31 production (measured fragment) and rescued cell death in a dose-dependent manner. The effective compounds fell into several classes including SERCA inhibitors, inhibitors of Wnt signaling, and calcium channel antagonists. Further studies are underway to evaluate the efficacy of lead compounds – identified here using cells and tissues expressing wt human APP – in mouse models of AD expressing mutated human APP, as well as to identify additional compounds and determine the mechanisms by which they exert their effects. PMID:28261092

Amyloidogenesis of Natively Unfolded Proteins

PubMed Central

Uversky, Vladimir N.

2009-01-01

Aggregation and subsequent development of protein deposition diseases originate from conformational changes in corresponding amyloidogenic proteins. The accumulated data support the model where protein fibrillogenesis proceeds via the formation of a relatively unfolded amyloidogenic conformation, which shares many structural properties with the pre-molten globule state, a partially folded intermediate first found during the equilibrium and kinetic (un)folding studies of several globular proteins and later described as one of the structural forms of natively unfolded proteins. The flexibility of this structural form is essential for the conformational rearrangements driving the formation of the core cross-beta structure of the amyloid fibril. Obviously, molecular mechanisms describing amyloidogenesis of ordered and natively unfolded proteins are different. For ordered protein to fibrillate, its unique and rigid structure has to be destabilized and partially unfolded. On the other hand, fibrillogenesis of a natively unfolded protein involves the formation of partially folded conformation; i.e., partial folding rather than unfolding. In this review recent findings are surveyed to illustrate some unique features of the natively unfolded proteins amyloidogenesis. PMID:18537543

Bacoside-A, an anti-amyloid natural substance, inhibits membrane disruption by the amyloidogenic determinant of prion protein through accelerating fibril formation.

PubMed

Malishev, Ravit; Nandi, Sukhendu; Kolusheva, Sofiya; Shaham-Niv, Shira; Gazit, Ehud; Jelinek, Raz

2016-09-01

Bacosides, class of compounds extracted from the Bacopa monniera plant, exhibit interesting therapeutic properties, particularly enhancing cognitive functions and putative anti-amyloid activity. We show that bacoside-A exerted significant effects upon fibrillation and membrane interactions of the amyloidogenic fragment of the prion protein [PrP(106-126)]. Specifically, when co-incubated with PrP(106-126), bacoside-A accelerated fibril formation in the presence of lipid bilayers and in parallel inhibited bilayer interactions of the peptide aggregates formed in solution. These interesting phenomena were studied by spectroscopic and microscopic techniques, which suggest that bacoside A-promoted fibrillation reduced the concentration of membrane-active pre-fibrillar species of the prion fragment. This study suggests that induction of fibril formation and corresponding inhibition of membrane interactions are likely the underlying factors for ameliorating amyloid protein toxicity by bacoside-A. Copyright © 2016 Elsevier B.V. All rights reserved.

Amyloidogenesis abolished by proline substitutions but enhanced by lipid binding.

PubMed

Jiang, Ping; Xu, Weixin; Mu, Yuguang

2009-04-01

The influence of lipid molecules on the aggregation of a highly amyloidogenic segment of human islet amyloid polypeptide, hIAPP20-29, and the corresponding sequence from rat has been studied by all-atom replica exchange molecular dynamics (REMD) simulations with explicit solvent model. hIAPP20-29 fragments aggregate into partially ordered beta-sheet oligomers and then undergo large conformational reorganization and convert into parallel/antiparallel beta-sheet oligomers in mixed in-register and out-of-register patterns. The hydrophobic interaction between lipid tails and residues at positions 23-25 is found to stabilize the ordered beta-sheet structure, indicating a catalysis role of lipid molecules in hIAPP20-29 self-assembly. The rat IAPP variants with three proline residues maintain unstructured micelle-like oligomers, which is consistent with non-amyloidogenic behavior observed in experimental studies. Our study provides the atomic resolution descriptions of the catalytic function of lipid molecules on the aggregation of IAPP peptides.

Amyloidogenesis Abolished by Proline Substitutions but Enhanced by Lipid Binding

PubMed Central

Jiang, Ping; Xu, Weixin; Mu, Yuguang

2009-01-01

The influence of lipid molecules on the aggregation of a highly amyloidogenic segment of human islet amyloid polypeptide, hIAPP20–29, and the corresponding sequence from rat has been studied by all-atom replica exchange molecular dynamics (REMD) simulations with explicit solvent model. hIAPP20–29 fragments aggregate into partially ordered β-sheet oligomers and then undergo large conformational reorganization and convert into parallel/antiparallel β-sheet oligomers in mixed in-register and out-of-register patterns. The hydrophobic interaction between lipid tails and residues at positions 23–25 is found to stabilize the ordered β-sheet structure, indicating a catalysis role of lipid molecules in hIAPP20–29 self-assembly. The rat IAPP variants with three proline residues maintain unstructured micelle-like oligomers, which is consistent with non-amyloidogenic behavior observed in experimental studies. Our study provides the atomic resolution descriptions of the catalytic function of lipid molecules on the aggregation of IAPP peptides. PMID:19360098

Pinpointing proline substitution to be responsible for the loss of amyloidogenesis in IAPP.

PubMed

Chakraborty, Sandipan; Mukherjee, Barnali; Basu, Soumalee

2013-10-01

Human islet amyloid polypeptide (hIAPP) is highly amyloidogenic, whereas its homologs in rodents are non-amyloidogenic. This observed non-amyloidogenecity of rodent IAPP has been attributed to substitutions by proline in a region of IAPP that forms the core of the fibril. By employing molecular dynamics simulation, we have analyzed effects of position-specific proline substitution on amyloidogenesis of the core region of the hIAPP fibril (22-28). We depict that substitution to proline at the 25th position is primarily responsible for the loss of amyloidogenecity of the peptide. In addition, 25th and 26th double mutation to proline and valine has been observed to show significant fibril destabilizing ability. On the contrary, substitution at 28th position to proline has the least ability to destabilize the amyloid fibril. Results obtained from this study are particularly important to design variants of the existing antihyperglycemic drug with minimalistic mutation approach for use in patients with diabetes. © 2013 John Wiley & Sons A/S.

A universal method for detection of amyloidogenic misfolded proteins.

PubMed

Yam, Alice Y; Wang, Xuemei; Gao, Carol Man; Connolly, Michael D; Zuckermann, Ronald N; Bleu, Thieu; Hall, John; Fedynyshyn, Joseph P; Allauzen, Sophie; Peretz, David; Salisbury, Cleo M

2011-05-24

Diseases associated with the misfolding of endogenous proteins, such as Alzheimer's disease and type II diabetes, are becoming increasingly prevalent. The pathophysiology of these diseases is not totally understood, but mounting evidence suggests that the misfolded protein aggregates themselves may be toxic to cells and serve as key mediators of cell death. As such, an assay that can detect aggregates in a sensitive and selective fashion could provide the basis for early detection of disease, before cellular damage occurs. Here we report the evolution of a reagent that can selectively capture diverse misfolded proteins by interacting with a common supramolecular feature of protein aggregates. By coupling this enrichment tool with protein specific immunoassays, diverse misfolded proteins and sub-femtomole amounts of oligomeric aggregates can be detected in complex biological matrices. We anticipate that this near-universal approach for quantitative misfolded protein detection will become a useful research tool for better understanding amyloidogenic protein pathology as well as serve as the basis for early detection of misfolded protein diseases.

A de novo designed 11 kDa polypeptide: model for amyloidogenic intrinsically disordered proteins.

PubMed

Topilina, Natalya I; Ermolenkov, Vladimir V; Sikirzhytski, Vitali; Higashiya, Seiichiro; Lednev, Igor K; Welch, John T

2010-07-01

A de novo polypeptide GH(6)[(GA)(3)GY(GA)(3)GE](8)GAH(6) (YE8) has a significant number of identical weakly interacting beta-strands with the turns and termini functionalized by charged amino acids to control polypeptide folding and aggregation. YE8 exists in a soluble, disordered form at neutral pH but is responsive to changes in pH and ionic strength. The evolution of YE8 secondary structure has been successfully quantified during all stages of polypeptide fibrillation by deep UV resonance Raman (DUVRR) spectroscopy combined with other morphological, structural, spectral, and tinctorial characterization. The YE8 folding kinetics at pH 3.5 are strongly dependent on polypeptide concentration with a lag phase that can be eliminated by seeding with a solution of folded fibrillar YE8. The lag phase of polypeptide folding is concentration dependent leading to the conclusion that beta-sheet folding of the 11-kDa amyloidogenic polypeptide is completely aggregation driven.

γ-Secretase Modulators and APH1 Isoforms Modulate γ-Secretase Cleavage but Not Position of ε-Cleavage of the Amyloid Precursor Protein (APP).

PubMed

Lessard, Christian B; Cottrell, Barbara A; Maruyama, Hiroko; Suresh, Suraj; Golde, Todd E; Koo, Edward H

2015-01-01

The relative increase in Aβ42 peptides from familial Alzheimer disease (FAD) linked APP and PSEN mutations can be related to changes in both ε-cleavage site utilization and subsequent step-wise cleavage. Cleavage at the ε-site releases the amyloid precursor protein (APP) intracellular domain (AICD), and perturbations in the position of ε-cleavage are closely associated with changes in the profile of amyloid β-protein (Aβ) species that are produced and secreted. The mechanisms by which γ-secretase modulators (GSMs) or FAD mutations affect the various γ-secretase cleavages to alter the generation of Aβ peptides have not been fully elucidated. Recent studies suggested that GSMs do not modulate ε-cleavage of APP, but the data were derived principally from recombinant truncated epitope tagged APP substrate. Here, using full length APP from transfected cells, we investigated whether GSMs modify the ε-cleavage of APP under more native conditions. Our results confirmed the previous findings that ε-cleavage is insensitive to GSMs. In addition, fenofibrate, an inverse GSM (iGSM), did not alter the position or kinetics of ε-cleavage position in vitro. APH1A and APH1B, a subunit of the γ-secretase complex, also modulated Aβ42/Aβ40 ratio without any alterations in ε-cleavage, a result in contrast to what has been observed with PS1 and APP FAD mutations. Consequently, GSMs and APH1 appear to modulate γ-secretase activity and Aβ42 generation by altering processivity but not ε-cleavage site utilization.

Nutrient Losses from Non-Point Sources or from Unidentified Point Sources? Application Examples of the Smartphone Based Nitrate App.

NASA Astrophysics Data System (ADS)

Rozemeijer, J.; Ekkelenkamp, R.; van der Zaan, B.

2017-12-01

In 2016 Deltares launched the free to use Nitrate App which accurately reads and interprets nitrate test strips. The app directly displays the measured concentration and gives the option to share the result. Shared results are visualised in map functionality within the app and online. Since its introduction we've been seeing an increasing number of nitrate app applications. In this presentation we show some unanticipated types of application. The Nitrate App was originally intended to enable farmers to measure nitrate concentrations on their own farms. This may encourage farmers to talk to specialists about the right nutrient best management practices (BMP's) for their farm. Several groups of farmers have recently started to apply the Nitrate App and to discuss their results with each other and with the authorities. Nitrate concentration routings in catchments have proven to be another useful application. Within a day a person can generate a catchment scale nitrate concentration map identifying nitrate loss hotspots. In several routings in agricultural catchments clear point sources were found, for example at small scale manure processing plants. These routings proved that the Nitrate App can help water managers to target conservation practices more accurately to areas with the highest nitrate concentrations and loads. Other current applications are the screening of domestic water wells in California, the collection of extra measurements (also pH and NH4) in the National Monitoring Network for the Evaluation of the Manure Policy in the Netherlands, and several educational initiatives in cooperation with schools and universities.

Photo dynamics of BLUF domain mutant H44R of AppA from Rhodobacter sphaeroides

NASA Astrophysics Data System (ADS)

Zirak, P.; Penzkofer, A.; Hegemann, P.; Mathes, T.

2007-05-01

The photo-cycle dynamics of the H44R mutant of the BLUF domain of the transcriptional anti-repressor protein AppA (AppA-H44R) from the non-sulfur anoxyphototropic purple bacterium Rhodobacter sphaeroides is studied in order to gain information on the involvement of His44 in the photo-cyclic mechanism of the AppA BLUF domain and to add information to the involved processes. The amino acid residue histidine at position 44 is replaced by arginine. A 12 nm red-shifted signalling state is formed upon blue-light excitation, while in wild-type AppA (AppA-wt) the red-shift is 16 nm. The recovery to the receptor dark state is approximately a factor of 2.5 faster ( τrec ≈ 6.5 min) than the recovery of the wild-type counterpart. Extended light exposure of the mutant causes photo-degradation of flavin (mainly free flavin conversion to lumichrome and re-equilibration between free and non-covalently bound flavin) and protein aggregation (showing up as light scattering). No photo-degradation was observed for AppA-wt. The quantum efficiency of signalling-state formation determined by intensity dependent absorption measurements is found to be ϕs ≈ 0.3 (for AppA-wt: ϕs ≈ 0.24). A two-component single-exponential fluorescence relaxation was observed, which is interpreted as fast fluorescence quenching to an equilibrium value by photo-induced electron transfer followed by slower fluorescence decay due to charge recombination. Based on the experimental findings, an extended photo-cycle model for BLUF domains is proposed.

Development of 'Twazon': An Arabic App for Weight Loss.

PubMed

Alnasser, Aroub; Sathiaseelan, Arjuna; Al-Khalifa, Abdulrahman; Marais, Debbi

2016-05-16

Weight gain and its related illnesses have become a major public health issue across the world, with Saudi Arabia and other Gulf countries seeing dramatic increases in obesity and overweight, and yet there is very little information on how to intervene with this demographic due to cultural and linguistic barriers. As the use of smartphones and apps has also increased in the region, information communication technologies could be a cost-effective means of facilitating the delivery of behavior-modification interventions directly to the target population. Although there are existing apps that offer lifestyle-modification tools, they do not give consideration to the evidence-based practices for weight management. This offers an opportunity to create an Arabic language weight loss app that offers localized content and adheres to evidence-informed practices that are needed for effective weight loss. This paper describes the process of developing an Arabic weight loss app designed to facilitate the modification of key nutritional and physical activity behaviors among Saudi adults, while taking into consideration cultural norms. The development of the Twazon app involved: (1) reviewing all available Arabic weight loss apps and compared with evidence-based practices for weight loss, (2) conducting a qualitative study with overweight and obese Saudi women to ascertain their preferences, (3) selecting which behavioral change strategies and guidelines to be used in the app, (4) creating the Saudi Food Database, (5) deciding on graphic design for both iPhone operating system and Android platforms, including user interface, relational database, and programming code, and (6) testing the beta version of the app with health professionals and potential users. The Twazon app took 23 months to develop and included the compilation of an original Saudi Food database. Eight subjects gave feedback regarding the content validity and usability of the app and its features during a pilot study. The predominant issue among the group was the lack of information explaining how to use the app. This has since been resolved through the implementation of a tutorial. No other changes were required to be made. Information communication technologies, such as smartphone apps, may be an effective tool for facilitating the modification of unhealthy lifestyle habits in Saudi; however, consideration must be given to the target population, cultural norms, and changing trends in the global market. The effectiveness of the app will be better determined during a 6-month intervention with 200 overweight and obese Saudi women.

AppEEARS: A Simple Tool that Eases Complex Data Integration and Visualization Challenges for Users

NASA Astrophysics Data System (ADS)

Maiersperger, T.

2017-12-01

The Application for Extracting and Exploring Analysis-Ready Samples (AppEEARS) offers a simple and efficient way to perform discovery, processing, visualization, and acquisition across large quantities and varieties of Earth science data. AppEEARS brings significant value to a very broad array of user communities by 1) significantly reducing data volumes, at-archive, based on user-defined space-time-variable subsets, 2) promoting interoperability across a wide variety of datasets via format and coordinate reference system harmonization, 3) increasing the velocity of both data analysis and insight by providing analysis-ready data packages and by allowing interactive visual exploration of those packages, and 4) ensuring veracity by making data quality measures more apparent and usable and by providing standards-based metadata and processing provenance. Development and operation of AppEEARS is led by the National Aeronautics and Space Administration (NASA) Land Processes Distributed Active Archive Center (LP DAAC). The LP DAAC also partners with several other archives to extend the capability across a larger federation of geospatial data providers. Over one hundred datasets are currently available, covering a diversity of variables including land cover, population, elevation, vegetation indices, and land surface temperature. Many hundreds of users have already used this new web-based capability to make the complex tasks of data integration and visualization much simpler and more efficient.

Development of an IOS App Using Situated Learning, Communities of Practice, and Augmented Reality for Autism Spectrum Disorder

ERIC Educational Resources Information Center

Clarkson, Jessica

2014-01-01

This paper presents the development process and framework used to construct a transportation app that uses situated learning, augmented reality, and communities of practice. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that can cause social impairments as well as the limit the potential for the individual to achieve independence…

Exploring Learning Performance toward Cognitive Approaches of a Virtual Companion System in LINE App for m-Learning

ERIC Educational Resources Information Center

Hsieh, Sheng-Wen; Wu, Min-Ping

2013-01-01

This paper used a Virtual Companion System (VCS) to examine how specific design variables within virtual learning companion affect the learning process of learners as defined by the cognitive continuum of field-dependent, field-independent and field-mixed learners in LINE app for m-learning. The data were collected from 198 participants in a…

Online thesis guidance management information system

NASA Astrophysics Data System (ADS)

Nasution, T. H.; Pratama, F.; Tanjung, K.; Siregar, I.; Amalia, A.

2018-03-01

The development of internet technology in education is still not maximized, especially in the process of thesis guidance between students and lecturers. Difficulties met the lecturers to help students during thesis guidance is the limited communication time and the compatibility of schedule between students and lecturer. To solve this problem, we designed an online thesis guidance management information system that helps students and lecturers to do thesis tutoring process anytime, anywhere. The system consists of a web-based admin app for usage management and an android-based app for students and lecturers.

Smartphone Analytics: Mobilizing the Lab into the Cloud for Omic-Scale Analyses.

PubMed

Montenegro-Burke, J Rafael; Phommavongsay, Thiery; Aisporna, Aries E; Huan, Tao; Rinehart, Duane; Forsberg, Erica; Poole, Farris L; Thorgersen, Michael P; Adams, Michael W W; Krantz, Gregory; Fields, Matthew W; Northen, Trent R; Robbins, Paul D; Niedernhofer, Laura J; Lairson, Luke; Benton, H Paul; Siuzdak, Gary

2016-10-04

Active data screening is an integral part of many scientific activities, and mobile technologies have greatly facilitated this process by minimizing the reliance on large hardware instrumentation. In order to meet with the increasingly growing field of metabolomics and heavy workload of data processing, we designed the first remote metabolomic data screening platform for mobile devices. Two mobile applications (apps), XCMS Mobile and METLIN Mobile, facilitate access to XCMS and METLIN, which are the most important components in the computer-based XCMS Online platforms. These mobile apps allow for the visualization and analysis of metabolic data throughout the entire analytical process. Specifically, XCMS Mobile and METLIN Mobile provide the capabilities for remote monitoring of data processing, real time notifications for the data processing, visualization and interactive analysis of processed data (e.g., cloud plots, principle component analysis, box-plots, extracted ion chromatograms, and hierarchical cluster analysis), and database searching for metabolite identification. These apps, available on Apple iOS and Google Android operating systems, allow for the migration of metabolomic research onto mobile devices for better accessibility beyond direct instrument operation. The utility of XCMS Mobile and METLIN Mobile functionalities was developed and is demonstrated here through the metabolomic LC-MS analyses of stem cells, colon cancer, aging, and bacterial metabolism.

Smartphone Analytics: Mobilizing the Lab into the Cloud for Omic-Scale Analyses

PubMed Central

2016-01-01

Active data screening is an integral part of many scientific activities, and mobile technologies have greatly facilitated this process by minimizing the reliance on large hardware instrumentation. In order to meet with the increasingly growing field of metabolomics and heavy workload of data processing, we designed the first remote metabolomic data screening platform for mobile devices. Two mobile applications (apps), XCMS Mobile and METLIN Mobile, facilitate access to XCMS and METLIN, which are the most important components in the computer-based XCMS Online platforms. These mobile apps allow for the visualization and analysis of metabolic data throughout the entire analytical process. Specifically, XCMS Mobile and METLIN Mobile provide the capabilities for remote monitoring of data processing, real time notifications for the data processing, visualization and interactive analysis of processed data (e.g., cloud plots, principle component analysis, box-plots, extracted ion chromatograms, and hierarchical cluster analysis), and database searching for metabolite identification. These apps, available on Apple iOS and Google Android operating systems, allow for the migration of metabolomic research onto mobile devices for better accessibility beyond direct instrument operation. The utility of XCMS Mobile and METLIN Mobile functionalities was developed and is demonstrated here through the metabolomic LC-MS analyses of stem cells, colon cancer, aging, and bacterial metabolism. PMID:27560777

Smartphone Analytics: Mobilizing the Lab into the Cloud for Omic-Scale Analyses

DOE PAGES

Montenegro-Burke, J. Rafael; Phommavongsay, Thiery; Aisporna, Aries E.; ...

2016-08-25

Active data screening is an integral part of many scientific activities, and mobile technologies have greatly facilitated this process by minimizing the reliance on large hardware instrumentation. In order to meet with the increasingly growing field of metabolomics and heavy workload of data processing, we designed the first remote metabolomic data screening platform for mobile devices. Two mobile applications (apps), XCMS Mobile and METLIN Mobile, facilitate access to XCMS and METLIN, which are the most important components in the computer-based XCMS Online platforms. These mobile apps allow for the visualization and analysis of metabolic data throughout the entire analytical process.more » Specifically, XCMS Mobile and METLIN Mobile provide the capabilities for remote monitoring of data processing, real time notifications for the data processing, visualization and interactive analysis of processed data (e.g., cloud plots, principle component analysis, box-plots, extracted ion chromatograms, and hierarchical cluster analysis), and database searching for metabolite identification. These apps, available on Apple iOS and Google Android operating systems, allow for the migration of metabolomic research onto mobile devices for better accessibility beyond direct instrument operation. The utility of XCMS Mobile and METLIN Mobile functionalities was developed and is demonstrated here through the metabolomic LC-MS analyses of stem cells, colon cancer, aging, and bacterial metabolism.« less

Smartphone Analytics: Mobilizing the Lab into the Cloud for Omic-Scale Analyses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Montenegro-Burke, J. Rafael; Phommavongsay, Thiery; Aisporna, Aries E.

Active data screening is an integral part of many scientific activities, and mobile technologies have greatly facilitated this process by minimizing the reliance on large hardware instrumentation. In order to meet with the increasingly growing field of metabolomics and heavy workload of data processing, we designed the first remote metabolomic data screening platform for mobile devices. Two mobile applications (apps), XCMS Mobile and METLIN Mobile, facilitate access to XCMS and METLIN, which are the most important components in the computer-based XCMS Online platforms. These mobile apps allow for the visualization and analysis of metabolic data throughout the entire analytical process.more » Specifically, XCMS Mobile and METLIN Mobile provide the capabilities for remote monitoring of data processing, real time notifications for the data processing, visualization and interactive analysis of processed data (e.g., cloud plots, principle component analysis, box-plots, extracted ion chromatograms, and hierarchical cluster analysis), and database searching for metabolite identification. These apps, available on Apple iOS and Google Android operating systems, allow for the migration of metabolomic research onto mobile devices for better accessibility beyond direct instrument operation. The utility of XCMS Mobile and METLIN Mobile functionalities was developed and is demonstrated here through the metabolomic LC-MS analyses of stem cells, colon cancer, aging, and bacterial metabolism.« less

A study on interaction App platform between expert knowledge and community applied on disaster education

NASA Astrophysics Data System (ADS)

Ruljigaljig, T.; Huang, M. L.

2015-12-01

This study development interface for Mobile Application (App) use cloud technology, Web 2.0 and online community of technology to build the Environmental-Geological Disaster Network(EDN). The interaction App platform between expert knowledge and community is developed as a teaching tool, which bases on the open data released by Central Geological Survey. The APP can through Augmented Reality technology to potential hazards position through the camera lens, the real show in real-world environment. The interaction with experts in the community to improve the general public awareness of disaster. Training people to record the occurrence of geological disasters precursor, thereby awakened their to natural disaster consciousness and attention.General users obtain real-time information during travel, mountaineering and teaching process. Using App platform to upload and represent the environmental geological disaster data collected by themselves. It is expected that by public joint the open platform can accumulate environmental geological disaster data effectively, quickly, extensively and correctly. The most important thing of this study is rooting the concept of disaster prevention, reduction, and avoidance through public participation.

MyShake - A smartphone app to detect earthquake

NASA Astrophysics Data System (ADS)

Kong, Q.; Allen, R. M.; Schreier, L.; Kwon, Y. W.

2015-12-01

We designed an android app that harnesses the accelerometers in personal smartphones to record earthquake-shaking data for research, hazard information and warnings. The app has the function to distinguish earthquake shakings from daily human activities based on the different patterns behind the movements. It also can be triggered by the traditional earthquake early warning (EEW) system to record for a certain amount of time to collect earthquake data. When the app is triggered by the earthquake-like movements, it sends the trigger information back to our server which contains time and location of the trigger, at the same time, it stores the waveform data on local phone first, and upload to our server later. Trigger information from multiple phones will be processed in real time on the server to find the coherent signal to confirm the earthquakes. Therefore, the app provides the basis to form a smartphone seismic network that can detect earthquake and even provide warnings. A planned public roll-out of MyShake could collect millions of seismic recordings for large earthquakes in many regions around the world.

The Space Apps Challenge: Using Open Innovation Competitions to Engage The Public in the Scientific Process

NASA Astrophysics Data System (ADS)

Gupta, S. S.

2016-12-01

NASA's Space Apps Challenge encourages innovation, creativity and collaborative problem solving by gathering coders, builders, artists, designers, and storytellers in a 48-hour hackathon. Open Innovation competitions such as the Space Apps Challenge bring the scientific world to members of the public, regardless of age, experience, credentials, or expertise. In the past five years, this model of public engagement has been widely employed by government, nonprofit and academic institutions, allowing the building of partnerships between the scientific community and the individuals and communities they serve. Furthermore, advances in technology and challenge models have lowered the barriers and costs to scientific collaboration with and for the public. NASA's Space Apps Challenge, structured as a competition seeking solutions from the public to posed problems, brings together teams and forges collaborations between individuals and groups who would otherwise have never worked together for a short but high intensity problem solving session, Space Apps has has created a pathway to public engagement and innovation that is often faster, cheaper, and more impactful than traditional approaches.

BIDS apps: Improving ease of use, accessibility, and reproducibility of neuroimaging data analysis methods

PubMed Central

Auer, Tibor; Churchill, Nathan W.; Flandin, Guillaume; Guntupalli, J. Swaroop; Raffelt, David; Quirion, Pierre-Olivier; Smith, Robert E.; Strother, Stephen C.; Varoquaux, Gaël

2017-01-01

The rate of progress in human neurosciences is limited by the inability to easily apply a wide range of analysis methods to the plethora of different datasets acquired in labs around the world. In this work, we introduce a framework for creating, testing, versioning and archiving portable applications for analyzing neuroimaging data organized and described in compliance with the Brain Imaging Data Structure (BIDS). The portability of these applications (BIDS Apps) is achieved by using container technologies that encapsulate all binary and other dependencies in one convenient package. BIDS Apps run on all three major operating systems with no need for complex setup and configuration and thanks to the comprehensiveness of the BIDS standard they require little manual user input. Previous containerized data processing solutions were limited to single user environments and not compatible with most multi-tenant High Performance Computing systems. BIDS Apps overcome this limitation by taking advantage of the Singularity container technology. As a proof of concept, this work is accompanied by 22 ready to use BIDS Apps, packaging a diverse set of commonly used neuroimaging algorithms. PMID:28278228

A lattice protein with an amyloidogenic latent state: stability and folding kinetics.

PubMed

Palyanov, Andrey Yu; Krivov, Sergei V; Karplus, Martin; Chekmarev, Sergei F

2007-03-15

We have designed a model lattice protein that has two stable folded states, the lower free energy native state and a latent state of somewhat higher energy. The two states have a sizable part of their structures in common (two "alpha-helices") and differ in the content of "alpha-helices" and "beta-strands" in the rest of their structures; i.e. for the native state, this part is alpha-helical, and for the latent state it is composed of beta-strands. Thus, the lattice protein free energy surface mimics that of amyloidogenic proteins that form well organized fibrils under appropriate conditions. A Go-like potential was used and the folding process was simulated with a Monte Carlo method. To gain insight into the equilibrium free energy surface and the folding kinetics, we have combined standard approaches (reduced free energy surfaces, contact maps, time-dependent populations of the characteristic states, and folding time distributions) with a new approach. The latter is based on a principal coordinate analysis of the entire set of contacts, which makes possible the introduction of unbiased reaction coordinates and the construction of a kinetic network for the folding process. The system is found to have four characteristic basins, namely a semicompact globule, an on-pathway intermediate (the bifurcation basin), and the native and latent states. The bifurcation basin is shallow and consists of the structure common to the native and latent states, with the rest disorganized. On the basis of the simulation results, a simple kinetic model describing the transitions between the characteristic states was developed, and the rate constants for the essential transitions were estimated. During the folding process the system dwells in the bifurcation basin for a relatively short time before it proceeds to the native or latent state. We suggest that such a bifurcation may occur generally for proteins in which native and latent states have a sizable part of their structures in common. Moreover, there is the possibility of introducing changes in the system (e.g., mutations), which guide the system toward the native or misfolded state.

Exploring the structural diversity in inhibitors of α-synuclein amyloidogenic folding, aggregation and neurotoxicity

NASA Astrophysics Data System (ADS)

Das, Sukanya; Pukala, Tara L.; Smid, Scott D.

2018-05-01

Aggregation of α-Synuclein (αS) protein to amyloid fibrils is a neuropathological hallmark of Parkinson’s disease (PD). Growing evidence suggests that extracellular αS aggregation plays a pivotal role in neurodegeneration found in PD in addition to the intracellular αS aggregates in Lewy bodies (LB). Here, we identified and compared a diverse set of molecules capable of mitigating protein aggregation and exogenous toxicity of αSA53T, a more aggregation-prone αS mutant found in familial PD. For the first time, we investigated the αS anti-amyloid activity of semi-synthetic flavonoid 2', 3', 4' trihydroxyflavone or 2-D08, which was compared with natural flavones myricetin and transilitin, as well as such structurally diverse polyphenols as honokiol and punicalagin. Additionally, two novel synthetic compounds with a dibenzyl imidazolidine scaffold, Compound 1 and Compound 2, were also investigated as they exhibited favourable binding with αSA53T. All seven compounds inhibited αSA53T aggregation as demonstrated by Thioflavin T fluorescence assays, with modified fibril morphology observed by transmission electron microscopy. Ion mobility-mass spectrometry (IM-MS) was used to monitor the structural conversion of native αSA53T into amyloidogenic conformations and all seven compounds preserved the native unfolded conformations of αSA53T following 48 hrs incubation. The presence of each test compound in a 1:2 molar ratio was also shown to inhibit the neurotoxicity of preincubated αSA53T using phaeochromocytoma (PC12) cell viability assays. Among the seven tested compounds 2-D08, honokiol and the synthetic Compound 2 demonstrated the highest inhibition of aggregation, coupled with neuroprotection from preincubated αSA53T in vitro. Molecular docking predicted that all compounds bound near the lysine-rich region of the N-terminus of αSA53T, where the flavonoids and honokiol predominantly interacted with Lys 23. Overall, these findings highlight that i) restricted vicinal trihydroxylation in the flavone B-ring is more effective in stabilizing the native αS conformations, thus blocking amyloidogenic aggregation, than dihydroxylation in both A and B-ring, and ii) honokiol, punicalagin and the synthetic imidazolidine Compound 2 also inhibit αS amyloidogenic aggregation by stabilizing its native conformations. This diverse set of molecules acting on a singular pathological target with predicted binding to αSA53T in the folding-prone N-terminal region may contribute towards novel drug-design for PD.

Exploring the Structural Diversity in Inhibitors of α-Synuclein Amyloidogenic Folding, Aggregation, and Neurotoxicity

PubMed Central

Das, Sukanya; Pukala, Tara L.; Smid, Scott D.

2018-01-01

Aggregation of α-Synuclein (αS) protein to amyloid fibrils is a neuropathological hallmark of Parkinson's disease (PD). Growing evidence suggests that extracellular αS aggregation plays a pivotal role in neurodegeneration found in PD in addition to the intracellular αS aggregates in Lewy bodies (LB). Here, we identified and compared a diverse set of molecules capable of mitigating protein aggregation and exogenous toxicity of αSA53T, a more aggregation-prone αS mutant found in familial PD. For the first time, we investigated the αS anti-amyloid activity of semi-synthetic flavonoid 2′, 3′, 4′ trihydroxyflavone or 2-D08, which was compared with natural flavones myricetin and transilitin, as well as such structurally diverse polyphenols as honokiol and punicalagin. Additionally, two novel synthetic compounds with a dibenzyl imidazolidine scaffold, Compound 1 and Compound 2, were also investigated as they exhibited favorable binding with αSA53T. All seven compounds inhibited αSA53T aggregation as demonstrated by Thioflavin T fluorescence assays, with modified fibril morphology observed by transmission electron microscopy. Ion mobility-mass spectrometry (IM-MS) was used to monitor the structural conversion of native αSA53T into amyloidogenic conformations and all seven compounds preserved the native unfolded conformations of αSA53T following 48 h incubation. The presence of each test compound in a 1:2 molar ratio was also shown to inhibit the neurotoxicity of preincubated αSA53T using phaeochromocytoma (PC12) cell viability assays. Among the seven tested compounds 2-D08, honokiol, and the synthetic Compound 2 demonstrated the highest inhibition of aggregation, coupled with neuroprotection from preincubated αSA53T in vitro. Molecular docking predicted that all compounds bound near the lysine-rich region of the N-terminus of αSA53T, where the flavonoids and honokiol predominantly interacted with Lys 23. Overall, these findings highlight that (i) restricted vicinal trihydroxylation in the flavone B-ring is more effective in stabilizing the native αS conformations, thus blocking amyloidogenic aggregation, than dihydroxylation aggregation in both A and B-ring, and (ii) honokiol, punicalagin, and the synthetic imidazolidine Compound 2 also inhibit αS amyloidogenic aggregation by stabilizing its native conformations. This diverse set of molecules acting on a singular pathological target with predicted binding to αSA53T in the folding-prone N-terminal region may contribute toward novel drug-design for PD. PMID:29888220

Secreted Amyloid β-Proteins in a Cell Culture Model Include N-Terminally Extended Peptides That Impair Synaptic Plasticity

PubMed Central

2014-01-01

Evidence for a central role of amyloid β-protein (Aβ) in the genesis of Alzheimer’s disease (AD) has led to advanced human trials of Aβ-lowering agents. The “amyloid hypothesis” of AD postulates deleterious effects of small, soluble forms of Aβ on synaptic form and function. Because selectively targeting synaptotoxic forms of soluble Aβ could be therapeutically advantageous, it is important to understand the full range of soluble Aβ derivatives. We previously described a Chinese hamster ovary (CHO) cell line (7PA2 cells) that stably expresses mutant human amyloid precursor protein (APP). Here, we extend this work by purifying an sodium dodecyl sulfate (SDS)-stable, ∼8 kDa Aβ species from the 7PA2 medium. Mass spectrometry confirmed its identity as a noncovalently bonded Aβ40 homodimer that impaired hippocampal long-term potentiation (LTP) in vivo. We further report the detection of Aβ-containing fragments of APP in the 7PA2 medium that extend N-terminal from Asp1 of Aβ. These N-terminally extended Aβ-containing monomeric fragments are distinct from soluble Aβ oligomers formed from Aβ1-40/42 monomers and are bioactive synaptotoxins secreted by 7PA2 cells. Importantly, decreasing β-secretase processing of APP elevated these alternative synaptotoxic APP fragments. We conclude that certain synaptotoxic Aβ-containing species can arise from APP processing events N-terminal to the classical β-secretase cleavage site. PMID:24840308

Smartphone Applications with Sensors Used in a Tertiary Hospital—Current Status and Future Challenges

PubMed Central

Park, Yu Rang; Lee, Yura; Lee, Guna; Lee, Jae Ho; Shin, Soo-Yong

2015-01-01

Smartphones have been widely used recently to monitor heart rate and activity, since they have the necessary processing power, non-invasive and cost-effective sensors, and wireless communication capabilities. Consequently, healthcare applications (apps) using smartphone-based sensors have been highlighted for non-invasive physiological monitoring. In addition, several healthcare apps have received FDA clearance. However, in spite of their potential, healthcare apps with smartphone-based sensors are mostly used outside of hospitals and have not been widely adopted for patient care in hospitals until recently. In this paper, we describe the experience of using smartphone apps with sensors in a large medical center in Korea. Among >20 apps developed in our medical center, four were extensively analyzed (“My Cancer Diary”, “Point-of-Care HIV Check”, “Blood Culture” and “mAMIS”), since they use smartphone-based sensors such as the camera and barcode reader to enter data into the electronic health record system. By analyzing the usage patterns of these apps for data entry with sensors, the current limitations of smartphone-based sensors in a clinical setting, hurdles against adoption in the medical center, benefits of smartphone-based sensors and potential future research directions could be evaluated. PMID:25923933

Formative research to develop a lifestyle application (app) for African American breast cancer survivors

PubMed Central

Smith, Selina A.; Whitehead, Mary S.; Sheats, Joyce Q.; Fontenot, Brittney; Alema-Mensah, Ernest; Ansa, Benjamin

2016-01-01

Background There is a proliferation of lifestyle-oriented mobile technologies; however, few have targeted users. Through intervention mapping, investigators and community partners completed Steps 1–3 (needs assessment, formulation of change objectives, and selection of theory-based methods) of a process to develop a mobile cancer prevention application (app) for cancer prevention. The aim of this qualitative study was to complete Step 4 (intervention development) by eliciting input from African American (AA) breast cancer survivors (BCSs) to guide app development. Methods Four focus group discussions (n=60) and three individual semi-structured interviews (n=36) were conducted with AA BCSs (40–72 years of age) to assess barriers and strategies for lifestyle change. All focus groups and interviews were recorded and transcribed verbatim. Data were analyzed with NVivo qualitative data analysis software version 10, allowing categories, themes, and patterns to emerge. Results Three categories and related themes emerged from the analysis: 1) perceptions about modifiable risk factors; 2) strategies related to adherence to cancer prevention guidelines; and 3) app components to address barriers to adherence. Participant perceptions, strategies, and recommended components guided development of the app. Conclusions For development of a mobile cancer prevention app, these findings will assist investigators in targeting features that are usable, acceptable, and accessible for AA BCSs. PMID:27583307

Implementation of a Substance Use Recovery Support Mobile Phone App in Community Settings: Qualitative Study of Clinician and Staff Perspectives of Facilitators and Barriers.

PubMed

Lord, Sarah; Moore, Sarah K; Ramsey, Alex; Dinauer, Susan; Johnson, Kimberly

2016-06-28

Research supports the effectiveness of technology-based treatment approaches for substance use disorders. These approaches have the potential to broaden the reach of evidence-based care. Yet, there is limited understanding of factors associated with implementation of technology-based care approaches in different service settings. In this study, we explored provider and staff perceptions of facilitators and barriers to implementation of a mobile phone substance use recovery support app with clients in 4 service settings. Interviews were conducted with leadership and provider stakeholders (N=12) from 4 agencies in the first year of an implementation trial of the mobile phone app. We used the Consolidated Framework for Implementation Research as the conceptual foundation for identifying facilitators and barriers to implementation. Implementation process facilitators included careful planning of all aspects of implementation before launch, engaging a dedicated team to implement and foster motivation, working collaboratively with the app development team to address technical barriers and adapt the app to meet client and agency needs, and consistently reviewing app usage data to inform progress. Implementation support strategies included training all staff to promote organization awareness about the recovery support app and emphasize its priority as a clinical care tool, encouraging clients to try the technology before committing to use, scaling rollout to clients, setting clear expectations with clients about use of the app, and using peer coaches and consistent client-centered messaging to promote engagement. Perceived compatibility of the mobile phone app with agency and client needs and readiness to implement emerged as salient agency-level implementation facilitators. Facilitating characteristics of the recovery support app itself included evidence of its impact for recovery support, perceived relative advantage of the app over usual care, the ability to adapt the app to improve client use, and its ease of use. The mobile phone itself was a strong motivation for clients to opt in to use the app in settings that provided phones. App access was limited in settings that did not provide phones owing to lack of mobile phone ownership or incompatibility of the app with clients' mobile phones. Individual differences in technology literacy and provider beliefs about substance use care either facilitated or challenged implementation. Awareness of patient needs and resources facilitated implementation, whereas external policies and regulations regarding technology use introduced barriers to implementation. The conceptually grounded facilitators and barriers identified in this study can guide systematic targeting of strategies to improve implementation of mobile phone interventions in community treatment settings. Results also inform the design of technology-based therapeutic tools. This study highlights directions for research with regard to implementation of technology-based behavioral health care approaches.

Implementation of a Substance Use Recovery Support Mobile Phone App in Community Settings: Qualitative Study of Clinician and Staff Perspectives of Facilitators and Barriers

PubMed Central

Moore, Sarah K; Ramsey, Alex; Dinauer, Susan; Johnson, Kimberly

2016-01-01

Background Research supports the effectiveness of technology-based treatment approaches for substance use disorders. These approaches have the potential to broaden the reach of evidence-based care. Yet, there is limited understanding of factors associated with implementation of technology-based care approaches in different service settings. Objectives In this study, we explored provider and staff perceptions of facilitators and barriers to implementation of a mobile phone substance use recovery support app with clients in 4 service settings. Methods Interviews were conducted with leadership and provider stakeholders (N=12) from 4 agencies in the first year of an implementation trial of the mobile phone app. We used the Consolidated Framework for Implementation Research as the conceptual foundation for identifying facilitators and barriers to implementation. Results Implementation process facilitators included careful planning of all aspects of implementation before launch, engaging a dedicated team to implement and foster motivation, working collaboratively with the app development team to address technical barriers and adapt the app to meet client and agency needs, and consistently reviewing app usage data to inform progress. Implementation support strategies included training all staff to promote organization awareness about the recovery support app and emphasize its priority as a clinical care tool, encouraging clients to try the technology before committing to use, scaling rollout to clients, setting clear expectations with clients about use of the app, and using peer coaches and consistent client-centered messaging to promote engagement. Perceived compatibility of the mobile phone app with agency and client needs and readiness to implement emerged as salient agency-level implementation facilitators. Facilitating characteristics of the recovery support app itself included evidence of its impact for recovery support, perceived relative advantage of the app over usual care, the ability to adapt the app to improve client use, and its ease of use. The mobile phone itself was a strong motivation for clients to opt in to use the app in settings that provided phones. App access was limited in settings that did not provide phones owing to lack of mobile phone ownership or incompatibility of the app with clients’ mobile phones. Individual differences in technology literacy and provider beliefs about substance use care either facilitated or challenged implementation. Awareness of patient needs and resources facilitated implementation, whereas external policies and regulations regarding technology use introduced barriers to implementation. Conclusions The conceptually grounded facilitators and barriers identified in this study can guide systematic targeting of strategies to improve implementation of mobile phone interventions in community treatment settings. Results also inform the design of technology-based therapeutic tools. This study highlights directions for research with regard to implementation of technology-based behavioral health care approaches. PMID:27352884

Popular Nutrition-Related Mobile Apps: A Feature Assessment.

PubMed

Franco, Rodrigo Zenun; Fallaize, Rosalind; Lovegrove, Julie A; Hwang, Faustina

2016-08-01

A key challenge in human nutrition is the assessment of usual food intake. This is of particular interest given recent proposals of eHealth personalized interventions. The adoption of mobile phones has created an opportunity for assessing and improving nutrient intake as they can be used for digitalizing dietary assessments and providing feedback. In the last few years, hundreds of nutrition-related mobile apps have been launched and installed by millions of users. This study aims to analyze the main features of the most popular nutrition apps and to compare their strategies and technologies for dietary assessment and user feedback. Apps were selected from the two largest online stores of the most popular mobile operating systems-the Google Play Store for Android and the iTunes App Store for iOS-based on popularity as measured by the number of installs and reviews. The keywords used in the search were as follows: calorie(s), diet, diet tracker, dietician, dietitian, eating, fit, fitness, food, food diary, food tracker, health, lose weight, nutrition, nutritionist, weight, weight loss, weight management, weight watcher, and ww calculator. The inclusion criteria were as follows: English language, minimum number of installs (1 million for Google Play Store) or reviews (7500 for iTunes App Store), relation to nutrition (ie, diet monitoring or recommendation), and independence from any device (eg, wearable) or subscription. A total of 13 apps were classified as popular for inclusion in the analysis. Nine apps offered prospective recording of food intake using a food diary feature. Food selection was available via text search or barcode scanner technologies. Portion size selection was only textual (ie, without images or icons). All nine of these apps were also capable of collecting physical activity (PA) information using self-report, the global positioning system (GPS), or wearable integrations. Their outputs focused predominantly on energy balance between dietary intake and PA. None of these nine apps offered features directly related to diet plans and motivational coaching. In contrast, the remaining four of the 13 apps focused on these opportunities, but without food diaries. One app-FatSecret-also had an innovative feature for connecting users with health professionals, and another-S Health-provided a nutrient balance score. The high number of installs indicates that there is a clear interest and opportunity for diet monitoring and recommendation using mobile apps. All the apps collecting dietary intake used the same nutrition assessment method (ie, food diary record) and technologies for data input (ie, text search and barcode scanner). Emerging technologies, such as image recognition, natural language processing, and artificial intelligence, were not identified. None of the apps had a decision engine capable of providing personalized diet advice.

[Reimbursement of health apps by the German statutory health insurance].

PubMed

Gregor-Haack, Johanna

2018-03-01

A reimbursement category for "apps" does not exist in German statutory health insurance. Nevertheless different ways for reimbursement of digital health care products or processes exist. This article provides an overview and a description of the most relevant finance and reimbursement categories for apps in German statutory health insurance. The legal qualifications and preconditions of reimbursement in the context of single contracts with one health insurance fund will be discussed as well as collective contracts with national statutory health insurance funds. The benefit of a general outline appeals especially in respect to the numerous new players and products in the health care market. The article will highlight that health apps can challenge existing legal market access and reimbursement criteria and paths. At the same time, these criteria and paths exist. In terms of a learning system, they need to be met and followed.

WhatsApp Messenger as an Adjunctive Tool for Telemedicine: An Overview

PubMed Central

2017-01-01

Background The advent of telemedicine has allowed physicians to deliver medical treatment to patients from a distance. Mobile apps such as WhatsApp Messenger, an instant messaging service, came as a novel concept in all fields of social life, including medicine. The use of instant messaging services has been shown to improve communication within medical teams by providing means for quick teleconsultation, information sharing, and starting treatment as soon as possible. Objective The aim of this study was to perform a comprehensive systematic review of present literature on the use of the WhatsApp Messenger app as an adjunctive health care tool for medical doctors. Methods Searches were performed in PubMed, EMBASE, and the Cochrane Library using the term “whatsapp*” in articles published before January 2016. A bibliography of all relevant original articles that used the WhatsApp Messenger app was created. The level of evidence of each study was determined according to the Oxford Levels of Evidence ranking system produced by the Oxford Centre for Evidence-Based Medicine. The impact and the indications of WhatsApp Messenger are discussed in order to understand the extent to which this app currently functions as an adjunctive tool for telemedicine. Results The database search identified a total of 30 studies in which the term “whatsapp*” was used. Each article’s list of references was evaluated item-by-item. After literature reviews, letters to the editor, and low-quality studies were excluded, a total of 10 studies were found to be eligible for inclusion. Of these studies, 9 had been published in the English language and 1 had been published in Spanish. Five were published by medical doctors. Conclusions The pooled data presents compelling evidence that the WhatsApp Messenger app is a promising system, whether used as a communication tool between health care professionals, as a means of communication between health care professionals and the general public, or as a learning tool for providing health care information to professionals or to the general population. However, high-quality and properly evaluated research is needed, as are improvements in descriptions of the methodology and the study processes. These improvements will allow WhatsApp Messenger to be categorically defined as an effective telemedicine tool in many different fields of health care. PMID:28733273

Lessons from the pilot of a mobile application to map assistive technology suppliers in Africa.

PubMed

Visagie, Surona J; Matter, Rebecca; Kayange, George M; Chiwaula, Mussa; Harniss, Mark; Mji, Gubela; Scheffler, Elsje

2018-01-01

A pilot project to develop and implement a mobile smartphone application (App) that tracks and maps assistive technology (AT) availability in southern Africa was launched in Botswana in 2016. The App was developed and tested through an iterative process. The concept of the App (AT-Info-Map) was well received by most stakeholders within the pilot country, and broader networks. Several technical and logistical obstacles were encountered. These included high data costs; difficulty in accessing AT information from the public healthcare sector, the largest supplier of AT; and the high human resource demand of collecting and keeping up-to-date device-level information within a complex and fragmented supply sector that spans private, public and civil society entities. The challenges were dealt with by keeping the data burden low and eliminating product-level tracking. The App design was expanded to include disability services, contextually specific AT categories and make navigation more intuitive. Long-term sustainability strategies like generating funding through advertisements on the App or supplier usage fees must be explored. Outreach and sensitisation programmes about both the App and AT in general must be intensified. The project team must continually strengthen partnerships with private and public stakeholders to ensure ongoing project engagement. The lessons learnt might be of value to others who wish to embark on initiatives in AT and/or implement Apps in health or disability in southern Africa and in low-resourced settings around the world.