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Sample records for reduce excess amyloid

  1. Nanomaterials for reducing amyloid cytotoxicity.

    PubMed

    Zhang, Min; Mao, Xiaobo; Yu, Yue; Wang, Chen-Xuan; Yang, Yan-Lian; Wang, Chen

    2013-07-26

    This review is intended to reflect the recent progress on therapeutic applications of nanomaterials in amyloid diseases. The progress on anti-amyloid functions of various nanomaterials including inorganic nanoparticles, polymeric nanoparticles, carbon nanomaterials and biomolecular aggregates, is reviewed and discussed. The main functionalization strategies for general nanoparticle modifications are reviewed for potential applications of targeted therapeutics. The interaction mechanisms between amyloid peptides and nanomaterials are discussed from the perspectives of dominant interactions and kinetics. The encapsulation of anti-amyloid drugs, targeted drug delivery, controlled drug release and drug delivery crossing blood brain barrier by application of nanomaterials would also improve the therapeutics of amyloid diseases.

  2. Matrix metalloproteinase-9 reduces islet amyloid formation by degrading islet amyloid polypeptide.

    PubMed

    Aston-Mourney, Kathryn; Zraika, Sakeneh; Udayasankar, Jayalakshmi; Subramanian, Shoba L; Green, Pattie S; Kahn, Steven E; Hull, Rebecca L

    2013-02-01

    Deposition of islet amyloid polypeptide (IAPP) as amyloid is a pathological hallmark of the islet in type 2 diabetes, which is toxic to β-cells. We previously showed that the enzyme neprilysin reduces islet amyloid deposition and thereby reduces β-cell apoptosis, by inhibiting fibril formation. Two other enzymes, matrix metalloproteinase (MMP)-2 and MMP-9, are extracellular gelatinases capable of degrading another amyloidogenic peptide, Aβ, the constituent of amyloid deposits in Alzheimer disease. We therefore investigated whether MMP-2 and MMP-9 play a role in reducing islet amyloid deposition. MMP-2 and MMP-9 mRNA were present in mouse islets but only MMP-9 activity was detectable. In an islet culture model where human IAPP (hIAPP) transgenic mouse islets develop amyloid but nontransgenic islets do not, a broad spectrum MMP inhibitor (GM6001) and an MMP-2/9 inhibitor increased amyloid formation and the resultant β-cell apoptosis. In contrast, a specific MMP-2 inhibitor had no effect on either amyloid deposition or β-cell apoptosis. Mass spectrometry demonstrated that MMP-9 degraded amyloidogenic hIAPP but not nonamyloidogenic mouse IAPP. Thus, MMP-9 constitutes an endogenous islet protease that limits islet amyloid deposition and its toxic effects via degradation of hIAPP. Because islet MMP-9 mRNA levels are decreased in type 2 diabetic subjects, islet MMP-9 activity may also be decreased in human type 2 diabetes, thereby contributing to increased islet amyloid deposition and β-cell loss. Approaches to increase islet MMP-9 activity could reduce or prevent amyloid deposition and its toxic effects in type 2 diabetes.

  3. Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity

    NASA Astrophysics Data System (ADS)

    Cheng, Pin-Nan; Liu, Cong; Zhao, Minglei; Eisenberg, David; Nowick, James S.

    2012-11-01

    The amyloid protein aggregation associated with diseases such as Alzheimer's, Parkinson's and type II diabetes (among many others) features a bewildering variety of β-sheet-rich structures in transition from native proteins to ordered oligomers and fibres. The variation in the amino-acid sequences of the β-structures presents a challenge to developing a model system of β-sheets for the study of various amyloid aggregates. Here, we introduce a family of robust β-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid β-sheet mimics (ABSMs) to antagonize the aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from the amyloid-β peptide associated with Alzheimer's disease, β2-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles.

  4. Brazilin inhibits amyloid β-protein fibrillogenesis, remodels amyloid fibrils and reduces amyloid cytotoxicity

    NASA Astrophysics Data System (ADS)

    Du, Wen-Jie; Guo, Jing-Jing; Gao, Ming-Tao; Hu, Sheng-Quan; Dong, Xiao-Yan; Han, Yi-Fan; Liu, Fu-Feng; Jiang, Shaoyi; Sun, Yan

    2015-01-01

    Soluble amyloid β-protein (Aβ) oligomers, the main neurotoxic species, are predominantly formed from monomers through a fibril-catalyzed secondary nucleation. Herein, we virtually screened an in-house library of natural compounds and discovered brazilin as a dual functional compound in both Aβ42 fibrillogenesis inhibition and mature fibril remodeling, leading to significant reduction in Aβ42 cytotoxicity. The potent inhibitory effect of brazilin was proven by an IC50 of 1.5 +/- 0.3 μM, which was smaller than that of (-)-epigallocatechin gallate in Phase III clinical trials and about one order of magnitude smaller than those of curcumin and resveratrol. Most importantly, it was found that brazilin redirected Aβ42 monomers and its mature fibrils into unstructured Aβ aggregates with some β-sheet structures, which could prevent both the primary nucleation and the fibril-catalyzed secondary nucleation. Molecular simulations demonstrated that brazilin inhibited Aβ42 fibrillogenesis by directly binding to Aβ42 species via hydrophobic interactions and hydrogen bonding and remodeled mature fibrils by disrupting the intermolecular salt bridge Asp23-Lys28 via hydrogen bonding. Both experimental and computational studies revealed a different working mechanism of brazilin from that of known inhibitors. These findings indicate that brazilin is of great potential as a neuroprotective and therapeutic agent for Alzheimer's disease.

  5. Reducing Available Soluble β-Amyloid Prevents Progression of Cerebral Amyloid Angiopathy in Transgenic Mice

    PubMed Central

    Gregory, Julia L.; Prada, Claudia M.; Fine, Sara J.; Garcia-Alloza, Monica; Betensky, Rebecca A.; Arbel-Ornath, Michal; Greenberg, Steven M.; Bacskai, Brian J.; Frosch, Matthew P.

    2012-01-01

    Cerebral amyloid angiopathy (CAA), the accumulation of β-amyloid (Aβ) in the walls of leptomeningeal and cortical blood vessels of the brain, is a major cause of intracerebral hemorrhage and cognitive impairment, and is commonly associated with Alzheimer disease (AD). CAA progression, as measured in transgenic mice by longitudinal imaging with multiphoton microscopy, occurs in a predictable linear manner. The dynamics of Aβ deposition in and clearance from vascular walls and their relationship to the concentration of Aβ in the brain is poorly understood. We manipulated Aβ levels in the brain using 2 approaches: peripheral clearance via administration of the amyloid binding “peripheral sink” protein gelsolin, and direct inhibition of its formation via administration of LY-411575, a small molecule γ-secretase inhibitor. We found that gelsolin and LY-411575 both reduced the rate of CAA progression in Tg2576 mice from untreated rates of 0.58 ± 0.15% and 0.52 ± 0.09% to 0.11 ± 0.18% (p = 0.04) and −0.17 ± 0.09% (p < 0.001) of affected vessel per day, respectively, in the absence of an immune response. CAA progression was also halted when gelsolin was combined with LY-411575 (−0.004 ± 0.10%, p < 0.003). These data suggest that CAA progression can be prevented with non-immune approaches that may reduce the availability of soluble Aβ, but without evidence of substantial amyloid clearance from vessels. PMID:23095848

  6. Amyloid fibril systems reduce, stabilize and deliver bioavailable nanosized iron

    NASA Astrophysics Data System (ADS)

    Shen, Yi; Posavec, Lidija; Bolisetty, Sreenath; Hilty, Florentine M.; Nyström, Gustav; Kohlbrecher, Joachim; Hilbe, Monika; Rossi, Antonella; Baumgartner, Jeannine; Zimmermann, Michael B.; Mezzenga, Raffaele

    2017-07-01

    Iron-deficiency anaemia (IDA) is a major global public health problem. A sustainable and cost-effective strategy to reduce IDA is iron fortification of foods, but the most bioavailable fortificants cause adverse organoleptic changes in foods. Iron nanoparticles are a promising solution in food matrices, although their tendency to oxidize and rapidly aggregate in solution severely limits their use in fortification. Amyloid fibrils are protein aggregates initially known for their association with neurodegenerative disorders, but recently described in the context of biological functions in living organisms and emerging as unique biomaterial building blocks. Here, we show an original application for these protein fibrils as efficient carriers for iron fortification. We use biodegradable amyloid fibrils from β-lactoglobulin, an inexpensive milk protein with natural reducing effects, as anti-oxidizing nanocarriers and colloidal stabilizers for iron nanoparticles. The resulting hybrid material forms a stable protein-iron colloidal dispersion that undergoes rapid dissolution and releases iron ions during acidic and enzymatic in vitro digestion. Importantly, this hybrid shows high in vivo iron bioavailability, equivalent to ferrous sulfate in haemoglobin-repletion and stable-isotope studies in rats, but with reduced organoleptic changes in foods. Feeding the rats with these hybrid materials did not result in abnormal iron accumulation in any organs, or changes in whole blood glutathione concentrations, inferring their primary safety. Therefore, these iron-amyloid fibril hybrids emerge as novel, highly effective delivery systems for iron in both solid and liquid matrices.

  7. Docosahexaenoic Acid Reduces Amyloid β Production via Multiple Pleiotropic Mechanisms*

    PubMed Central

    Grimm, Marcus O. W.; Kuchenbecker, Johanna; Grösgen, Sven; Burg, Verena K.; Hundsdörfer, Benjamin; Rothhaar, Tatjana L.; Friess, Petra; de Wilde, Martijn C.; Broersen, Laus M.; Penke, Botond; Péter, Mária; Vígh, László; Grimm, Heike S.; Hartmann, Tobias

    2011-01-01

    Alzheimer disease is characterized by accumulation of the β-amyloid peptide (Aβ) generated by β- and γ-secretase processing of the amyloid precursor protein (APP). The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) has been associated with decreased amyloid deposition and a reduced risk in Alzheimer disease in several epidemiological trials; however, the exact underlying molecular mechanism remains to be elucidated. Here, we systematically investigate the effect of DHA on amyloidogenic and nonamyloidogenic APP processing and the potential cross-links to cholesterol metabolism in vivo and in vitro. DHA reduces amyloidogenic processing by decreasing β- and γ-secretase activity, whereas the expression and protein levels of BACE1 and presenilin1 remain unchanged. In addition, DHA increases protein stability of α-secretase resulting in increased nonamyloidogenic processing. Besides the known effect of DHA to decrease cholesterol de novo synthesis, we found cholesterol distribution in plasma membrane to be altered. In the presence of DHA, cholesterol shifts from raft to non-raft domains, and this is accompanied by a shift in γ-secretase activity and presenilin1 protein levels. Taken together, DHA directs amyloidogenic processing of APP toward nonamyloidogenic processing, effectively reducing Aβ release. DHA has a typical pleiotropic effect; DHA-mediated Aβ reduction is not the consequence of a single major mechanism but is the result of combined multiple effects. PMID:21324907

  8. A subcutaneous cellular implant for passive immunization against amyloidreduces brain amyloid and tau pathologies.

    PubMed

    Lathuilière, Aurélien; Laversenne, Vanessa; Astolfo, Alberto; Kopetzki, Erhard; Jacobsen, Helmut; Stampanoni, Marco; Bohrmann, Bernd; Schneider, Bernard L; Aebischer, Patrick

    2016-05-01

    Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. Mifepristone alters amyloid precursor protein processing to preclude amyloid beta and also reduces tau pathology.

    PubMed

    Baglietto-Vargas, David; Medeiros, Rodrigo; Martinez-Coria, Hilda; LaFerla, Frank M; Green, Kim N

    2013-09-01

    Increased circulating glucocorticoids are features of both aging and Alzheimer's disease (AD), and increased glucocorticoids accelerate the accumulation of AD pathologies. Here, we analyzed the effects of the glucocorticoid receptor antagonist mifepristone (RU486) in the 3xTg-AD mouse model at an age where hippocampal damage leads to high circulating corticosterone levels. The effects of mifepristone were investigated in 3xTg-AD mice using a combination of biochemical, histological, and behavior analyses. Mifepristone treatment rescues the pathologically induced cognitive impairments and markedly reduces amyloid beta (Aβ)-load and levels, as well as tau pathologies. Analysis of amyloid precursor protein (APP) processing revealed concomitant decreases in both APP C-terminal fragments C99 and C83 and the appearance of a larger 17-kDa C-terminal fragment. Hence, mifepristone induces a novel C-terminal cleavage of APP that prevents it being cleaved by α- or β-secretase, thereby precluding Aβ generation in the central nervous system; this cleavage and the production of the 17-kDa APP fragment was generated by a calcium-dependent cysteine protease. In addition, mifepristone treatment also reduced the phosphorylation and accumulation of tau, concomitant with reductions in p25. Notably, deficits in cyclic-AMP response element-binding protein signaling were restored with the treatment. These preclinical results point to a potential therapeutic role for mifepristone as an effective treatment for AD and further highlight the impact the glucocorticoid system has as a regulator of Aβ generation. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  10. Peripherally expressed neprilysin reduces brain amyloid burden: A novel approach for treating Alzheimer’s disease

    PubMed Central

    Guan, Hanjun; Liu, Yinxing; Daily, Abigail; Police, Sara; Kim, Myung-Hee; Oddo, Salvatore; LaFerla, Frank M.; Pauly, James R.; Murphy, M. Paul; Hersh, Louis B.

    2009-01-01

    A number of therapeutic strategies for treating Alzheimer’s disease have focused on reducing amyloid burden in the brain. Amongst these approaches, the expression of amyloid β peptide (Aβ)-degrading enzymes in the brain has been shown to be effective, but to date not practical for treating patients. We report here a novel strategy for lowering amyloid burden in the brain by peripherally expressing the Aβ-degrading enzyme neprilysin on leukocytes in the 3×Tg-AD mouse model of Alzheimer’s disease. Through transplantation of lentivirus transduced bone marrow cells, the Aβ-degrading protease neprilysin was expressed on the surface of leukocytes. This peripheral neprilysin reduced soluble brain amyloid β peptide levels by ~30% and lowered the accumulation of amyloid β peptides by 50–60% when transplantation was performed at both young and early adult age. In addition, peripheral neprilysin expression reduced amyloid dependent performance deficits as measured by the Morris Water Maze. Unlike other methods designed to lower amyloid β peptide levels in blood, which cause a net increase in peptide, neprilysin expression results in the catabolism of the amyloid β peptide to small innocuous peptide fragments. These findings demonstrate that peripherally expressed neprilysin, and likely other amyloid β peptide degrading enzymes, has the potential for being utilized as a therapeutic approach to prevent and treat Alzheimer’s disease and suggest this approach should be further explored. PMID:19021293

  11. Opportunities to reduce children's excessive consumption of calories from beverages.

    PubMed

    Rader, Ryan K; Mullen, Kathy B; Sterkel, Randall; Strunk, Robert C; Garbutt, Jane M

    2014-10-01

    To describe children's consumption of sugar-sweetened beverages (SSBs) and 100% fruit juice (FJ), and identify factors that may reduce excessive consumption. A total of 830 parents of young children completed a 36-item questionnaire at the pediatricians' office. Children consumed soda (62.2%), other SSBs (61.6%), and FJ (88.2%): 26.9% exceeded the American Academy of Pediatrics' recommended daily FJ intake. 157 (18.9%) children consumed excessive calories (>200 kcal/d) from beverages (median = 292.2 kcal/d, range 203.8-2177.0 kcal/d). Risk factors for excessive calorie consumption from beverages were exceeding recommendations for FJ (odds ratio [OR] = 119.7, 95% confidence interval [CI] = 52.2-274.7), being 7 to 12 years old (OR = 4.3, 95%CI = 1.9-9.9), and having Medicaid insurance (OR = 2.6, 95%CI = 1.1-6.0). Parents would likely reduce beverage consumption if recommended by the physician (65.6%). About 1 in 5 children consumes excessive calories from soda, other SSBs and FJ, with FJ the major contributor. © The Author(s) 2014.

  12. Adeno-associated Virus Gene Therapy With Cholesterol 24-Hydroxylase Reduces the Amyloid Pathology Before or After the Onset of Amyloid Plaques in Mouse Models of Alzheimer's Disease

    PubMed Central

    Hudry, Eloise; Van Dam, Debby; Kulik, Wim; De Deyn, Peter P; Stet, Femke S; Ahouansou, Ornella; Benraiss, Abdellatif; Delacourte, André; Bougnères, Pierre; Aubourg, Patrick; Cartier, Nathalie

    2009-01-01

    The development of Alzheimer's disease (AD) is closely connected with cholesterol metabolism. Cholesterol increases the production and deposition of amyloid-β (Aβ) peptides that result in the formation of amyloid plaques, a hallmark of the pathology. In the brain, cholesterol is synthesized in situ but cannot be degraded nor cross the blood–brain barrier. The major exportable form of brain cholesterol is 24S-hydroxycholesterol, an oxysterol generated by the neuronal cholesterol 24-hydroxylase encoded by the CYP46A1 gene. We report that the injection of adeno-associated vector (AAV) encoding CYP46A1 in the cortex and hippocampus of APP23 mice before the onset of amyloid deposits markedly reduces Aβ peptides, amyloid deposits and trimeric oligomers at 12 months of age. The Morris water maze (MWM) procedure also demonstrated improvement of spatial memory at 6 months, before the onset of amyloid deposits. AAV5-wtCYP46A1 vector injection in the cortex and hippocampus of amyloid precursor protein/presenilin 1 (APP/PS) mice after the onset of amyloid deposits also reduced markedly the number of amyloid plaques in the hippocampus, and to a less extent in the cortex, 3 months after the injection. Our data demonstrate that neuronal overexpression of CYP46A1 before or after the onset of amyloid plaques significantly reduces Aβ pathology in mouse models of AD. PMID:19654569

  13. Oligovalent Amyloid-Binding Agents Reduce SEVI-Mediated Enhancement of HIV-1 Infection

    PubMed Central

    Capule, Christina C.; Brown, Caitlin; Olsen, Joanna S.; Dewhurst, Stephen; Yang, Jerry

    2012-01-01

    This paper evaluates the use of oligovalent amyloid-binding molecules as potential agents that can reduce the enhancement of HIV-1 infection in cells by SEVI fibrils. These naturally occurring amyloid fibrils found in semen have been implicated as mediators that can facilitate the attachment and internalization of HIV-1 virions to immune cells. Molecules that are capable of reducing the role of SEVI in HIV-1 infection may, therefore, represent a novel strategy to reduce the rate of sexual transmission of HIV-1 in humans. Here, we evaluated a set of synthetic, oligovalent derivatives of BTA (a known amyloid-binding molecule) for their capability to bind cooperatively to aggregated amyloid peptides and to neutralize the effects of SEVI in HIV-1 infection. We demonstrate that these BTA derivatives exhibit a general trend of increased binding to aggregated amyloids as a function of increasing valence number of the oligomer. Importantly, we find that oligomers of BTA show improved capability to reduce SEVI-mediated infection of HIV-1 in cells compared to a BTA monomer, with the pentamer exhibiting a 65-fold improvement in efficacy compared to a previously reported monomeric BTA derivative. These results, thus, support the use of amyloid-targeting molecules as potential supplements for microbicides to curb the spread of HIV-1 through sexual contact. PMID:22239120

  14. Ethanol reduces amyloid aggregation in vitro and prevents toxicity in cell lines.

    PubMed

    Ormeño, David; Romero, Fernando; López-Fenner, Julio; Avila, Andres; Martínez-Torres, Ataulfo; Parodi, Jorge

    2013-01-01

    Alzheimer's disease (AD) alters cognitive functions. A mixture of soluble β-amyloid aggregates (Aβ) are known to act as toxic agents. It has been suggested that moderate alcohol intake reduces the development of neurodegenerative diseases, but the molecular mechanisms leading to this type of prevention have been elusive. We show the ethanol effect in the generation of complex Aβ in vitro and the impact on the viability of two cell lines. The effect of ethanol on the kinetics of β-amyloid aggregation in vitro was assessed by turbimetry. Soluble- and ethanol-treated β-amyloid were added to the cell lines HEK and PC-12 to compare their effects on metabolic activity using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. In addition, we used molecular modeling to assess the impact of exposure to ethanol on the structure of β-amyloid. Exposure to soluble β-amyloid was toxic to both cell lines; however, exposing the cells to β-amyloid aggregated in 10 mmol ethanol prevented the effect. In silico modeling suggested that ethanol alters the dynamics for assembling Aβ by disrupting a critical salt bridge between residues Asp 23 and Lys 28, required for amyloid dimerization. Thus, ethanol prevented the formation of complex short (∼100 nm) Aβ, which are related to higher cell toxicity. Ethanol prevents the formation of stable Aβ dimers in vitro, thus protecting the cells maintained in culture. Accordingly, in silico modelling predicts that soluble β-amyloid molecules do not form stable multimers when exposed to ethanol. Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.

  15. Mechanisms for Reduced Excess Sludge Production in the Cannibal Process.

    PubMed

    Labelle, Marc-André; Dold, Peter L; Comeau, Yves

    2015-08-01

    Reducing excess sludge production is increasingly attractive as a result of rising costs and constraints with respect to sludge treatment and disposal. A technology in which the mechanisms remain not well understood is the Cannibal process, for which very low sludge yields have been reported. The objective of this work was to use modeling as a means to characterize excess sludge production at a full-scale Cannibal facility by providing a long sludge retention time and removing trash and grit by physical processes. The facility was characterized by using its historical data, from discussion with the staff and by conducting a sampling campaign to prepare a solids inventory and an overall mass balance. At the evaluated sludge retention time of 400 days, the sum of the daily loss of suspended solids to the effluent and of the waste activated sludge solids contributed approximately equally to the sum of solids that are wasted daily as trash and grit from the solids separation module. The overall sludge production was estimated to be 0.14 g total suspended solids produced/g chemical oxygen demand removed. The essential functions of the Cannibal process for the reduction of sludge production appear to be to remove trash and grit from the sludge by physical processes of microscreening and hydrocycloning, respectively, and to provide a long sludge retention time, which allows the slow degradation of the "unbiodegradable" influent particulate organics (XU,Inf) and the endogenous residue (XE). The high energy demand of 1.6 kWh/m³ of treated wastewater at the studied facility limits the niche of the Cannibal process to small- to medium-sized facilities in which sludge disposal costs are high but electricity costs are low.

  16. Nicotinamide Reduces Amyloid Precursor Protein and Presenilin 1 in Brain Tissues of Amyloid Beta-Tail Vein Injected Mice

    PubMed Central

    Kim, Eun Jin

    2017-01-01

    The purpose of this study is to investigate whether nicotinic acid (NA) and nicotinamide (NAM) reduce the Alzheimer disease (AD)-related gene expression in brain tissues of amyloid beta (Aβ)-injected mice. Male Crj:CD1 (ICR) mice were divided into 6 treatment groups; 1) control, 2) Aβ control, 3) Aβ + NA 20 mg/kg/day (NA20), 4) Aβ + NA40, 5) Aβ + NAM 200 mg/kg/day (NAM200), and 6) Aβ + NAM400. After 1-week acclimation period, the mice orally received NA or NAM once a day for a total of 7 successive days. On day 7, biotinylated Aβ42 was injected into mouse tail vein. At 5 hours after the injection, blood and tissues were collected. Aβ42 injection was confirmed by Western blot analysis of Aβ42 protein in brain tissue. NAM400 pre-treatment significantly reduced the gene expression of amyloid precursor protein and presenilin 1 in brain tissues. And, NAM200 and NAM400 pre-treatments significantly increased sirtuin 1 expression in brain tissues, which is accompanied by the decreased brain expression of nuclear factor kappa B by 2 doses of NAM. Increased expression of AD-related genes was attenuated by the NAM treatment, which suggests that NAM supplementation may be a potential preventive strategy against AD-related deleterious changes. PMID:28503509

  17. A behavioral intervention to reduce excessive gestational weight gain

    USDA-ARS?s Scientific Manuscript database

    Excessive gestational weight gain (GWG) is a key modifiable risk factor for negative maternal and child health. We examined the efficacy of a behavioral intervention in preventing excessive GWG. 230 participants (87.8% Caucasian, mean age= 29.1 years; second parity) completed the 36 week gestational...

  18. Study of Using Excess Stock to Reduce Naval Aviation Depot-Level Repairable Piece Part Backorders

    DTIC Science & Technology

    2016-12-01

    NAVAL POSTGRADUATE SCHOOL MONTEREY, CALIFORNIA MBA PROFESSIONAL REPORT STUDY OF USING EXCESS STOCK TO REDUCE NAVAL AVIATION... STUDY OF USING EXCESS STOCK TO REDUCE NAVAL AVIATION DEPOT-LEVEL REPAIRABLE PIECE PART BACKORDERS 5. FUNDING NUMBERS 6. AUTHOR(S) Jennifer L...unlimited. STUDY OF USING EXCESS STOCK TO REDUCE NAVAL AVIATION DEPOT-LEVEL REPAIRABLE PIECE PART BACKORDERS Jennifer L. Custard, Lieutenant

  19. Curcumin Reduces Amyloid Fibrillation of Prion Protein and Decreases Reactive Oxidative Stress

    PubMed Central

    Lin, Chi-Fen; Yu, Kun-Hua; Jheng, Cheng-Ping; Chung, Raymond; Lee, Cheng-I

    2013-01-01

    Misfolding and aggregation into amyloids of the prion protein (PrP) is responsible for the development of fatal transmissible neurodegenerative diseases. Various studies on curcumin demonstrate promise for the prevention of Alzheimer’s disease and inhibition of PrPres accumulation. To evaluate the effect of curcumin on amyloid fibrillation of prion protein, we first investigated the effect of curcumin on mouse prion protein (mPrP) in a cell-free system. Curcumin reduced the prion fibril formation significantly. Furthermore, we monitored the change in apoptosis and reactive oxygen species (ROS) level upon curcumin treatment in mouse neuroblastoma cells (N2a). Curcumin effectively rescues the cells from apoptosis and decreases the ROS level caused by subsequent co-incubation with prion amyloid fibrils. The assays in cell-free mPrP and in N2a cells of this work verified the promising effect of curcumin on the prevention of transmissible neurodegenerative diseases. PMID:25437204

  20. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease

    PubMed Central

    Wahrle, Suzanne E.; Jiang, Hong; Parsadanian, Maia; Kim, Jungsu; Li, Aimin; Knoten, Amanda; Jain, Sanjay; Hirsch-Reinshagen, Veronica; Wellington, Cheryl L.; Bales, Kelly R.; Paul, Steven M.; Holtzman, David M.

    2008-01-01

    APOE genotype is a major genetic risk factor for late-onset Alzheimer disease (AD). ABCA1, a member of the ATP-binding cassette family of active transporters, lipidates apoE in the CNS. Abca1–/– mice have decreased lipid associated with apoE and increased amyloid deposition in several AD mouse models. We hypothesized that mice overexpressing ABCA1 in the brain would have increased lipidation of apoE-containing lipoproteins and decreased amyloid deposition. To address these hypotheses, we created PrP-mAbca1 Tg mice that overexpress mouse Abca1 throughout the brain under the control of the mouse prion promoter. We bred the PrP-mAbca1 mice to the PDAPP AD mouse model, a transgenic line overexpressing a mutant human amyloid precursor protein. PDAPP/Abca1 Tg mice developed a phenotype remarkably similar to that seen in PDAPP/Apoe–/– mice: there was significantly less amyloid β-peptide (Aβ) deposition, a redistribution of Aβ to the hilus of the dentate gyrus in the hippocampus, and an almost complete absence of thioflavine S–positive amyloid plaques. Analyses of CSF from PrP-mAbca1 Tg mice and media conditioned by PrP-mAbca1 Tg primary astrocytes demonstrated increased lipidation of apoE-containing particles. These data support the conclusions that increased ABCA1-mediated lipidation of apoE in the CNS can reduce amyloid burden and that increasing ABCA1 function may have a therapeutic effect on AD. PMID:18202749

  1. Long-term dantrolene treatment reduced intraneuronal amyloid in aged Alzheimer triple transgenic mice.

    PubMed

    Wu, Zhen; Yang, Bin; Liu, Chunxia; Liang, Ge; Liu, Weixia; Pickup, Stephen; Meng, Qingcheng; Tian, Yuke; Li, Shitong; Eckenhoff, Maryellen F; Wei, Huafeng

    2015-01-01

    In this study, we investigated the long-term treatment of dantrolene on amyloid and tau neuropathology, brain volume, and cognitive function in aged triple transgenic Alzheimer (3xTg-AD) mice. Fifteen-month old 3xTg-AD mice and wild-type controls were treated with oral dantrolene (5 mg/kg) or vehicle control twice a week for 6 months. Learning and memory were examined using the Morris Water Maze at 21 and 22 months of age. After the behavioral testing, hippocampal and cortical brain volumes were calculated with magnetic resonance imaging and motor function was evaluated using the rotorod. The amyloid burden and tau neurofibrillary tangles in the hippocampus were determined using immunohistochemistry. We found that dantrolene significantly decreased the intraneuronal amyloid accumulation by as much as 76% compared with its corresponding vehicle control, together with a trend to reduce phosphorylated tau in the hippocampus. No significant differences could be detected in hippocampal or cortical brain volume, motor function or cognition among all experimental groups, indicating that the mice were still presymptomatic for Alzheimer disease. Thus, presymptomatic and long-term dantrolene treatment significantly decreased the intraneuronal amyloid burden in aged 3xTg-AD mice before significant changes in brain volume, or cognition.

  2. Amyloid reduction by amyloid-β vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer’s disease

    PubMed Central

    Wilcock, Donna M.; Gharkholonarehe, Nastaran; Van Nostrand, William E.; Davis, Judianne; Vitek, Michael P.; Colton, Carol A.

    2010-01-01

    Shown to lower amyloid deposits and improve cognition in APP transgenic mouse models, immunotherapy appears to be a promising approach for the treatment of Alzheimer’s disease (AD). Due to limitations in available animal models, however, it has been unclear whether targeting amyloid is sufficient to reduce the other pathological hallmarks of AD—namely, accumulation of pathological, non-mutated tau and neuronal loss. We have now developed two transgenic mouse models (APPSw/NOS2−/− and APPSwDI/NOS2−/−) that more closely model AD. These mice show amyloid pathology, hyperphosphorylated and aggregated normal mouse tau, significant neuron loss, and cognitive deficits. Aβ1–42 or KLH vaccinations were started in these animals at 12 months, when disease progression and cognitive decline are well underway, and continued for 4 months. Vaccinated APPSwDI/NOS2−/− mice, which have predominantly vascular amyloid pathology, showed a 30% decrease in brain Aβ and a 35–45% reduction in hyperphosphorylated tau. Neuron loss and cognitive deficits were partially reduced. In APPSw/NOS2−/− vaccinated mice, brain Aβ was reduced by 65–85% and hyperphosphorylated tau by 50–60 percent. Furthermore, neurons were completely protected, and memory deficits were fully reversed. Microhemorrhage was observed in all vaccinated APPSw/NOS2−/− mice and remains a significant adverse event associated with immunotherapy. Nevertheless, by providing evidence that reducing amyloid pathology also reduces non-mutant tau pathology and blocks neuron loss, these data support the development of amyloid-lowering therapies for disease-modifying treatment of AD. PMID:19553436

  3. Increased expression of reticulon 3 in neurons leads to reduced axonal transport of β site amyloid precursor protein-cleaving enzyme 1.

    PubMed

    Deng, Minzi; He, Wanxia; Tan, Ya; Han, Hailong; Hu, Xiangyou; Xia, Kun; Zhang, Zhuohua; Yan, Riqiang

    2013-10-18

    BACE1 is the sole enzyme responsible for cleaving amyloid precursor protein at the β-secretase site, and this cleavage initiates the generation of β-amyloid peptide (Aβ). Because amyloid precursor protein is predominantly expressed by neurons and deposition of Aβ aggregates in the human brain is highly correlated with the Aβ released at axonal terminals, we focused our investigation of BACE1 localization on the neuritic region. We show that BACE1 was not only enriched in the late Golgi, trans-Golgi network, and early endosomes but also in both axons and dendrites. BACE1 was colocalized with the presynaptic vesicle marker synaptophysin, indicating the presence of BACE1 in synapses. Because the excessive release of Aβ from synapses is attributable to an increase in amyloid deposition, we further explored whether the presence of BACE1 in synapses was regulated by reticulon 3 (RTN3), a protein identified previously as a negative regulator of BACE1. We found that RTN3 is not only localized in the endoplasmic reticulum but also in neuritic regions where no endoplasmic reticulum-shaping proteins are detected, implicating additional functions of RTN3 in neurons. Coexpression of RTN3 with BACE1 in cultured neurons was sufficient to reduce colocalization of BACE1 with synaptophysin. This reduction correlated with decreased anterograde transport of BACE1 in axons in response to overexpressed RTN3. Our results in this study suggest that altered RTN3 levels can impact the axonal transport of BACE1 and demonstrate that reducing axonal transport of BACE1 in axons is a viable strategy for decreasing BACE1 in axonal terminals and, perhaps, reducing amyloid deposition.

  4. Flavonoid-mediated presenilin-1 phosphorylation reduces Alzheimer's disease β-amyloid production

    PubMed Central

    Rezai-Zadeh, Kavon; Douglas Shytle, R; Bai, Yun; Tian, Jun; Hou, Huayan; Mori, Takashi; Zeng, Jin; Obregon, Demian; Town, Terrence; Tan, Jun

    2009-01-01

    Abstract Glycogen synthase kinase 3 (GSK-3) dysregulation is implicated in the two Alzheimer's disease (AD) pathological hallmarks: β-amyloid plaques and neurofibrillary tangles. GSK-3 inhibitors may abrogate AD pathology by inhibiting amyloidogenic γ-secretase cleavage of amyloid precursor protein (APP). Here, we report that the citrus bioflavonoid luteolin reduces amyloid-β (Aβ) peptide generation in both human ‘Swedish’ mutant APP transgene-bearing neuron-like cells and primary neurons. We also find that luteolin induces changes consistent with GSK-3 inhibition that (i) decrease amyloidogenic γ-secretase APP processing, and (ii) promote presenilin-1 (PS1) carboxyl-terminal fragment (CTF) phosphorylation. Importantly, we find GSK-3α activity is essential for both PS1 CTF phosphorylation and PS1-APP interaction. As validation of these findings in vivo, we find that luteolin, when applied to the Tg2576 mouse model of AD, decreases soluble Aβ levels, reduces GSK-3 activity, and disrupts PS1-APP association. In addition, we find that Tg2576 mice treated with diosmin, a glycoside of a flavonoid structurally similar to luteolin, display significantly reduced Aβ pathology. We suggest that GSK-3 inhibition is a viable therapeutic approach for AD by impacting PS1 phosphorylation-dependent regulation of amyloidogenesis. PMID:18410522

  5. Defense Inventory: Services Generally Have Reduced Excess Inventory, but Additional Actions Are Needed

    DTIC Science & Technology

    2015-04-01

    DEFENSE INVENTORY Services Generally Have Reduced Excess Inventory, but Additional Actions Are Needed Report to...information, including suggestions for reducing this burden, to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215... Reduced Excess Inventory, but Additional Actions Are Needed 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d

  6. Neuronal-Targeted TFEB Accelerates Lysosomal Degradation of APP, Reducing Aβ Generation and Amyloid Plaque Pathogenesis.

    PubMed

    Xiao, Qingli; Yan, Ping; Ma, Xiucui; Liu, Haiyan; Perez, Ronaldo; Zhu, Alec; Gonzales, Ernesto; Tripoli, Danielle L; Czerniewski, Leah; Ballabio, Andrea; Cirrito, John R; Diwan, Abhinav; Lee, Jin-Moo

    2015-09-02

    In AD, an imbalance between Aβ production and removal drives elevated brain Aβ levels and eventual amyloid plaque deposition. APP undergoes nonamyloidogenic processing via α-cleavage at the plasma membrane, amyloidogenic β- and γ-cleavage within endosomes to generate Aβ, or lysosomal degradation in neurons. Considering multiple reports implicating impaired lysosome function as a driver of increased amyloidogenic processing of APP, we explored the efficacy of targeting transcription factor EB (TFEB), a master regulator of lysosomal pathways, to reduce Aβ levels. CMV promoter-driven TFEB, transduced via stereotactic hippocampal injections of adeno-associated virus particles in APP/PS1 mice, localized primarily to neuronal nuclei and upregulated lysosome biogenesis. This resulted in reduction of APP protein, the α and β C-terminal APP fragments (CTFs), and in the steady-state Aβ levels in the brain interstitial fluid. In aged mice, total Aβ levels and amyloid plaque load were selectively reduced in the TFEB-transduced hippocampi. TFEB transfection in N2a cells stably expressing APP695, stimulated lysosome biogenesis, reduced steady-state levels of APP and α- and β-CTFs, and attenuated Aβ generation by accelerating flux through the endosome-lysosome pathway. Cycloheximide chase assays revealed a shortening of APP half-life with exogenous TFEB expression, which was prevented by concomitant inhibition of lysosomal acidification. These data indicate that TFEB enhances flux through lysosomal degradative pathways to induce APP degradation and reduce Aβ generation. Activation of TFEB in neurons is an effective strategy to attenuate Aβ generation and attenuate amyloid plaque deposition in AD. A key driver for AD pathogenesis is the net balance between production and clearance of Aβ, the major component of amyloid plaques. Here we demonstrate that lysosomal degradation of holo-APP influences Aβ production by limiting the availability of APP for amyloidogenic

  7. Neuronal-Targeted TFEB Accelerates Lysosomal Degradation of APP, Reducing Aβ Generation and Amyloid Plaque Pathogenesis

    PubMed Central

    Xiao, Qingli; Yan, Ping; Ma, Xiucui; Liu, Haiyan; Perez, Ronaldo; Zhu, Alec; Gonzales, Ernesto; Tripoli, Danielle L.; Czerniewski, Leah; Ballabio, Andrea; Cirrito, John R.

    2015-01-01

    In AD, an imbalance between Aβ production and removal drives elevated brain Aβ levels and eventual amyloid plaque deposition. APP undergoes nonamyloidogenic processing via α-cleavage at the plasma membrane, amyloidogenic β- and γ-cleavage within endosomes to generate Aβ, or lysosomal degradation in neurons. Considering multiple reports implicating impaired lysosome function as a driver of increased amyloidogenic processing of APP, we explored the efficacy of targeting transcription factor EB (TFEB), a master regulator of lysosomal pathways, to reduce Aβ levels. CMV promoter-driven TFEB, transduced via stereotactic hippocampal injections of adeno-associated virus particles in APP/PS1 mice, localized primarily to neuronal nuclei and upregulated lysosome biogenesis. This resulted in reduction of APP protein, the α and β C-terminal APP fragments (CTFs), and in the steady-state Aβ levels in the brain interstitial fluid. In aged mice, total Aβ levels and amyloid plaque load were selectively reduced in the TFEB-transduced hippocampi. TFEB transfection in N2a cells stably expressing APP695, stimulated lysosome biogenesis, reduced steady-state levels of APP and α- and β-CTFs, and attenuated Aβ generation by accelerating flux through the endosome-lysosome pathway. Cycloheximide chase assays revealed a shortening of APP half-life with exogenous TFEB expression, which was prevented by concomitant inhibition of lysosomal acidification. These data indicate that TFEB enhances flux through lysosomal degradative pathways to induce APP degradation and reduce Aβ generation. Activation of TFEB in neurons is an effective strategy to attenuate Aβ generation and attenuate amyloid plaque deposition in AD. SIGNIFICANCE STATEMENT A key driver for AD pathogenesis is the net balance between production and clearance of Aβ, the major component of amyloid plaques. Here we demonstrate that lysosomal degradation of holo-APP influences Aβ production by limiting the availability of

  8. Analysis of the ability of pramlintide to inhibit amyloid formation by human islet amyloid polypeptide reveals a balance between optimal recognition and reduced amyloidogenicity.

    PubMed

    Wang, Hui; Ridgway, Zachary; Cao, Ping; Ruzsicska, Bela; Raleigh, Daniel P

    2015-11-10

    The hormone human islet amyloid polypeptide (hIAPP or amylin) plays a role in glucose metabolism, but forms amyloid in the pancreas in type 2 diabetes (T2D) and is associated with β-cell death and dysfunction in the disease. Inhibitors of islet amyloid have therapeutic potential; however, there are no clinically approved inhibitors, and the mode of action of existing inhibitors is not well understood. Rat IAPP (rIAPP) differs from hIAPP at six positions, does not form amyloid, and is an inhibitor of amyloid formation by hIAPP. Five of the six differences are located within the segment of residues 20-29, and three of them are Pro residues, which are well-known disruptors of β-sheet structure. rIAPP is thus a natural example of a "β-breaker inhibitor", a molecule that combines a recognition element with an entity that inhibits β-sheet formation. Pramlintide (PM) is a peptide drug approved for use as an adjunct to insulin therapy for treatment of diabetes. PM was developed by introducing the three Pro substitutions found in rIAPP into hIAPP. Thus, it more closely resembles the human peptide than does rIAPP. Here we examine and compare the ability of rIAPP, PM, and a set of designed analogues of hIAPP to inhibit amyloid formation by hIAPP, to elucidate the factors that lead to effective peptide-based inhibitors. Our results reveal, for this class of molecules, a balance between the reduced amyloidogenicity of the inhibitory sequence on one hand and its ability to recognize hIAPP on the other.

  9. Analysis of the Ability of Pramlintide to Inhibit Amyloid Formation by Human Islet Amyloid Polypeptide Reveals a Balance between Optimum Recognition and Reduced Amyloidgenicity

    PubMed Central

    Wang, Hui; Ridgway, Zachary; Cao, Ping; Ruzsicska, Bela; Raleigh, Daniel P.

    2015-01-01

    The hormone human islet amyloid polypeptide (hIAPP or amylin) plays a role in glucose metabolism, but forms amyloid in the pancreas in type 2 diabetes (T2D) and is associated with β-cell death and dysfunction in the disease. Inhibitors of islet amyloid have therapeutic potential, however there are no clinically approved inhibitors and the mode of action of existing inhibitors is not well understood. Rat IAPP (rIAPP), differs from hIAPP at six positions, does not form amyloid and is an inhibitor of amyloid formation by hIAPP. Five of the six differences are located within residues 20-29, and three of them are Pro residues, which are well known disruptors of β-sheet structure. rIAPP is thus a natural example of a “β-breaker inhibitor”; a molecule which combines a recognition element with an entity that inhibits β-sheet formation. Pramlintide (PM) is a peptide drug approved for use as an adjunct to insulin therapy for treatment of diabetes. PM was developed by introducing the three Pro substitutions found in rIAPP into hIAPP. Thus, it more closely resembles the human peptide than does rIAPP. Here we examine and compare the ability of rIAPP, PM and a set of designed analogs of hIAPP to inhibit amyloid formation by hIAPP, in order to elucidate the factors which lead to effective peptide based inhibitors. Our results reveal, for this class of molecules, a balance between the reduced amyloidogenicity of the inhibitory sequence on the one hand and its ability to recognize hIAPP on the other. PMID:26407043

  10. Transcutaneous β-amyloid immunization reduces cerebral β-amyloid deposits without T cell infiltration and microhemorrhage

    PubMed Central

    Nikolic, William V.; Bai, Yun; Obregon, Demian; Hou, Huayan; Mori, Takashi; Zeng, Jin; Ehrhart, Jared; Shytle, R. Douglas; Giunta, Brian; Morgan, Dave; Town, Terrence; Tan, Jun

    2007-01-01

    Alzheimer's disease (AD) immunotherapy accomplished by vaccination with β-amyloid (Aβ) peptide has proved efficacious in AD mouse models. However, “active” Aβ vaccination strategies for the treatment of cerebral amyloidosis without concurrent induction of detrimental side effects are lacking. We have developed a transcutaneous (t.c.) Aβ vaccination approach and evaluated efficacy and monitored for deleterious side effects, including meningoencephalitis and microhemorrhage, in WT mice and a transgenic mouse model of AD. We demonstrate that t.c. immunization of WT mice with aggregated Aβ1–42 plus the adjuvant cholera toxin (CT) results in high-titer Aβ antibodies (mainly of the Ig G1 class) and Aβ1–42-specific splenocyte immune responses. Confocal microscopy of the t.c. immunization site revealed Langerhans cells in areas of the skin containing the Aβ1–42 immunogen, suggesting that these unique innate immune cells participate in Aβ1–42 antigen processing. To evaluate the efficacy of t.c. immunization in reducing cerebral amyloidosis, transgenic PSAPP (APPsw, PSEN1dE9) mice were immunized with aggregated Aβ1–42 peptide plus CT. Similar to WT mice, PSAPP mice showed high Aβ antibody titers. Most importantly, t.c. immunization with Aβ1–42 plus CT resulted in significant decreases in cerebral Aβ1–40,42 levels coincident with increased circulating levels of Aβ1–40,42, suggesting brain-to-blood efflux of Aβ. Reduction in cerebral amyloidosis was not associated with deleterious side effects, including brain T cell infiltration or cerebral microhemorrhage. Together, these data suggest that t.c. immunization constitutes an effective and potentially safe treatment strategy for AD. PMID:17264212

  11. Reduced aggregation and cytotoxicity of amyloid peptides by graphene oxide/gold nanocomposites prepared by pulsed laser ablation in water.

    PubMed

    Li, Jingying; Han, Qiusen; Wang, Xinhuan; Yu, Ning; Yang, Lin; Yang, Rong; Wang, Chen

    2014-11-12

    A novel and convenient method to synthesize the nanocomposites combining graphene oxides (GO) with gold nanoparticles (AuNPs) is reported and their applications to modulate amyloid peptide aggregation are demonstrated. The nanocomposites produced by pulsed laser ablation (PLA) in water show good biocompatibility and solubility. The reduced aggregation of amyloid peptides by the nanocomposites is confirmed by Thioflavin T fluorescence and atomic force microscopy. The cell viability experiments reveals that the presence of the nanocomposites can significantly reduce the cytotoxicity of the amyloid peptides. Furthermore, the depolymerization of peptide fibrils and inhibition of their cellular cytotoxicity by GO/AuNPs is also observed. These observations suggest that the nanocomposites combining GO and AuNPs have a great potential for designing new therapeutic agents and are promising for future treatment of amyloid-related diseases.

  12. Minocycline Reduces Spontaneous Hemorrhage in Mouse Models of Cerebral Amyloid Angiopathy

    PubMed Central

    Liao, Fan; Xiao, Qingli; Kraft, Andrew; Gonzales, Ernie; Perez, Ron; Greenberg, Steven M.; Holtzman, David; Lee, Jin-Moo

    2015-01-01

    Background and Purpose Cerebral Amyloid Angiopathy (CAA) is a common cause of recurrent intracerebral hemorrhage (ICH) in the elderly. Previous studies have shown that CAA induces inflammation and expression of matrix metalloproteinase-2 and -9 (gelatinases) in amyloid-laden vessels. Here, we inhibited both using minocycline in CAA mouse models to determine if spontaneous ICH could be reduced. Methods Tg2576 (n=16) and 5×FAD/ApoE4 knock-in mice (n=16), aged to 17 and 12 months, respectively, were treated with minocycline (50 mg/kg, i.p.) or saline every other day for two months. Brains were extracted and stained with X-34 (to quantify amyloid), Perl’s blue (to quantify hemorrhage), and immunostained to examined Aβ load, gliosis (GFAP, Iba-1), and vascular markers of blood-brain-barrier integrity (ZO-1 and collagen IV). Brain extracts were used to quantify mRNA for a variety of inflammatory genes. Results Minocycline treatment significantly reduced hemorrhage frequency in the brains of Tg2576 and 5×FAD/ApoE4 mice relative to the saline-treated mice, without affecting CAA load. Gliosis (GFAP and Iba-1 immunostaining), gelatinase activity, and expression of a variety of inflammatory genes (MMP-9, Nox4, CD45, S-100b, Iba-1) were also significantly reduced. Higher levels of microvascular tight junction and basal lamina proteins were found in the brains of minocycline-treated Tg2576 mice relative to saline-treated controls. Conclusions Minocycline reduced gliosis, inflammatory gene expression, gelatinase activity, and spontaneous hemorrhage in two different mouse models of CAA, supporting the importance of MMP-related and inflammatory pathways in ICH pathogenesis. As an FDA-approved drug, minocycline might be considered for clinical trials to test efficacy in preventing CAA-related ICH. PMID:25944329

  13. Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice.

    PubMed

    Garcia-Alloza, Monica; Prada, Claudia; Lattarulo, Carli; Fine, Sara; Borrelli, Laura A; Betensky, Rebecca; Greenberg, Steven M; Frosch, Matthew P; Bacskai, Brian J

    2009-06-01

    Cerebral amyloid angiopathy (CAA), characterized by extracellular beta-amyloid peptide (Abeta) deposits in vessel walls, is present in the majority of cases of Alzheimer's disease and is a major cause of hemorrhagic stroke. Although the molecular pathways activated by vascular Abeta are poorly understood, extracellular matrix metalloproteinases (MMP) and Abeta-induced oxidative stress appear to play important roles. We adapted fluorogenic assays for MMP activity and reactive oxygen species generation for use in vivo. Using multiphoton microscopy in APPswe/PS1dE9 and Tg-2576 transgenic mice, we observed strong associations between MMP activation, oxidative stress, and CAA deposition in leptomeningeal vessels. Antioxidant treatment with alpha-phenyl-N-tert-butyl-nitrone reduced oxidative stress associated with CAA (approximately 50% reduction) without affecting MMP activation. Conversely, a selection of agents that inhibit MMP by different mechanisms of action, including minocycline, simvastatin, and GM6001, reduced not only CAA-associated MMP activation (approximately 30-40% reduction) but also oxidative stress (approximately 40% reduction). The inhibitors of MMP did not have direct antioxidant effects. Treatment of animals with alpha-phenyl-N-tert-butyl-nitrone or minocycline did not have a significant effect on CAA progression rates. These data suggest a close association between Abeta-related MMP activation and oxidative stress in vivo and raise the possibility that treatment with MMP inhibitors may have beneficial effects by indirectly reducing the oxidative stress associated with CAA.

  14. Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity

    PubMed Central

    2015-01-01

    Multifunctional metal chelators that can modulate the amyloid β (Aβ) peptide aggregation and its interaction with metal ions such as copper and zinc hold considerable promise as therapeutic agents for Alzheimer’s disease (AD). However, specific rather than systemic metal chelation by these compounds is needed in order to limit any side effects. Reported herein are two novel small bifunctional chelators, 2-[2-hydroxy-4-(diethylamino)phenyl]benzothiazole (L1) and 2-(2-hydroxy-3-methoxyphenyl)benzothiazole (L2), in which the metal-binding donor atoms are integrated within a molecular framework derived from the amyloid-binding fluorescent dye thioflavin T (ThT). The metal-binding properties of L1 and L2 were probed by pH spectrophotometric titrations to determine their pKa values and the corresponding metal complex stability constants, and the isolated metal complexes were structurally characterized. The amyloid-fibril-binding properties of L1 and L2 were investigated by fluorescence titrations and ThT competition assays. Interestingly, L1 and L2 do not lead to the formation of neurotoxic Aβ42 oligomers in the presence or absence of metal ions, as observed by native gel electrophoresis, Western blotting, and transmission electron microscopy. In addition, L1 and L2 were able to reduce the cell toxicity of preformed Aβ42 oligomers and of the copper-stabilized Aβ42 oligomers. Given their ability to reduce the toxicity of soluble Aβ42 and Cu-Aβ42 species, L1 and L2 are promising lead compounds for the development of chemical agents that can control the neurotoxicity of soluble Aβ42 species in AD. PMID:25333939

  15. Formation of Amyloid Fibers by Monomeric Light Chain Variable Domains*

    PubMed Central

    Brumshtein, Boris; Esswein, Shannon R.; Landau, Meytal; Ryan, Christopher M.; Whitelegge, Julian P.; Phillips, Martin L.; Cascio, Duilio; Sawaya, Michael R.; Eisenberg, David S.

    2014-01-01

    Systemic light chain amyloidosis is a lethal disease characterized by excess immunoglobulin light chains and light chain fragments composed of variable domains, which aggregate into amyloid fibers. These fibers accumulate and damage organs. Some light chains induce formation of amyloid fibers, whereas others do not, making it unclear what distinguishes amyloid formers from non-formers. One mechanism by which sequence variation may reduce propensity to form amyloid fibers is by shifting the equilibrium toward an amyloid-resistant quaternary structure. Here we identify the monomeric form of the Mcg immunoglobulin light chain variable domain as the quaternary unit required for amyloid fiber assembly. Dimers of Mcg variable domains remain stable and soluble, yet become prone to assemble into amyloid fibers upon disassociation into monomers. PMID:25138218

  16. Formation of amyloid fibers by monomeric light chain variable domains.

    PubMed

    Brumshtein, Boris; Esswein, Shannon R; Landau, Meytal; Ryan, Christopher M; Whitelegge, Julian P; Phillips, Martin L; Cascio, Duilio; Sawaya, Michael R; Eisenberg, David S

    2014-10-03

    Systemic light chain amyloidosis is a lethal disease characterized by excess immunoglobulin light chains and light chain fragments composed of variable domains, which aggregate into amyloid fibers. These fibers accumulate and damage organs. Some light chains induce formation of amyloid fibers, whereas others do not, making it unclear what distinguishes amyloid formers from non-formers. One mechanism by which sequence variation may reduce propensity to form amyloid fibers is by shifting the equilibrium toward an amyloid-resistant quaternary structure. Here we identify the monomeric form of the Mcg immunoglobulin light chain variable domain as the quaternary unit required for amyloid fiber assembly. Dimers of Mcg variable domains remain stable and soluble, yet become prone to assemble into amyloid fibers upon disassociation into monomers. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  17. SNX27 and SORLA Interact to Reduce Amyloidogenic Subcellular Distribution and Processing of Amyloid Precursor Protein

    PubMed Central

    Huang, Timothy Y.; Zhao, Yingjun; Li, Xiaoguang; Wang, Xin; Tseng, I-Chu; Thompson, Robert; Tu, Shichun; Willnow, Thomas E.; Zhang, Yun-wu

    2016-01-01

    Proteolytic generation of amyloidogenic amyloid β (Aβ) fragments from the amyloid precursor protein (APP) significantly contributes to Alzheimer's disease (AD). Although amyloidogenic APP proteolysis can be affected by trafficking through genetically associated AD components such as SORLA, how SORLA functionally interacts with other trafficking components is yet unclear. Here, we report that SNX27, an endosomal trafficking/recycling factor and a negative regulator of the γ-secretase complex, binds to the SORLA cytosolic tail to form a ternary complex with APP. SNX27 enhances cell surface SORLA and APP levels in human cell lines and mouse primary neurons, and depletion of SNX27 or SORLA reduces APP endosome-to-cell surface recycling kinetics. SNX27 overexpression enhances the generation of cell surface APP cleavage products such as soluble alpha-APP C-terminal fragment (CTFα) in a SORLA-dependent manner. SORLA-mediated Aβ reduction is attenuated by downregulation of SNX27. This indicates that an SNX27/SORLA complex functionally interacts to limit APP distribution to amyloidogenic compartments, forming a non-amyloidogenic shunt to promote APP recycling to the cell surface. SIGNIFICANCE STATEMENT Many genes have been identified as risk factors for Alzheimer's disease (AD), and a large proportion of these genes function to limit production or toxicity of the AD-associated amyloid β (Aβ) peptide. Whether and how these genes precisely operate to limit AD onset remains an important question. We identify binding and trafficking interactions between two of these factors, SORLA and SNX27, and demonstrate that SNX27 can direct trafficking of SORLA and the Aβ precursor APP to the cell surface to limit the production of Aβ. Diversion APP to the cell surface through modulation of this molecular complex may represent a complimentary strategy for future development in AD treatment. PMID:27466343

  18. Mildronate improves cognition and reduces amyloid-β pathology in transgenic Alzheimer's disease mice.

    PubMed

    Beitnere, Ulrika; van Groen, Thomas; Kumar, Ashish; Jansone, Baiba; Klusa, Vija; Kadish, Inga

    2014-03-01

    Mildronate, a carnitine congener drug, previously has been shown to provide neuroprotection in an azidothymidine-induced mouse model of neurotoxicity and in a Parkinson's disease rat model. The aim of this study was to investigate the effects of mildronate treatment on cognition and pathology in Alzheimer's disease (AD) model mice (APP(SweDI)). Mildronate was administered i.p. daily at 50 or 100 mg/kg for 28 days. At the end of treatment, the animals were behaviorally and cognitively tested, and brains were assessed for AD-related pathology, inflammation, synaptic markers, and acetylcholinesterase (AChE). The data show that mildronate treatment significantly improved animal performance in water maze and social recognition tests, lowered amyloid-β deposition in the hippocampus, increased expression of the microglia marker Iba-1, and decreased AChE staining, although it did not alter expression of proteins involved in synaptic plasticity (GAP-43, synaptophysin, and GAD67). Taken together, these findings indicate mildronate's ability to improve cognition and reduce amyloid-β pathology in a mouse model of AD and its possible therapeutic utility as a disease-modifying drug in AD patients. Copyright © 2013 Wiley Periodicals, Inc.

  19. Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production.

    PubMed

    Arendash, G W; Schleif, W; Rezai-Zadeh, K; Jackson, E K; Zacharia, L C; Cracchiolo, J R; Shippy, D; Tan, J

    2006-11-03

    A recent epidemiological study suggested that higher caffeine intake over decades reduces the risk of Alzheimer's disease (AD). The present study sought to determine any long-term protective effects of dietary caffeine intake in a controlled longitudinal study involving AD transgenic mice. Caffeine (an adenosine receptor antagonist) was added to the drinking water of amyloid precursor protein, Swedish mutation (APPsw) transgenic (Tg) mice between 4 and 9 months of age, with behavioral testing done during the final 6 weeks of treatment. The average daily intake of caffeine per mouse (1.5 mg) was the human equivalent of 500 mg caffeine, the amount typically found in five cups of coffee per day. Across multiple cognitive tasks of spatial learning/reference memory, working memory, and recognition/identification, Tg mice given caffeine performed significantly better than Tg control mice and similar to non-transgenic controls. In both behaviorally-tested and aged Tg mice, long-term caffeine administration resulted in lower hippocampal beta-amyloid (Abeta) levels. Expression of both Presenilin 1 (PS1) and beta-secretase (BACE) was reduced in caffeine-treated Tg mice, indicating decreased Abeta production as a likely mechanism of caffeine's cognitive protection. The ability of caffeine to reduce Abeta production was confirmed in SweAPP N2a neuronal cultures, wherein concentration-dependent decreases in both Abeta1-40 and Abeta1-42 were observed. Although adenosine A(1) or A(2A) receptor densities in cortex or hippocampus were not affected by caffeine treatment, brain adenosine levels in Tg mice were restored back to normal by dietary caffeine and could be involved in the cognitive protection provided by caffeine. Our data demonstrate that moderate daily intake of caffeine may delay or reduce the risk of AD.

  20. Tongxinluo improves the cognition by reducing β-amyloid accumulation in spontaneous hypertensive rats.

    PubMed

    Fei, Yu-Lang; Lv, Hong-Jun; Li, Yan-Bo; Liu, Jie; Qian, Yi-Hua; Yang, Wei-Na; Ma, Kai-Ge; Li, Hong-Bao; Qu, Qiu-Min

    2017-03-05

    β-amyloid (Aβ) accumulation in the brain is the major pathophysiology of Alzheimer disease (AD). Hypertension is a risk factor for AD by promoting Aβ deposition. Traditional Chinese medicinal compound tongxinluo (TXL) can improve blood circulation and endothelium-dependent vasodilation. This study investigates the effects of TXL on cognition and Aβ accumulation using spontaneously hypertensive rats (SHRs). TXL was intragastrically administered to SHRs at low-dose, mid-dose and high-dose for 15, 30 or 60 days. Cognition was evaluated with a Morris Water Maze (MWM). Aβ accumulation in the brain was detected by Thioflavin-S staining and ELISA. Western blot and RT-PCR were employed to exam the expression of receptor for advanced glycation end products (RAGE), low-density lipoprotein receptor-related protein-1 (LRP-1) and amyloid precursor protein (APP). After TXL treatment for 60 days, compared with the vehicle, the number of crossed platform and the time spent in the target quadrant increased in parallel with the increasing length of treatment in MWM. Moreover, the Aβ accumulation in the hippocampus significantly decreased compared to the vehicle group, both in Thioflavin-S staining and ELISA. Additionally, TXL reduced RAGE expression in a dose- and time-depended manner, but LRP-1 expression had no difference between TXL groups and vehicle groups. Furthermore, the β-secretase expression was significantly decreased compared to the vehicle group, but APP expression had no difference. In conclusion, TXL improved cognition and reduced Aβ accumulation in SHRs in a dose- and time-dependent manner, the underlying mechanism may involved in inhibiting RAGE and β-secretase expression.

  1. Reduced oligomeric and vascular amyloid-beta following immunization of TgCRND8 mice with an Alzheimer's DNA vaccine.

    PubMed

    DaSilva, Kevin A; Brown, Mary E; McLaurin, JoAnne

    2009-02-25

    Immunization with amyloid-beta (Abeta) peptide reduces amyloid load in animal studies and in humans; however clinical trials resulted in the development of a pro-inflammatory cellular response to Abeta. Apoptosis has been employed to stimulate humoral and Th2-biased cellular immune responses. Thus, we sought to investigate whether immunization using a DNA vaccine encoding Abeta in conjunction with an attenuated caspase generates therapeutically effective antibodies. Plasmids encoding Abeta and an attenuated caspase were less effective in reducing amyloid pathology than those encoding Abeta alone. Moreover, use of Abeta with an Arctic mutation (E22G) as an immunogen was less effective than wild-type Abeta in terms of improvements in pathology. Low levels of IgG and IgM were generated in response to immunization with a plasmid encoding wild-type Abeta. These antibodies decreased plaque load by as much as 36+/-8% and insoluble Abeta42 levels by 56+/-3%. Clearance of Abeta was most effective when antibodies were directed against N-terminal epitopes of Abeta. Moreover, immunization reduced CAA by as much as 69+/-12% in TgCRND8 mice. Finally, high-molecular-weight oligomers and Abeta trimers were significantly reduced with immunization. Thus, immunization with a plasmid encoding Abeta alone drives an attenuated immune response that is sufficient to clear amyloid pathology in a mouse model of Alzheimer's disease.

  2. Adenosine triphosphate (ATP) reduces amyloid-β protein misfolding in vitro.

    PubMed

    Coskuner, Orkid; Murray, Ian V J

    2014-01-01

    Alzheimer's disease (AD) is a devastating disease of aging that initiates decades prior to clinical manifestation and represents an impending epidemic. Two early features of AD are metabolic dysfunction and changes in amyloid-β protein (Aβ) levels. Since levels of ATP decrease over the course of the disease and Aβ is an early biomarker of AD, we sought to uncover novel linkages between the two. First and remarkably, a GxxxG motif is common between both Aβ (oligomerization motif) and nucleotide binding proteins (Rossmann fold). Second, ATP was demonstrated to protect against Aβ mediated cytotoxicity. Last, there is structural similarity between ATP and amyloid binding/inhibitory compounds such as ThioT, melatonin, and indoles. Thus, we investigated whether ATP alters misfolding of the pathologically relevant Aβ42. To test this hypothesis, we performed computational and biochemical studies. Our computational studies demonstrate that ATP interacts strongly with Tyr10 and Ser26 of Aβ fibrils in solution. Experimentally, both ATP and ADP reduced Aβ misfolding at physiological intracellular concentrations, with thresholds at ~500 μM and 1 mM respectively. This inhibition of Aβ misfolding is specific; requiring Tyr10 of Aβ and is enhanced by magnesium. Last, cerebrospinal fluid ATP levels are in the nanomolar range and decreased with AD pathology. This initial and novel finding regarding the ATP interaction with Aβ and reduction of Aβ misfolding has potential significance to the AD field. It provides an underlying mechanism for published links between metabolic dysfunction and AD. It also suggests a potential role of ATP in AD pathology, as the occurrence of misfolded extracellular Aβ mirrors lowered extracellular ATP levels. Last, the findings suggest that Aβ conformation change may be a sensor of metabolic dysfunction.

  3. Astrocytic gap junctional communication is reduced in amyloid-β-treated cultured astrocytes, but not in Alzheimer's disease transgenic mice

    PubMed Central

    Cruz, Nancy F; Ball, Kelly K; Dienel, Gerald A

    2010-01-01

    Alzheimer's disease is characterized by accumulation of amyloid deposits in brain, progressive cognitive deficits and reduced glucose utilization. Many consequences of the disease are attributed to neuronal dysfunction, but roles of astrocytes in its pathogenesis are not well understood. Astrocytes are extensively coupled via gap junctions, and abnormal trafficking of metabolites and signalling molecules within astrocytic syncytia could alter functional interactions among cells comprising the neurovascular unit. To evaluate the influence of amyloid-β on astrocyte gap junctional communication, cultured astrocytes were treated with monomerized amyloid-β1–40 (1 μmol/l) for intervals ranging from 2 h to 5 days, and the areas labelled by test compounds were determined by impaling a single astrocyte with a micropipette and diffusion of material into coupled cells. Amyloid-β-treated astrocytes had rapid, sustained 50–70% reductions in the area labelled by Lucifer Yellow, anionic Alexa Fluor® dyes and energy-related compounds, 6-NBDG (a fluorescent glucose analogue), NADH and NADPH. Amyloid-β treatment also caused a transient increase in oxidative stress. In striking contrast with these results, spreading of Lucifer Yellow within astrocytic networks in brain slices from three regions of 8.5–14-month-old control and transgenic Alzheimer's model mice was variable, labelling 10–2000 cells; there were no statistically significant differences in the number of dye-labelled cells among the groups or with age. Thus amyloid-induced dysfunction of gap junctional communication in cultured astrocytes does not reflect the maintenance of dye transfer through astrocytic syncytial networks in transgenic mice; the pathophysiology of Alzheimer's disease is not appropriately represented by the cell culture system. PMID:20730033

  4. Statins reduce amyloid β-peptide production by modulating amyloid precursor protein maturation and phosphorylation through a cholesterol-independent mechanism in cultured neurons.

    PubMed

    Hosaka, Ai; Araki, Wataru; Oda, Akiko; Tomidokoro, Yasushi; Tamaoka, Akira

    2013-03-01

    Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, have been reported to attenuate amyloid-β peptide (Aβ) production in various cellular models. However, the mechanisms by which statins affect neuronal Aβ production have not yet been clarified. Here, we investigated this issue in rat primary cortical neurons using two statins, pitavastatin (PV) and atorvastatin (AV). Treatment of neurons with 0.2-2.5 μM PV or AV for 4 days induced a concentration- and time-dependent reduction in the secretion of both Aβ40 and Aβ42. Moreover, Western blot analyses of cell lysates showed that treatment with PV or AV significantly reduced expression levels of the mature form of amyloid precursor protein (APP) and Thr668-phosphorylated APP (P-APP), but not immature form of APP; the decreases in P-APP levels were more notable than those of mature APP levels. The statin treatment did not alter expression of BACE1 (β-site APP-cleaving enzyme 1) or γ-secretase complex proteins (presenilin 1, nicastrin, APH-1, and PEN-2). In neurons overexpressing APP via recombinant adenoviruses, PV or AV similarly reduced Aβ secretion and the levels of mature APP and P-APP. Statins also markedly reduced cellular cholesterol content in neurons in a concentration-dependent manner. Co-treatment with mevalonate reversed the statin-induced decreases in Aβ secretion and mature APP and P-APP levels, whereas co-treatment with cholesterol did not, despite recovery of cellular cholesterol levels. Finally, cell-surface biotinylation experiments revealed that both statins significantly reduced the levels of cell-surface P-APP without changing those of cell surface mature APP. These results suggest that statins reduce Aβ production by selectively modulating APP maturation and phosphorylation through a mechanism independent of cholesterol reduction in cultured neurons.

  5. Identifying opportunities to reduce excess nitrogen in croplands while maintaining current crop yields

    NASA Astrophysics Data System (ADS)

    West, P. C.; Mueller, N. D.; Foley, J. A.

    2011-12-01

    Use of synthetic nitrogen fertilizer has greatly contributed to the increased crop yields brought about by the Green Revolution. Unfortunately, it also has also contributed to substantial excess nitrogen in the environment. Application of excess nitrogen not only is a waste of energy and other resources used to produce, transport and apply it, it also pollutes aquatic ecosystems and has led to the development of more than 200 hypoxic-or "dead"-zones in coastal areas around the world. How can we decrease use of excess nitrogen without compromising crop yields? To help address this challenge, our study (1) quantified hot spots of excess nitrogen, and (2) estimated how much nitrogen reduction is possible in these areas while still maintaining yields. We estimated excess nitrogen for major crops using a mass balance approach and global spatial data sets of crop area and yield, fertilizer application rates, and nitrogen deposition. Hot spots of excess nitrogen were identified by quantifying the smallest area within large river basins that contributed 25% and 50% of the total load within each basin. Nitrogen reduction scenarios were developed using a yield response model to estimate nitrogen application rates needed to maintain current yields. Our research indicated that excess nitrogen is concentrated in very small portions of croplands within river basins, with 25% of the total nitrogen load in each basin from ~10% of the cropland, and 50% of the total nitrogen load in each basin from ~25% of the cropland. Targeting reductions in application rates in these hot spots can allow us to maintain current crop yields while greatly reducing nitrogen loading to coastal areas and creating the opportunity to reallocate resources to boost yields on nitrogen-limited croplands elsewhere.

  6. Cooking rice in excess water reduces both arsenic and enriched vitamins in the cooked grain.

    PubMed

    Gray, Patrick J; Conklin, Sean D; Todorov, Todor I; Kasko, Sasha M

    2016-01-01

    This paper reports the effects of rinsing rice and cooking it in variable amounts of water on total arsenic, inorganic arsenic, iron, cadmium, manganese, folate, thiamin and niacin in the cooked grain. We prepared multiple rice varietals both rinsed and unrinsed and with varying amounts of cooking water. Rinsing rice before cooking has a minimal effect on the arsenic (As) content of the cooked grain, but washes enriched iron, folate, thiamin and niacin from polished and parboiled rice. Cooking rice in excess water efficiently reduces the amount of As in the cooked grain. Excess water cooking reduces average inorganic As by 40% from long grain polished, 60% from parboiled and 50% from brown rice. Iron, folate, niacin and thiamin are reduced by 50-70% for enriched polished and parboiled rice, but significantly less so for brown rice, which is not enriched.

  7. A new tacrine-melatonin hybrid reduces amyloid burden and behavioral deficits in a mouse model of Alzheimer's disease.

    PubMed

    Spuch, Carlos; Antequera, Desiree; Isabel Fernandez-Bachiller, M; Isabel Rodríguez-Franco, M; Carro, Eva

    2010-05-01

    Alzheimer's disease (AD) is a progressive degenerative disorder characterized by the presence of amyloid deposits, neurofibrillary tangles and neuron loss. Emerging evidence indicates that antioxidants could be useful either for the prevention or treatment of AD. Tacrine and melatonin are well-known drugs which act as an acetylcholinesterase inhibitor and a free radical scavenger, respectively. In this study, we evaluated the effects of a new tacrine-melatonin hybrid on behavior and the biochemical and neuropathologic changes observed in amyloid precursor protein/presenilin 1 (APP/Ps1) transgenic mice. Our findings showed that direct intracerebral administration of this hybrid decreased amyloid beta peptide (Abeta)-induced cell death and amyloid burden in the brain parenchyma of APP/Ps1 mice. This reduction in Abeta pathology was accompanied by a recovery in cognitive function. Since this tacrine-melatonin hybrid apparently reduces brain Abeta and behavioral deficits, we believe this drug has remarkable and significant neuroprotective effects and might be considered a potential therapeutic strategy in AD.

  8. MILD CHOLESTEROL DEPLETION REDUCES AMYLOID-β PRODUCTION BY IMPAIRING APP TRAFFICKING TO THE CELL SURFACE

    PubMed Central

    Guardia-Laguarta, Cristina; Coma, Mireia; Pera, Marta; Clarimón, Jordi; Sereno, Lidia; Agulló, José M.; Molina-Porcel, Laura; Gallardo, Eduard; Deng, Amy; Berezovska, Oksana; Hyman, Bradley T.; Blesa, Rafael; Gómez-Isla, Teresa; Lleó, Alberto

    2009-01-01

    It has been suggested that cellular cholesterol levels can modulate the metabolism of the amyloid precursor protein (APP) but the underlying mechanism remains controversial. In the current study, we investigate in detail the relationship between cholesterol reduction, APP processing and γ-secretase function in cell culture studies. We found that mild membrane cholesterol reduction led to a decrease in Aβ40 and Aβ42 in different cell types. We did not detect changes in APP intracellular domain or Notch intracellular domain generation. Western blot analyses showed a cholesterol-dependent decrease in the APP C-terminal fragments and cell surface APP. Finally, we applied a fluorescence resonance energy transfer (FRET)-based technique to study APP-Presenilin 1 (PS1) interactions and lipid rafts in intact cells. Our data indicate that cholesterol depletion reduces association of APP into lipid rafts and disrupts APP-PS1 interaction. Taken together, our results suggest that mild membrane cholesterol reduction impacts the cleavage of APP upstream of γ-secretase and appears to be mediated by changes in APP trafficking and partitioning into lipid rafts. PMID:19457132

  9. Excessive hydrogen peroxide enhances the attachment of amyloid β1-42 in the lens epithelium of UPL rats, a hereditary model for cataracts.

    PubMed

    Nagai, Noriaki; Ito, Yoshimasa

    2014-01-06

    Several studies have reported that hydrogen peroxide (H2O2) is related to the toxicity of amyloid β (Aβ), and that the accumulation of Aβ in the lenses of humans causes lens opacification. In this study, we investigate the accumulation of Aβ1-42 in the lenses of UPL rats, which then leads to lens opacification. In addition, we demonstrate the effect of disulfiram eye drops (DSF), a potent radical scavenger, on Aβ1-42 accumulation in the lenses of UPL rats. The H2O2 levels in 46- to 60-day-old UPL rat lenses are significantly higher than in normal rats, and the Aβ1-42 levels in 53- and 60-day-old UPL rats are also increased only in lens epithelium containing capsules (capsule-epithelium), not in the lens cortex and nucleus. However, no increases in amyloid precursor protein (APP), β- or γ-secretase mRNA were observed in lenses of the corresponding ages. It has been thought that Aβ1-42 that accumulates in the lenses of UPL rats is actually produced in another tissue containing neuronal cells, such as brain or retina. Aβ1-42 levels in the brain and retina rise with aging, and the levels of APP, β- and γ-secretase mRNA in the retinas of 53-day-old UPL rats with opaque lenses are significantly higher than in 25-day-old UPL rats with transparent lenses. In contrast to the results in retinas, the levels of APP, β- and γ-secretase mRNA in the brains of 25- and 53-day-old UPL rats are similar. On the other hand, in an in vitro study, Aβ1-42 attachment in the lens capsule-epithelium of UPL rats was found to increase in H2O2. In addition, in an in vivo study, the inhibition of H2O2 by DSF was found to attenuate the increase in Aβ1-42 in the lens capsule-epithelium of 60-day-old UPL rats. Taken together, we hypothesize that excessive H2O2 in the lens enhances the attachment of Aβ1-42 in the lens capsule-epithelium of UPL rats, and that the instillation of DSF has the ability to attenuate the attachment of Aβ1-42 by inhibiting H2O2 production in lens. These

  10. The effectiveness of tax policy interventions for reducing excessive alcohol consumption and related harms.

    PubMed

    Elder, Randy W; Lawrence, Briana; Ferguson, Aneeqah; Naimi, Timothy S; Brewer, Robert D; Chattopadhyay, Sajal K; Toomey, Traci L; Fielding, Jonathan E

    2010-02-01

    A systematic review of the literature to assess the effectiveness of alcohol tax policy interventions for reducing excessive alcohol consumption and related harms was conducted for the Guide to Community Preventive Services (Community Guide). Seventy-two papers or technical reports, which were published prior to July 2005, met specified quality criteria, and included evaluation outcomes relevant to public health (e.g., binge drinking, alcohol-related crash fatalities), were included in the final review. Nearly all studies, including those with different study designs, found that there was an inverse relationship between the tax or price of alcohol and indices of excessive drinking or alcohol-related health outcomes. Among studies restricted to underage populations, most found that increased taxes were also significantly associated with reduced consumption and alcohol-related harms. According to Community Guide rules of evidence, these results constitute strong evidence that raising alcohol excise taxes is an effective strategy for reducing excessive alcohol consumption and related harms. The impact of a potential tax increase is expected to be proportional to its magnitude and to be modified by such factors as disposable income and the demand elasticity for alcohol among various population groups.

  11. The Effectiveness of Tax Policy Interventions for Reducing Excessive Alcohol Consumption and Related Harms

    PubMed Central

    Elder, Randy W.; Lawrence, Briana; Ferguson, Aneeqah; Naimi, Timothy S.; Brewer, Robert D.; Chattopadhyay, Sajal K.; Toomey, Traci L.; Fielding, Jonathan E.

    2013-01-01

    A systematic review of the literature to assess the effectiveness of alcohol tax policy interventions for reducing excessive alcohol consumption and related harms was conducted for the Guide to Community Preventive Services (Community Guide). Seventy-two papers or technical reports, which were published prior to July 2005, met specifıed quality criteria, and included evaluation outcomes relevant to public health (e.g., binge drinking, alcohol-related crash fatalities), were included in the fınal review. Nearly all studies, including those with different study designs, found that there was an inverse relationship between the tax or price of alcohol and indices of excessive drinking or alcohol-related health outcomes. Among studies restricted to underage populations, most found that increased taxes were also signifıcantly associated with reduced consumption and alcohol-related harms. According to Community Guide rules of evidence, these results constitute strong evidence that raising alcohol excise taxes is an effective strategy for reducing excessive alcohol consumption and related harms. The impact of a potential tax increase is expected to be proportional to its magnitude and to be modifıed by such factors as disposable income and the demand elasticity for alcohol among various population groups. PMID:20117579

  12. Phenylpropanoids from cinnamon bark reduced β-amyloid production by the inhibition of β-secretase in Chinese hamster ovarian cells stably expressing amyloid precursor protein.

    PubMed

    Kang, Yu Jeong; Seo, Dae-Gun; Park, So-Young

    2016-11-01

    β-Amyloid (Aβ) is a substance of Alzheimer disease (AD), which is generated via the amyloidogenic pathway from amyloid precursor protein (APP) by β-secretase and γ-secretase. Inhibition of Aβ production is a potential therapeutic approach to AD. Thus, we tested the hypothesis that cinnamon bark (Cinnamomi Cortex Spissus), the dried bark of Cinnamomum cassia Blume (Lauraceae), and its constituents are beneficial to AD. The methanol extract of cinnamon bark efficiently reduced Aβ40 production in Chinese hamster ovarian (CHO) cells stably expressing APP as determined by enzyme-linked immunosorbent assay. Bioassay-guided isolation of cinnamon bark extract was carried out using open column chromatography and high-performance liquid chromatography, and the following 6 phenylpropanoids were isolated: syringaresinol (1); medioresinol (2); coumarin (3); 2-hydroxycinnamaldehyde (4); cryptamygin A (5); and 3',5,7-trimethoxy epicatechin (6). Among these, 4 μg/mL medioresinol and cryptamygin A reduced Aβ40 production by 50% and 60%, respectively, compared with dimethyl sulfoxide-treated control cells. The IC50 values of medioresinol and cryptamygin A for the inhibition of Aβ40 production were 10.8 and 8.2 μg/mL, respectively. Furthermore, treatment of APP-CHO cells with either compound decreased the amount of β-secretase and sAPPβ (the proteolytic fragment of APP catalyzed by β-secretase). These results suggest that the antiamyloidogenic activity of cinnamon bark extract was exerted by medioresinol and cryptamygin A via a reduction in the amount of β-secretase. The extract of cinnamon bark contains potentially valuable antiamyloidogenic agents for the prevention and treatment of AD. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Environmental enrichment strengthens corticocortical interactions and reduces amyloid-β oligomers in aged mice

    PubMed Central

    Mainardi, Marco; Di Garbo, Angelo; Caleo, Matteo; Berardi, Nicoletta; Sale, Alessandro; Maffei, Lamberto

    2013-01-01

    Brain aging is characterized by global changes which are thought to underlie age-related cognitive decline. These include variations in brain activity and the progressive increase in the concentration of soluble amyloid-β (Aβ) oligomers, directly impairing synaptic function and plasticity even in the absence of any neurodegenerative disorder. Considering the high social impact of the decline in brain performance associated to aging, there is an urgent need to better understand how it can be prevented or contrasted. Lifestyle components, such as social interaction, motor exercise and cognitive activity, are thought to modulate brain physiology and its susceptibility to age-related pathologies. However, the precise functional and molecular factors that respond to environmental stimuli and might mediate their protective action again pathological aging still need to be clearly identified. To address this issue, we exploited environmental enrichment (EE), a reliable model for studying the effect of experience on the brain based on the enhancement of cognitive, social and motor experience, in aged wild-type mice. We analyzed the functional consequences of EE on aged brain physiology by performing in vivo local field potential (LFP) recordings with chronic implants. In addition, we also investigated changes induced by EE on molecular markers of neural plasticity and on the levels of soluble Aβ oligomers. We report that EE induced profound changes in the activity of the primary visual and auditory cortices and in their functional interaction. At the molecular level, EE enhanced plasticity by an upward shift of the cortical excitation/inhibition balance. In addition, EE reduced brain Aβ oligomers and increased synthesis of the Aβ-degrading enzyme neprilysin. Our findings strengthen the potential of EE procedures as a non-invasive paradigm for counteracting brain aging processes. PMID:24478697

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

    PubMed

    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.

  15. 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

  16. Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer's disease mouse models.

    PubMed

    Huang, Yunhong; Skwarek-Maruszewska, Aneta; Horré, Katrien; Vandewyer, Elke; Wolfs, Leen; Snellinx, An; Saito, Takashi; Radaelli, Enrico; Corthout, Nikky; Colombelli, Julien; Lo, Adrian C; Van Aerschot, Leen; Callaerts-Vegh, Zsuzsanna; Trabzuni, Daniah; Bossers, Koen; Verhaagen, Joost; Ryten, Mina; Munck, Sebastian; D'Hooge, Rudi; Swaab, Dick F; Hardy, John; Saido, Takaomi C; De Strooper, Bart; Thathiah, Amantha

    2015-10-14

    The orphan G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) GPR3 regulates activity of the γ-secretase complex in the absence of an effect on Notch proteolysis, providing a potential therapeutic target for Alzheimer's disease (AD). However, given the vast resources required to develop and evaluate any new therapy for AD and the multiple failures involved in translational research, demonstration of the pathophysiological relevance of research findings in multiple disease-relevant models is necessary before initiating costly drug development programs. We evaluated the physiological consequences of loss of Gpr3 in four AD transgenic mouse models, including two that contain the humanized murine Aβ sequence and express similar amyloid precursor protein (APP) levels as wild-type mice, thereby reducing potential artificial phenotypes. Our findings reveal that genetic deletion of Gpr3 reduced amyloid pathology in all of the AD mouse models and alleviated cognitive deficits in APP/PS1 mice. Additional three-dimensional visualization and analysis of the amyloid plaque burden provided accurate information on the amyloid load, distribution, and volume in the structurally intact adult mouse brain. Analysis of 10 different regions in healthy human postmortem brain tissue indicated that GPR3 expression was stable during aging. However, two cohorts of human AD postmortem brain tissue samples showed a correlation between elevated GPR3 and AD progression. Collectively, these studies provide evidence that GPR3 mediates the amyloidogenic proteolysis of APP in four AD transgenic mouse models as well as the physiological processing of APP in wild-type mice, suggesting that GPR3 may be a potential therapeutic target for AD drug development. Copyright © 2015, American Association for the Advancement of Science.

  17. Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice.

    PubMed

    Wiley, Jesse C; Pettan-Brewer, Christina; Ladiges, Warren C

    2011-06-01

    Trafficking through the secretory pathway is known to regulate the maturation of the APP-cleaving secretases and APP proteolysis. The coupling of stress signaling and pathological deterioration of the brain in Alzheimer's disease (AD) supports a mechanistic connection between endoplasmic reticulum (ER) stress and neurodegeneration. Consequently, small molecular chaperones, which promote protein folding and minimize ER stress, might be effective in delaying or attenuating the deleterious progression of AD. We tested this hypothesis by treating APPswePS1delta9 AD transgenic mice with the molecular chaperone phenylbutyric acid (PBA) for 14 months at a dose of 1 mg PBA g(-1) of body weight in the drinking water. Phenylbutyric acid treatment increased secretase-mediated APP cleavage, but was not associated with any increase in amyloid biosynthesis. The PBA-treated AD transgenic mice had significantly decreased incidence and size of amyloid plaques throughout the cortex and hippocampus. There was no change in total amyloid levels suggesting that PBA modifies amyloid aggregation or pathogenesis independently of biogenesis. The decrease in amyloid plaques was paralleled by increased memory retention, as PBA treatment facilitated cognitive performance in a spatial memory task in both wild-type and AD transgenic mice. The molecular mechanism underlying the cognitive facilitation of PBA is not clear; however, increased levels of both metabotropic and ionotropic glutamate receptors, as well as ADAM10 and TACE, were observed in the cortex and hippocampus of PBA-treated mice. The data suggest that PBA ameliorates the cognitive and pathological features of AD and supports the investigation of PBA as a therapeutic for AD.

  18. A Study Protocol for Testing the Effectiveness of User-Generated Content in Reducing Excessive Consumption

    PubMed Central

    Herziger, Atar; Benzerga, Amel; Berkessel, Jana; Dinartika, Niken L.; Franklin, Matija; Steinnes, Kamilla K.; Sundström, Felicia

    2017-01-01

    Excessive consumption is on the rise, as is apparent in growing financial debt and global greenhouse gas emissions. Voluntary simplicity, a lifestyle choice of reduced consumption and sustainable consumer behavior, provides a potential solution for excessive consumers. However, voluntary simplicity is unpopular, difficult to adopt, and under researched. The outlined research project will test a method of promoting voluntary simplicity via user-generated content, thus mimicking an existing social media trend (Minimalism) in an empirical research design. The project will test (a) whether the Minimalism trend could benefit consumers interested in reducing their consumption, and (b) whether self-transcendence (i.e., biospheric) and self-enhancement (i.e., egoistic and hedonic) values and goals have a similar impact in promoting voluntary simplicity. A one-week intervention program will test the efficacy of watching user-generated voluntary simplicity videos in reducing non-essential consumption. Each of the two intervention conditions will present participants with similar tutorial videos on consumption reduction (e.g., decluttering, donating), while priming the relevant values and goals (self-transcendence or self-enhancement). These interventions will be compared to a control condition, involving no user-generated content. Participants will undergo baseline and post-intervention evaluations of: voluntary simplicity attitudes and behaviors, buying and shopping behaviors, values and goals in reducing consumption, and life satisfaction. Experience sampling will monitor affective state during the intervention. We provide a detailed stepwise procedure, materials, and equipment necessary for executing this intervention. The outlined research design is expected to contribute to the limited literature on voluntary simplicity, online behavioral change interventions, and the use of social marketing principles in consumer interventions. PMID:28649220

  19. A Study Protocol for Testing the Effectiveness of User-Generated Content in Reducing Excessive Consumption.

    PubMed

    Herziger, Atar; Benzerga, Amel; Berkessel, Jana; Dinartika, Niken L; Franklin, Matija; Steinnes, Kamilla K; Sundström, Felicia

    2017-01-01

    Excessive consumption is on the rise, as is apparent in growing financial debt and global greenhouse gas emissions. Voluntary simplicity, a lifestyle choice of reduced consumption and sustainable consumer behavior, provides a potential solution for excessive consumers. However, voluntary simplicity is unpopular, difficult to adopt, and under researched. The outlined research project will test a method of promoting voluntary simplicity via user-generated content, thus mimicking an existing social media trend (Minimalism) in an empirical research design. The project will test (a) whether the Minimalism trend could benefit consumers interested in reducing their consumption, and (b) whether self-transcendence (i.e., biospheric) and self-enhancement (i.e., egoistic and hedonic) values and goals have a similar impact in promoting voluntary simplicity. A one-week intervention program will test the efficacy of watching user-generated voluntary simplicity videos in reducing non-essential consumption. Each of the two intervention conditions will present participants with similar tutorial videos on consumption reduction (e.g., decluttering, donating), while priming the relevant values and goals (self-transcendence or self-enhancement). These interventions will be compared to a control condition, involving no user-generated content. Participants will undergo baseline and post-intervention evaluations of: voluntary simplicity attitudes and behaviors, buying and shopping behaviors, values and goals in reducing consumption, and life satisfaction. Experience sampling will monitor affective state during the intervention. We provide a detailed stepwise procedure, materials, and equipment necessary for executing this intervention. The outlined research design is expected to contribute to the limited literature on voluntary simplicity, online behavioral change interventions, and the use of social marketing principles in consumer interventions.

  20. The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease.

    PubMed

    Hutter-Paier, Birgit; Huttunen, Henri J; Puglielli, Luigi; Eckman, Christopher B; Kim, Doo Yeon; Hofmeister, Alexander; Moir, Robert D; Domnitz, Sarah B; Frosch, Matthew P; Windisch, Manfred; Kovacs, Dora M

    2004-10-14

    Amyloid beta-peptide (Abeta) accumulation in specific brain regions is a pathological hallmark of Alzheimer's disease (AD). We have previously reported that a well-characterized acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor, CP-113,818, inhibits Abeta production in cell-based experiments. Here, we assessed the efficacy of CP-113,818 in reducing AD-like pathology in the brains of transgenic mice expressing human APP(751) containing the London (V717I) and Swedish (K670M/N671L) mutations. Two months of treatment with CP-113,818 reduced the accumulation of amyloid plaques by 88%-99% and membrane/insoluble Abeta levels by 83%-96%, while also decreasing brain cholesteryl-esters by 86%. Additionally, soluble Abeta(42) was reduced by 34% in brain homogenates. Spatial learning was slightly improved and correlated with decreased Abeta levels. In nontransgenic littermates, CP-113,818 also reduced ectodomain shedding of endogenous APP in the brain. Our results suggest that ACAT inhibition may be effective in the prevention and treatment of AD by inhibiting generation of the Abeta peptide.

  1. Modulation of ABCA1 by an LXR Agonist Reduces Beta-Amyloid Levels and Improves Outcome after Traumatic Brain Injury

    PubMed Central

    Loane, David J.; Washington, Patricia M.; Vardanian, Lilit; Pocivavsek, Ana; Hoe, Hyang-Sook; Duff, Karen E.; Cernak, Ibolja; Rebeck, G. William; Faden, Alan I.

    2011-01-01

    Abstract Traumatic brain injury (TBI) increases brain beta-amyloid (Aβ) in humans and animals. Although the role of Aβ in the injury cascade is unknown, multiple preclinical studies have demonstrated a correlation between reduced Aβ and improved outcome. Therefore, therapeutic strategies that enhance Aβ clearance may be beneficial after TBI. Increased levels of ATP-binding cassette A1 (ABCA1) transporters can enhance Aβ clearance through an apolipoprotein E (apoE)-mediated pathway. By measuring Aβ and ABCA1 after experimental TBI in C57BL/6J mice, we found that Aβ peaked early after injury (1–3 days), whereas ABCA1 had a delayed response (beginning at 3 days). As ABCA1 levels increased, Aβ levels returned to baseline levels—consistent with the known role of ABCA1 in Aβ clearance. To test if enhancing ABCA1 levels could block TBI-induced Aβ, we treated TBI mice with the liver X-receptor (LXR) agonist T0901317. Pre- and post-injury treatment increased ABCA1 levels at 24 h post-injury, and reduced the TBI-induced increase in Aβ. This reduction in Aβ was not due to decreased amyloid precursor protein processing, or a shift in the solubility of Aβ, indicating enhanced clearance. T0901317 also limited motor coordination deficits in injured mice and reduced brain lesion volume. These data indicate that activation of LXR can reduce Aβ accumulation after TBI, and is accompanied by improved functional recovery. PMID:21175399

  2. Dietary copper in excess of nutritional requirement reduces plasma and breast muscle cholesterol of chickens.

    PubMed

    Bakalli, R I; Pesti, G M; Ragland, W L; Konjufca, V

    1995-02-01

    Male commercial broiler strain chickens were fed from hatching to 42 d of age either a control diet (based on corn and soybean meal) or the control diet supplemented with 250 mg copper/kg diet from cupric sulfate pentahydrate (for 35 or 42 d). Hypocholesterolemia (11.8% reduction) and decreased breast muscle cholesterol (20.4% reduction) were observed in copper-supplemented birds. There was a slight increase (P > .05) in breast muscle copper (14.5%), and all levels were very low (< .5 mg/kg). Feeding copper for 42 vs 35 d resulted in lower levels of cholesterol in the plasma (12.9 vs 10.8% reduction) and breast muscle (24.6 vs 16.2% reduction). Very similar results were found in two additional experiments in which hypocholesterolemia and reduced breast muscle cholesterol were associated with reduced plasma triglycerides and blood reduced glutathione. It is well known that hypercholesterolemia is a symptom of dietary copper deficiency. The data presented here indicate that blood and breast muscle cholesterol are inversely related to dietary copper in excess of the dietary requirement for maximal growth. The cholesterol content of the edible muscle tissue of broiler chickens can be reduced by approximately 25% after feeding a supranormal level of copper for 42 d without altering the growth of the chickens or substantially increasing the copper content of the edible meat.

  3. Amyloid Dysmetabolism Relates to Reduced Glucose Uptake in White Matter Hyperintensities

    PubMed Central

    Kalheim, Lisa Flem; Selnes, Per; Bjørnerud, Atle; Coello, Christopher; Vegge, Kjetil; Fladby, Tormod

    2016-01-01

    Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and cause of dementia and is characterized by amyloid plaques and neurofibrillary tangles. AD has traditionally been considered to primarily affect gray matter, but multiple lines of evidence also indicate white matter (WM) pathology and associated small-vessel cerebrovascular disease. WM glucose delivery and metabolism may have implications for local tissue integrity, and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) may be helpful to assess neuroglial and axonal function in WM. Hypothesizing that affection of oligodendroglia will be associated with loss of glucose uptake, we aimed to investigate glucose metabolism in magnetic resonance imaging (MRI) white matter hyperintensities (WMHs) and normal-appearing WM in patients with and without evidence of amyloid plaques. Subjects with mild cognitive impairment or subjective cognitive decline were included and dichotomized according to pathological (Aβ+) or normal (Aβ−) concentrations of cerebrospinal fluid amyloid-β 1–42. A total of 50 subjects were included, of whom 30 subjects were classified as Aβ(+) and 20 subjects as Aβ(−). All subjects were assessed with MRI and FDG-PET. FDG-PET images were corrected for effects of partial voluming and normalized to cerebellar WM, before determining WMH FDG-uptake. Although there were no significant differences between the groups in terms of age, WMH volume, number of individual WMHs, or WMH distribution, we found significantly lower (p = 0.021) FDG-uptake in WMHs in Aβ(+) subjects (mean = 0.662, SD = 0.113) compared to Aβ(−) subjects (mean = 0.596, SD = 0.073). There were no significant group differences in the FDG-uptake in normal-appearing WM. Similar results were obtained without correction for effects of partial voluming. Our findings add to the evidence for a link between Aβ dysmetabolism and WM pathology in AD. PMID:27917152

  4. Crude caffeine reduces memory impairment and amyloid β(1-42) levels in an Alzheimer's mouse model.

    PubMed

    Chu, Yi-Fang; Chang, Wen-Han; Black, Richard M; Liu, Jia-Ren; Sompol, Pradoldej; Chen, Yumin; Wei, Huilin; Zhao, Qiuyan; Cheng, Irene H

    2012-12-01

    Alzheimer's disease (AD), a chronic neurodegenerative disorder associated with the abnormal accumulations of amyloid β (Aβ) peptide and oxidative stress in the brain, is the most common form of dementia among the elderly. Crude caffeine (CC), a major by-product of the decaffeination of coffee, has potent hydrophilic antioxidant activity and may reduce inflammatory processes. Here, we showed that CC and pure caffeine intake had beneficial effects in a mouse model of AD. Administration of CC or pure caffeine for 2months partially prevented memory impairment in AD mice, with CC having greater effects than pure caffeine. Furthermore, consumption of CC, but not pure caffeine, reduced the Aβ(1-42) levels and the number of amyloid plaques in the hippocampus. Moreover, CC and caffeine protected primary neurons from Aβ-induced cell death and suppressed Aβ-induced caspase-3 activity. Our data indicate that CC may contain prophylactic agents against the cell death and the memory impairment in AD. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Cerebrolysin reduces amyloid-β deposits, apoptosis and autophagy in the thalamus and improves functional recovery after cortical infarction.

    PubMed

    Xing, Shihui; Zhang, Jian; Dang, Chao; Liu, Gang; Zhang, Yusheng; Li, Jingjing; Fan, Yuhua; Pei, Zhong; Zeng, Jinsheng

    2014-02-15

    Focal cerebral infarction causes amyloid-β (Aβ) deposits and secondary thalamic neuronal degeneration. The present study aimed to determine the protective effects of Cerebrolysin on Aβ deposits and secondary neuronal damage in thalamus after cerebral infarction. At 24h after distal middle cerebral artery occlusion (MCAO), Cerebrolysin (5 ml/kg) or saline as control was once daily administered for consecutive 13 days by intraperitoneal injection. Sensory function and secondary thalamic damage were assessed with adhesive-removal test, Nissl staining and immunofluorescence at 14 days after MCAO. Aβ deposits, activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), apoptosis and autophagy were determined by TUNEL staining, immunofluorescence and immunoblot. The results showed that Cerebrolysin significantly improved sensory deficit compared to controls (p<0.05). Aβ deposits and BACE1 were obviously reduced by Cerebrolysin, which was accompanied by decreases in neuronal loss and astroglial activation compared to controls (all p < 0.05). Coincidently, Cerebrolysin markedly inhibited cleaved caspase-3, conversion of LC3-II, downregulation of Bcl-2 and upregulation of Bax in the ipsilateral thalamus compared to controls (all p<0.05). These findings suggest that Cerebrolysin reduces Aβ deposits, apoptosis and autophagy in the ipsilateral thalamus, which may be associated with amelioration of secondary thalamic damage and functional recovery after cerebral infarction.

  6. Icariside II Effectively Reduces Spatial Learning and Memory Impairments in Alzheimer's Disease Model Mice Targeting Beta-Amyloid Production.

    PubMed

    Yan, Lingli; Deng, Yuanyuan; Gao, Jianmei; Liu, Yuangui; Li, Fei; Shi, Jingshan; Gong, Qihai

    2017-01-01

    Icariside II (ICS II) is a broad-spectrum anti-cancer natural compound extracted from Herba Epimedii Maxim. Recently, the role of ICS II has been investigated in central nervous system, especially have a neuroprotective effect in Alzheimer's disease (AD). In this study, we attempted to investigate the effects of ICS II, on cognitive deficits and beta-amyloid (Aβ) production in APPswe/PS1dE9 (APP/PS1) double transgenic mice. It was found that chronic ICS II administrated not only effectively ameliorated cognitive function deficits, but also inhibited neuronal degeneration and reduced the formation of plaque burden. ICS II significantly suppressed Aβ production via promoting non-amyloidogenic APP cleavage process by up-regulating a disintegrin and metalloproteinase domain 10 (ADAM10) expression, inhibited amyloidogenic APP processing pathway by down-regulating amyloid precursor protein (APP) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1) expression in APP/PS1 transgenic mice. Meanwhile, ICS II attenuated peroxisome proliferator-activated receptor-γ (PPARγ) degradation as well as inhibition of eukaryotic initiation factor α phosphorylation (p-eIF2α) and PKR endoplasmic reticulum regulating kinase phosphorylation (p-PERK). Moreover, phosphodiesterase type 5 inhibitors (PDE5-Is) have recently emerged as a possible therapeutic target for cognitive enhancement via inhibiting Aβ levels, and we also found that ICS II markedly decreased phosphodiesterase-5A (PDE5A) expression. In conclusion, the present study demonstrates that ICS II could attenuate spatial learning and memory impairments in APP/PS1 transgenic mice. This protection appears to be due to the increased ADAM10 expression and decreased expression of both APP and BACE1, resulting in inhibition of Aβ production in the hippocampus and cortex. Inhibition of PPARγ degradation and PERK/eIF2α phosphorylation are involved in the course, therefore suggesting that ICS II might be a promising

  7. Ca2+ Influx through Store-operated Ca2+ Channels Reduces Alzheimer Disease β-Amyloid Peptide Secretion*

    PubMed Central

    Zeiger, William; Vetrivel, Kulandaivelu S.; Buggia-Prévot, Virginie; Nguyen, Phuong D.; Wagner, Steven L.; Villereal, Mitchel L.; Thinakaran, Gopal

    2013-01-01

    Alzheimer disease (AD), the leading cause of dementia, is characterized by the accumulation of β-amyloid peptides (Aβ) in senile plaques in the brains of affected patients. Many cellular mechanisms are thought to play important roles in the development and progression of AD. Several lines of evidence point to the dysregulation of Ca2+ homeostasis as underlying aspects of AD pathogenesis. Moreover, direct roles in the regulation of Ca2+ homeostasis have been demonstrated for proteins encoded by familial AD-linked genes such as PSEN1, PSEN2, and APP, as well as Aβ peptides. Whereas these studies support the hypothesis that disruption of Ca2+ homeostasis contributes to AD, it is difficult to disentangle the effects of familial AD-linked genes on Aβ production from their effects on Ca2+ homeostasis. Here, we developed a system in which cellular Ca2+ homeostasis could be directly manipulated to study the effects on amyloid precursor protein metabolism and Aβ production. We overexpressed stromal interaction molecule 1 (STIM1) and Orai1, the components of the store-operated Ca2+ entry pathway, to generate cells with constitutive and store depletion-induced Ca2+ entry. We found striking effects of Ca2+ entry induced by overexpression of the constitutively active STIM1D76A mutant on amyloid precursor protein metabolism. Specifically, constitutive activation of Ca2+ entry by expression of STIM1D76A significantly reduced Aβ secretion. Our results suggest that disruptions in Ca2+ homeostasis may influence AD pathogenesis directly through the modulation of Aβ production. PMID:23902769

  8. Ca2+ influx through store-operated Ca2+ channels reduces Alzheimer disease β-amyloid peptide secretion.

    PubMed

    Zeiger, William; Vetrivel, Kulandaivelu S; Buggia-Prévot, Virginie; Nguyen, Phuong D; Wagner, Steven L; Villereal, Mitchel L; Thinakaran, Gopal

    2013-09-13

    Alzheimer disease (AD), the leading cause of dementia, is characterized by the accumulation of β-amyloid peptides (Aβ) in senile plaques in the brains of affected patients. Many cellular mechanisms are thought to play important roles in the development and progression of AD. Several lines of evidence point to the dysregulation of Ca(2+) homeostasis as underlying aspects of AD pathogenesis. Moreover, direct roles in the regulation of Ca(2+) homeostasis have been demonstrated for proteins encoded by familial AD-linked genes such as PSEN1, PSEN2, and APP, as well as Aβ peptides. Whereas these studies support the hypothesis that disruption of Ca(2+) homeostasis contributes to AD, it is difficult to disentangle the effects of familial AD-linked genes on Aβ production from their effects on Ca(2+) homeostasis. Here, we developed a system in which cellular Ca(2+) homeostasis could be directly manipulated to study the effects on amyloid precursor protein metabolism and Aβ production. We overexpressed stromal interaction molecule 1 (STIM1) and Orai1, the components of the store-operated Ca(2+) entry pathway, to generate cells with constitutive and store depletion-induced Ca(2+) entry. We found striking effects of Ca(2+) entry induced by overexpression of the constitutively active STIM1(D76A) mutant on amyloid precursor protein metabolism. Specifically, constitutive activation of Ca(2+) entry by expression of STIM1(D76A) significantly reduced Aβ secretion. Our results suggest that disruptions in Ca(2+) homeostasis may influence AD pathogenesis directly through the modulation of Aβ production.

  9. Inhibition of Cholesterol Biosynthesis Reduces γ-Secretase Activity and Amyloid-β Generation.

    PubMed

    Kim, Yoonhee; Kim, Chaeyoung; Jang, Hye Young; Mook-Jung, Inhee

    2016-01-01

    Amyloid-β (Aβ) is one of major molecules contributing to the pathogenesis of Alzheimer's disease (AD). Aβ is derived from amyloid-β protein precursor (AβPP) through sequential cleavages by β- and γ-secretases. Regulation of these components is thought to be an important factor in Aβ generation during the pathogenesis of AD. AβPP, β-secretase, and γ-secretase reside in lipid rafts, where cholesterol regulates the integrity and flexibility of membrane proteins and Aβ is generated. However, the relationship between cholesterol and Aβ generation is controversial. In this study, we aimed to elucidate the direct effects of cholesterol depletion on AβPP processing using AY9944, which blocks the last step of cholesterol biosynthesis and thus minimizes the unknown side effects of upstream inhibitors, such as HMG-CoA reductase inhibitors. Treatment with AY9944 decreased γ-secretase activity and Aβ generation. These results suggested that changes in membrane composition by lowering cholesterol with AY9944 affected γ-secretase activity and Aβ generation, which is associated with AD pathogenesis.

  10. Heat shock treatment reduces beta amyloid toxicity in vivo by diminishing oligomers.

    PubMed

    Wu, Yanjue; Cao, Zhiming; Klein, William L; Luo, Yuan

    2010-06-01

    Heat shock response, mediated by heat shock proteins, is a highly conserved physiological process in multicellular organisms for reestablishment of cellular homeostasis. Expression of heat shock factors and subsequent heat shock protein plays a role in protection against proteotoxicity in invertebrate and vertebrate models. Proteotoxicity due to beta-amyloid peptide (Abeta) oligomerization has been linked to the pathogenesis of Alzheimer's disease. Previously, we demonstrated that progressive paralysis induced by expression of human Abeta(1-42) in transgenic Caenorhabditis elegans was alleviated by Abeta oligomer inhibitors Ginkgo biloba extract and its constituents [Wu, Y., Wu, Z., Butko, P., Christen, Y., Lambert, M.P., Klein, W.L., Link, C.D., Luo, Y., 2006. Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J. Neurosci. 26(50): 13102-13113]. In this study, we apply a protective heat shock to the transgenic C. elegans and demonstrate: (1) a delay in paralysis, (2) increased expression of small heat shock protein HSP16.2, and (3) significant reduction of Abeta oligomers in a heat shock time-dependent manner. These results suggest that transient heat shock lessens Abeta toxicity by diminishing Abeta oligomerization, which provides a link between up regulation of endogenous chaperone proteins and protection against Abeta proteotoxicity in vivo.

  11. Beta-amyloid auto-antibodies are reduced in Alzheimer's disease.

    PubMed

    Qu, Bao-Xi; Gong, Yunhua; Moore, Carol; Fu, Min; German, Dwight C; Chang, Ling-Yu; Rosenberg, Roger; Diaz-Arrastia, Ramon

    2014-09-15

    Accumulation and cytotoxicity of amyloid beta (Aβ) are understood as the major cause of Alzheimer's disease (AD). There is evidence that naturally occurring antibodies against amyloid beta (Aβ) protein play a role in Aβ-clearance, and such a mechanism appears to be impaired in AD. In the present study, the anti-Aβ antibodies in the serum from individuals with and without late onset AD were measured using ELISA and dot-blot methods. Aβ auto-antibodies in serum were mainly targeted to Aβ1-15 epitope and its titer was significantly lower in AD patients than elderly non-AD controls (NC). The dot-blot analysis further demonstrated that auto-antibodies against fibrillar Aβ42, Aβ1-15 and Aβ16-30 epitopes were all in a lower level in AD than in NC. The isotypes of the auto-antibodies were mainly non-inflammatory IgG2 type. We also analyzed the relationship of auto-Aβ antibody levels with the genotypes of apolipoprotein E (ApoE) and ANKK1/DRD2 gene.

  12. Increased onset of vergence adaptation reduces excessive accommodation during the orthoptic treatment of convergence insufficiency.

    PubMed

    Sreenivasan, Vidhyapriya; Bobier, William R

    2015-06-01

    This research tested the hypothesis that the successful treatment of convergence insufficiency (CI) with vision-training (VT) procedures, leads to an increased capacity of vergence adaptation (VAdapt) allowing a more rapid downward adjustment of the convergence accommodation cross-link. Nine subjects with CI were recruited from a clinical population, based upon reduced fusional vergence amplitudes, receded near point of convergence or symptomology. VAdapt and the resulting changes to convergence accommodation (CA) were measured at specific intervals over 15 min (pre-training). Separate clinical measures of the accommodative convergence cross link, horizontal fusion limits and near point of convergence were taken and a symptomology questionnaire completed. Subjects then participated in a VT program composed of 2.5h at home and 1h in-office weekly for 12-14 weeks. Clinical testing was done weekly. VAdapt and CA measures were retaken once clinical measures normalized for 2 weeks (mid-training) and then again when symptoms had cleared (post-training). VAdapt and CA responses as well as the clinical measures were taken on a control group showing normal clinical findings. Six subjects provided complete data sets. CI clinical findings reached normal levels between 4 and 7 weeks of training but symptoms, VAdapt, and CA output remained significantly different from the controls until 12-14 weeks. The hypothesis was retained. The reduced VAdapt and excessive CA found in CI were normalized through orthoptic treatment. This time course was underestimated by clinical findings but matched symptom amelioration.

  13. Ryanodine receptors blockade reduces Amyloid-beta load and memory impairments in Tg2576 mouse model of Alzheimer disease

    PubMed Central

    Oulès, Bénédicte; Del Prete, Dolores; Greco, Barbara; Zhang, Xuexin; Lauritzen, Inger; Sevalle, Jean; Moreno, Sebastien; Paterlini-Bréchot, Patrizia; Trebak, Mohamed; Checler, Frédéric; Benfenati, Fabio; Chami, Mounia

    2012-01-01

    In Alzheimer disease (AD), the perturbation of the endoplasmic reticulum (ER) calcium (Ca2+) homeostasis has been linked to presenilins (PS), the catalytic core in γ-secretase complexes cleaving the amyloid precursor protein (APP) thereby generating amyloid-β (Aβ) peptides. Here we investigate whether APP contributes to ER Ca2+ homeostasis and whether ER Ca2+ could in turn influence Aβ production. We show that overexpression of wild-type human APP (APP695), or APP harboring the Swedish double mutation (APPswe) triggers increased Ryanodine receptors (RyR) expression and enhances RyR-mediated ER Ca2+ release in SH-SY5Y neuroblastoma cells and in APPswe-expressing (Tg2576) mice. Interestingly, dantrolene-induced lowering of RyR-mediated Ca2+ release leads to the reduction of both intracellular and extracellular Aβ load in neuroblastoma cells as well as in primary cultured neurons derived from Tg2576 mice. This Aβ reduction can be accounted for by decreased Thr-668-dependent APP phosphorylation and β- and γ-secretases activities. Importantly, dantrolene diminishes Aβ load, reduces Aβ-related histological lesions and slows down learning and memory deficits in Tg2576 mice. Overall, our data document a key role of RyR in Aβ production and learning and memory performances, and delineate RyR-mediated control of Ca2+ homeostasis as a physiological paradigm that could be targeted for innovative therapeutic approaches. PMID:22915123

  14. Antioxidant supplementation can reduce the survival costs of excess amino acid intake in honeybees.

    PubMed

    Archer, C Ruth; Köhler, Angela; Pirk, Christian W W; Oosthuizen, Vinette; Apostolides, Zeno; Nicolson, Susan W

    2014-12-01

    Over-consuming amino acids is associated with reduced survival in many species, including honeybees. The mechanisms responsible for this are unclear but one possibility is that excessive intake of amino acids increases oxidative damage. If this is the case, antioxidant supplementation may help reduce the survival costs of high amino acid intake. We tested this hypothesis in African honeybees (Apis mellifera scutellata) using the major antioxidant in green tea, epigallocatechin-3-gallate (EGCG). We first determined the dose-range of EGCG that improved survival of caged honeybees fed sucrose solution. We then provided bees with eight diets that differed in their ratio of essential amino acids (EAA) to carbohydrate (C) (0:1, 1:250, 1:100, 1:75, 1:50, 1:25, 1:10, 1:5 EAA:C) and also in their EGCG dose (0.0 or 0.4 mM). We found that bees fed sucrose only solution survived better than bees fed EAA diets. Despite this, bees preferred a diet that contained intermediate ratios of EAA:C (ca. 1:25), which may represent the high demands for nitrogen of developing nurse bees. EGCG supplementation improved honeybee survival but only at an intermediate dose (0.3-0.5 mM) and in bees fed low EAA diets (1:250, 1:100 EAA:C). That EGCG counteracted the lifespan reducing effects of eating low EAA diets suggests that oxidative damage may be involved in the association between EAAs and lifespan in honeybees. However, that EGCG had no effect on survival in bees fed high EAA diets suggests that there are other physiological costs of over-consuming EAAs in honeybees.

  15. The second-generation active Aβ immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects.

    PubMed

    Wiessner, Christoph; Wiederhold, Karl-Heinz; Tissot, Alain C; Frey, Peter; Danner, Simone; Jacobson, Laura H; Jennings, Gary T; Lüönd, Rainer; Ortmann, Rainer; Reichwald, Julia; Zurini, Mauro; Mir, Anis; Bachmann, Martin F; Staufenbiel, Matthias

    2011-06-22

    Immunization against amyloid-β (Aβ) can reduce amyloid accumulation in vivo and is considered a potential therapeutic approach for Alzheimer's disease. However, it has been associated with meningoencephalitis thought to be mediated by inflammatory T-cells. With the aim of producing an immunogenic vaccine without this side effect, we designed CAD106 comprising Aβ1-6 coupled to the virus-like particle Qβ. Immunization with this vaccine did not activate Aβ-specific T-cells. In APP transgenic mice, CAD106 induced efficacious Aβ antibody titers of different IgG subclasses mainly recognizing the Aβ3-6 epitope. CAD106 reduced brain amyloid accumulation in two APP transgenic mouse lines. Plaque number was a more sensitive readout than plaque area, followed by Aβ42 and Aβ40 levels. Studies with very strong overall amyloid reduction showed an increase in vascular Aβ, which atypically was nonfibrillar. The efficacy of Aβ immunotherapy depended on the Aβ levels and thus differed between animal models, brain regions, and stage of amyloid deposition. Therefore, animal studies may not quantitatively predict the effect in human Alzheimer's disease. Our studies provided no evidence for increased microhemorrhages or inflammatory reactions in amyloid-containing brain. In rhesus monkeys, CAD106 induced a similar antibody response as in mice. The antibodies stained amyloid deposits on tissue sections of mouse and human brain but did not label cellular structures containing APP. They reacted with Aβ monomers and oligomers and blocked Aβ toxicity in cell culture. We conclude that CAD106 immunization is suited to interfere with Aβ aggregation and its downstream detrimental effects.

  16. Excess of non-conservative amino acid changes in marine bacterioplankton lineages with reduced genomes.

    PubMed

    Luo, Haiwei; Huang, Yongjie; Stepanauskas, Ramunas; Tang, Jijun

    2017-06-12

    Surface ocean waters are dominated by planktonic bacterial lineages with highly reduced genomes. The best examples are the cyanobacterial genus Prochlorococcus, the alphaproteobacterial clade SAR11 and the gammaproteobacterial clade SAR86, which together represent over 50% of the cells in surface oceans. Several studies have identified signatures of selection on these lineages in today's ocean and have postulated selection as the primary force throughout their evolutionary history. However, massive loss of genomic DNA in these lineages often occurred in the distant past, and the selective pressures underlying these ancient events have not been assessed. Here, we probe ancient selective pressures by computing %GC-corrected rates of conservative and radical nonsynonymous nucleotide substitutions. Surprisingly, we found an excess of radical changes in several of these lineages in comparison to their relatives with larger genomes. Furthermore, analyses of allelic genome sequences of several populations within these lineages consistently supported that radical replacements are more likely to be deleterious than conservative changes. Our results suggest coincidence of massive genomic DNA losses and increased power of genetic drift, but we also suggest that additional evidence independent of the nucleotide substitution analyses is needed to support a primary role of genetic drift driving ancient genome reduction of marine bacterioplankton lineages.

  17. Excess coenzyme A reduces skeletal muscle performance and strength in mice overexpressing human PANK2.

    PubMed

    Corbin, Deborah R; Rehg, Jerold E; Shepherd, Danielle L; Stoilov, Peter; Percifield, Ryan J; Horner, Linda; Frase, Sharon; Zhang, Yong-Mei; Rock, Charles O; Hollander, John M; Jackowski, Suzanne; Leonardi, Roberta

    2017-02-03

    Coenzyme A (CoA) is a cofactor that is central to energy metabolism and CoA synthesis is controlled by the enzyme pantothenate kinase (PanK). A transgenic mouse strain expressing human PANK2 was derived to determine the physiological impact of PANK overexpression and elevated CoA levels. The Tg(PANK2) mice expressed high levels of the transgene in skeletal muscle and heart; however, CoA was substantially elevated only in skeletal muscle, possibly associated with the comparatively low endogenous levels of acetyl-CoA, a potent feedback inhibitor of PANK2. Tg(PANK2) mice were smaller, had less skeletal muscle mass and displayed significantly impaired exercise tolerance and grip strength. Skeletal myofibers were characterized by centralized nuclei and aberrant mitochondria. Both the content of fully assembled complex I of the electron transport chain and ATP levels were reduced, while markers of oxidative stress were elevated in Tg(PANK2) skeletal muscle. These abnormalities were not detected in the Tg(PANK2) heart muscle, with the exception of spotty loss of cristae organization in the mitochondria. The data demonstrate that excessively high CoA may be detrimental to skeletal muscle function.

  18. Reduced expression of pain mediators and pain sensitivity in amyloid precursor protein over-expressing CRND8 transgenic mice.

    PubMed

    Shukla, M; Quirion, R; Ma, W

    2013-10-10

    β-Amyloid (Aβ) peptides are derived from the sequential cleavage of the amyloid precursor protein (APP). They are enriched in plaques present in Alzheimer's brains and thus play important roles in the pathogenesis of this disease. APP is also known to be expressed in the neurons of dorsal root ganglion (DRG) and contributes to neuronal survival and axonal growth during development. However, whether APP and Aβ peptides are involved in nociception and pathological pain states is mostly unknown. In the present study, we have used behavioral, biochemical and morphological approaches to address this issue in both adult rats and APP over-expressing CRND8 transgenic mice. We observed that the Aβ peptide (17-24) was predominantly expressed in small-sized DRG neurons of rats. Following intraplantar (i.pl.) injection of complete Freud's adjuvant (CFA), the levels of APP and Aβ peptides were significantly reduced in the ipsilateral lumbar 4-6 rat DRG. In 3-, 12- and 24-month-old CRND8 mice, pain sensitivity in response to heat and mechanical stimulation was significantly dampened compared to their age-matched wild-type littermates. In parallel with reduced pain sensitivity, the expression of pain mediators such as substance P, calcitonin gene-related peptide and transient receptor potential vanilloid-1 was significantly reduced in L4-6 DRG of CRND8 mice. Although i.pl. injection of CFA induced a rather similar pattern of inflammatory pain in 3-month-old CRND8 mice and their wild-type littermates, recovery from inflammatory pain seemed faster in 12-month-old CRND8 mice than wild-type mice. These findings suggest that APP and Aβ peptides suppress both nociception and inflammatory pain and are likely involved in blunt pain perception of Alzheimer's patients in clinical settings.

  19. Lithium reduces BACE1 overexpression, β amyloid accumulation, and spatial learning deficits in mice with traumatic brain injury.

    PubMed

    Yu, Fengshan; Zhang, Yumin; Chuang, De-Maw

    2012-09-01

    Traumatic brain injury (TBI) leads to both acute injury and long-term neurodegeneration, and is a major risk factor for developing Alzheimer's disease (AD). Beta amyloid (Aβ) peptide deposits in the brain are one of the pathological hallmarks of AD. Aβ levels increase after TBI in animal models and in patients with head trauma, and reducing Aβ levels after TBI has beneficial effects. Lithium is known to be neuroprotective in various models of neurodegenerative disease, and can reduce Aβ generation by modulating glycogen synthase kinase-3 (GSK-3) activity. In this study we explored whether lithium would reduce Aβ load after TBI, and improve learning and memory in a mouse TBI model. Lithium chloride (1.5 mEq/kg, IP) was administered 15 min after TBI, and once daily thereafter for up to 3 weeks. At 3 days after injury, lithium attenuated TBI-induced Aβ load increases, amyloid precursor protein (APP) accumulation, and β-APP-cleaving enzyme-1 (BACE1) overexpression in the corpus callosum and hippocampus. Increased Tau protein phosphorylation in the thalamus was also attenuated after lithium treatment following TBI at the same time point. Notably, lithium treatment significantly improved spatial learning and memory in the Y-maze test conducted 10 days after TBI, and in the Morris water maze test performed 17-20 days post-TBI, in association with increased hippocampal preservation. Thus post-insult treatment with lithium appears to alleviate the TBI-induced Aβ load and consequently improves spatial memory. Our findings suggest that lithium is a potentially useful agent for managing memory impairments after TBI or other head trauma.

  20. Antioxidant activity, delayed aging, and reduced amyloid-β toxicity of methanol extracts of tea seed pomace from Camellia tenuifolia.

    PubMed

    Wei, Chia-Cheng; Yu, Chan-Wei; Yen, Pei-Ling; Lin, Huan-You; Chang, Shang-Tzen; Hsu, Fu-Lan; Liao, Vivian Hsiu-Chuan

    2014-11-05

    There is a growing interest in the exploitation of the residues generated by plants. This study explored the potential beneficial health effects from the main biowaste, tea seed pomace, produced when tea seed is processed. DPPH radical scavenging and total phenolic content assays were performed to evaluate the in vitro activities of the extracts. Caenorhabditis elegans was used as in vivo model to evaluate the beneficial health effects, including antioxidant activity, delayed aging, and reduced amyloid-β toxicity. Among all soluble fractions obtained from the extracts of tea seed pomace from Camellia tenuifolia, the methanol (MeOH)-soluble fraction has the best in vivo antioxidant activities. The MeOH-soluble extraction was further divided into six fractions by chromatography with a Diaion HP-20 column eluted with water/MeOH, and fraction 3 showed the best in vitro and in vivo antioxidant activities. Further analysis in C. elegans showed that the MeOH extract (fraction 3) of tea seed pomace significantly decreased intracellular reactive oxygen species, prolonged C. elegans lifespan, and reduced amyloid-β (Aβ) toxicity in transgenic C. elegans expressing human Aβ. Moreover, bioactivity-guided fractionation yielded two potent constituents from fraction 3 of the MeOH extract, namely, kaempferol 3-O-(2″-glucopyranosyl)-rutinoside and kaempferol 3-O-(2″-xylopyranosyl)-rutinoside, and both compounds exhibited excellent in vivo antioxidant activity. Taken together, MeOH extracts of tea seed pomace from C. tenuifolia have multiple beneficial health effects, suggesting that biowaste might be valuable to be explored for further development as nutraceutical products. Furthermore, the reuse of agricultural byproduct tea seed pomace also fulfills the environmental perspective.

  1. p75 reduces beta-amyloid-induced sympathetic innervation deficits in an Alzheimer's disease mouse model.

    PubMed

    Bengoechea, Tasha G; Chen, Zhijiang; O'Leary, Debra A; O'Leary, Deborah; Masliah, Eliezer; Lee, Kuo-Fen

    2009-05-12

    Beta-amyloid (Abeta) has adverse effects on brain cells, but little is known about its effects on the peripheral nervous system in Alzheimer's disease (AD). Several lines of in vitro evidence suggest that the neurotrophin receptor p75 mediates or exacerbates Abeta-induced neurotoxicity. Here, we show that p75-deficient sympathetic neurons are more sensitive to Abeta-induced neurite growth inhibition. To investigate the role of p75 in the sympathetic nervous system of AD, p75 mutant mice were crossed with a mouse line of AD model. The majority of p75-deficient AD mice died by 3 weeks of age. The lethality is associated with severe defects in sympathetic innervation to multiple organs. When 1 copy of the BACE1 gene encoding a protein essential in Abeta production was deleted in p75-deficient AD mice, sympathetic innervation was significantly restored. These results suggest that p75 is neuroprotective for the sympathetic nervous system in a mouse model of AD.

  2. Amyloid-beta increases acetylcholinesterase expression in neuroblastoma cells by reducing enzyme degradation.

    PubMed

    Hu, William; Gray, Noah W; Brimijoin, Stephen

    2003-07-01

    Amyloid-beta (Abeta) is the principal protein constituent of 'senile plaques' and is a suspected mediator in Alzheimer's disease (AD). Senile plaques also contain acetylcholinesterase (AChE; EC 3.1.1.7), which may have a role in promoting Alphabeta-toxicity. We have found that Alphabeta can affect AChE expression in a neuron-like line, the N1E.115 neuroblastoma cell. When 1 micro mAlphabeta 1-42 or 25-35 was added for 24 h to differentiating N1E.115 in culture, AChE activity increased 30-40% in adherent cells, and 100% or more in nonadherent cells. The changes in both tetrameric (G4) and monomeric (G1) AChE forms were comparable. Turnover studies indicated that the elevation of AChE activity reflected slowed AChE degradation rather than accelerated synthesis. With a similar time course, Alphabeta also increased the quantity of muscarinic receptors on the plasma membrane. Immunocytochemistry for a lysosomal membrane protein (LAMP-1) indicated no change in abundance or localization of lysosomes in treated cells. But decreased labeling by pH-sensitive fluorescent dye pointed to an impairment of lysosomal acidification. We consider that the alteration of AChE expression after Alphabeta-exposure could reflect lysosomal dysfunction, and might itself enhance Alphabeta-toxicity.

  3. Inhibitors of cathepsin B improve memory and reduce beta-amyloid in transgenic Alzheimer disease mice expressing the wild-type, but not the Swedish mutant, beta-secretase site of the amyloid precursor protein.

    PubMed

    Hook, Vivian Y H; Kindy, Mark; Hook, Gregory

    2008-03-21

    Elucidation of Abeta-lowering agents that inhibit processing of the wild-type (WT) beta-secretase amyloid precursor protein (APP) site, present in most Alzheimer disease (AD) patients, is a logical approach for improving memory deficit in AD. The cysteine protease inhibitors CA074Me and E64d were selected by inhibition of beta-secretase activity in regulated secretory vesicles that produce beta-amyloid (Abeta). The regulated secretory vesicle activity, represented by cathepsin B, selectively cleaves the WT beta-secretase site but not the rare Swedish mutant beta-secretase site. In vivo treatment of London APP mice, expressing the WT beta-secretase site, with these inhibitors resulted in substantial improvement in memory deficit assessed by the Morris water maze test. After inhibitor treatment, the improved memory function was accompanied by reduced amyloid plaque load, decreased Abeta40 and Abeta42, and reduced C-terminal beta-secretase fragment derived from APP by beta-secretase. However, the inhibitors had no effects on any of these parameters in mice expressing the Swedish mutant beta-secretase site of APP. The notable efficacy of these inhibitors to improve memory and reduce Abeta in an AD animal model expressing the WT beta-secretase APP site present in the majority of AD patients provides support for CA074Me and E64d inhibitors as potential AD therapeutic agents.

  4. Curcumin mediates presenilin-1 activity to reduce β-amyloid production in a model of Alzheimer's Disease.

    PubMed

    Xiong, Zhang; Hongmei, Zhang; Lu, Si; Yu, Li

    2011-01-01

    Curcumin has been reported to inhibit the generation of Aβ, but the underlying mechanisms by which this occurs remain unknown. Aβ is thought to play an important role in the pathogenesis of Alzheimer's disease (AD). The amyloid hypothesis argues that aggregates of Aβ trigger a complex pathological cascade that leads to neurodegeneration. Aβ is generated by the processing of APP (amyloid precursor protein) by β- and γ-secretases. Presenilin 1 (PS1) is central to γ-secretase activity and is a substrate for GSK-3β, both of which are implicated in the pathogenesis of AD. The present study aimed to investigate the effects of curcumin on the generation of Aβ in cultured neuroblastoma cells and on the in vitro expression of PS1 and GSK-3β. To stimulate Aβ production, a plasmid expressing APP was transfected into human SH-SY5Y neuroblastoma cells. The transfected cells were then treated with curcumin at 0-20 μM for 24 h or with 5 μM curcumin for 0-48 h, and the extracellular levels of Aβ(40/42) were determined by ELISA. The levels of PS1 and GSK-3β mRNA were measured by RT-PCR, and the expression of the PS1 and GSK-3β proteins (including the phosphorylated form of GSK-3β, p-GSK-3β-Ser9) were evaluated by western blotting. Curcumin treatment was found to markedly reduce the production of Aβ(40/42). Treatment with curcumin also decreased both PS1 and GSK-3β mRNA and protein levels in a dose- and time-dependent manner. Furthermore, curcumin increased the inhibitory phosphorylation of GSK-3β protein at Ser9. Therefore, we propose that curcumin decreases Aβ production by inhibiting GSK-3β-mediated PS1 activation.

  5. Ryanodine receptor blockade reduces amyloid-β load and memory impairments in Tg2576 mouse model of Alzheimer disease.

    PubMed

    Oulès, Bénédicte; Del Prete, Dolores; Greco, Barbara; Zhang, Xuexin; Lauritzen, Inger; Sevalle, Jean; Moreno, Sebastien; Paterlini-Bréchot, Patrizia; Trebak, Mohamed; Checler, Frédéric; Benfenati, Fabio; Chami, Mounia

    2012-08-22

    In Alzheimer disease (AD), the perturbation of the endoplasmic reticulum (ER) calcium (Ca²⁺) homeostasis has been linked to presenilins, the catalytic core in γ-secretase complexes cleaving the amyloid precursor protein (APP), thereby generating amyloid-β (Aβ) peptides. Here we investigate whether APP contributes to ER Ca²⁺ homeostasis and whether ER Ca²⁺ could in turn influence Aβ production. We show that overexpression of wild-type human APP (APP(695)), or APP harboring the Swedish double mutation (APP(swe)) triggers increased ryanodine receptor (RyR) expression and enhances RyR-mediated ER Ca²⁺ release in SH-SY5Y neuroblastoma cells and in APP(swe)-expressing (Tg2576) mice. Interestingly, dantrolene-induced lowering of RyR-mediated Ca²⁺ release leads to the reduction of both intracellular and extracellular Aβ load in neuroblastoma cells as well as in primary cultured neurons derived from Tg2576 mice. This Aβ reduction can be accounted for by decreased Thr-668-dependent APP phosphorylation and β- and γ-secretases activities. Importantly, dantrolene diminishes Aβ load, reduces Aβ-related histological lesions, and slows down learning and memory deficits in Tg2576 mice. Overall, our data document a key role of RyR in Aβ production and learning and memory performances, and delineate RyR-mediated control of Ca²⁺ homeostasis as a physiological paradigm that could be targeted for innovative therapeutic approaches.

  6. CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer’s Disease Mouse Models

    PubMed Central

    Lee, Sungho; Varvel, Nicholas H.; Konerth, Megan E.; Xu, Guixiang; Cardona, Astrid E.; Ransohoff, Richard M.; Lamb, Bruce T.

    2010-01-01

    Microglia, the primary immune effector cells in the brain, continually monitor the tissue parenchyma for pathological alterations and become activated in Alzheimer’s disease. Loss of signaling between neurons and microglia via deletion of the microglial receptor, CX3CR1, worsens phenotypes in various models of neurodegenerative diseases. In contrast, CX3CR1 deficiency ameliorates pathology in murine stroke models. To examine the role of CX3CR1 in Alzheimer’s disease–related β-amyloid pathology, we generated APPPS1 and R1.40 transgenic mouse models of Alzheimer’s disease deficient for CX3CR1. Surprisingly, CX3CR1 deficiency resulted in a gene dose-dependent reduction in β-amyloid deposition in both the APPPS1 and R1.40 mouse models of AD. Immunohistochemical analysis revealed reduced staining for CD68, a marker of microglial activation. Furthermore, quantitative immunohistochemical analysis revealed reduced numbers of microglia surrounding β-amyloid deposits in the CX3CR1-deficient APPPS1 animals. The reduced β-amyloid pathology correlated with reduced levels of TNFα and CCL2 mRNAs, but elevated IL1β mRNA levels, suggesting an altered neuroinflammatory milieu. Finally, to account for these seemingly disparate results, both in vitro and in vivo studies provided evidence that CX3CL1/CX3CR1 signaling alters the phagocytic capacity of microglia, including the uptake of Aβ fibrils. Taken together, these results demonstrate that loss of neuron-microglial fractalkine signaling leads to reduced β-amyloid deposition in mouse models of AD that is potentially mediated by altered activation and phagocytic capability of CX3CR1-deficient microglia. PMID:20864679

  7. The FDA-approved natural product dihydroergocristine reduces the production of the Alzheimer’s disease amyloid-β peptides

    PubMed Central

    Lei, Xiling; Yu, Jing; Niu, Qi; Liu, Jianhua; Fraering, Patrick C.; Wu, Fang

    2015-01-01

    Known γ-secretase inhibitors or modulators display an undesirable pharmacokinetic profile and toxicity and have therefore not been successful in clinical trials for Alzheimer’s disease (AD). So far, no compounds from natural products have been identified as direct inhibitors of γ-secretase. To search for bioactive molecules that can reduce the amount of amyloid-beta peptides (Aβ) and that have better pharmacokinetics and an improved safety profile, we completed a screen of ~400 natural products by using cell-based and cell-free γ-secretase activity assays. We identified dihydroergocristine (DHEC), a component of an FDA- (Food and Drug Administration)-approved drug, to be a direct inhibitor of γ-secretase. Micromolar concentrations of DHEC substantially reduced Aβ levels in different cell types, including a cell line derived from an AD patient. Structure-activity relationship studies implied that the key moiety for inhibiting γ-secretase is the cyclized tripeptide moiety of DHEC. A Surface Plasmon Resonance assay showed that DHEC binds directly to γ-secretase and Nicastrin, with equilibrium dissociation constants (Kd) of 25.7 nM and 9.8 μM, respectively. This study offers DHEC not only as a new chemical moiety for selectively modulating the activity of γ-secretase but also a candidate for drug repositioning in Alzheimer’s disease. PMID:26567970

  8. Reducing Potentially Excess Deaths from the Five Leading Causes of Death in the Rural United States

    PubMed

    Garcia, Macarena C; Faul, Mark; Massetti, Greta; Thomas, Cheryll C; Hong, Yuling; Bauer, Ursula E; Iademarco, Michael F

    2017-01-13

    In 2014, the all-cause age-adjusted death rate in the United States reached a historic low of 724.6 per 100,000 population (1). However, mortality in rural (nonmetropolitan) areas of the United States has decreased at a much slower pace, resulting in a widening gap between rural mortality rates (830.5) and urban mortality rates (704.3) (1). During 1999–2014, annual age-adjusted death rates for the five leading causes of death in the United States (heart disease, cancer, unintentional injury, chronic lower respiratory disease (CLRD), and stroke) were higher in rural areas than in urban (metropolitan) areas (Figure 1). In most public health regions (Figure 2), the proportion of deaths among persons aged <80 years (U.S. average life expectancy) (2) from the five leading causes that were potentially excess deaths was higher in rural areas compared with urban areas (Figure 3). Several factors probably influence the rural-urban gap in potentially excess deaths from the five leading causes, many of which are associated with sociodemographic differences between rural and urban areas. Residents of rural areas in the United States tend to be older, poorer, and sicker than their urban counterparts (3). A higher proportion of the rural U.S. population reports limited physical activity because of chronic conditions than urban populations (4). Moreover, social circumstances and behaviors have an impact on mortality and potentially contribute to approximately half of the determining causes of potentially excess deaths (5).

  9. Reduced nitric oxide bioavailability mediates cerebroarterial dysfunction independent of cerebral amyloid angiopathy in a mouse model of Alzheimer's disease.

    PubMed

    Merlini, Mario; Shi, Yi; Keller, Stephan; Savarese, Gianluigi; Akhmedov, Alexander; Derungs, Rebecca; Spescha, Remo D; Kulic, Luka; Nitsch, Roger M; Lüscher, Thomas F; Camici, Giovanni G

    2017-02-01

    In Alzheimer's disease (AD), cerebral arteries, in contrast to cerebral microvessels, show both cerebral amyloid angiopathy (CAA) -dependent and -independent vessel wall pathology. However, it remains unclear whether CAA-independent vessel wall pathology affects arterial function, thereby chronically reducing cerebral perfusion, and, if so, which mechanisms mediate this effect. To this end, we assessed the ex vivo vascular function of the basilar artery and a similar-sized peripheral artery (femoral artery) in the Swedish-Arctic (SweArc) transgenic AD mouse model at different disease stages. Furthermore, we used quantitative immunohistochemistry to analyze CAA, endothelial morphology, and molecular pathways pertinent to vascular relaxation. We found that endothelium-dependent, but not smooth muscle-dependent, vasorelaxation was significantly impaired in basilar and femoral arteries of 15-mo-old SweArc mice compared with that of age-matched wild-type and 6-mo-old SweArc mice. This impairment was accompanied by significantly reduced levels of cyclic GMP, indicating a reduced nitric oxide (NO) bioavailability. However, no age- and genotype-related differences in oxidative stress as measured by lipid peroxidation were observed. Although parenchymal capillaries, arterioles, and arteries showed abundant CAA in the 15-mo-old SweArc mice, no CAA or changes in endothelial morphology were detected histologically in the basilar and femoral artery. Thus our results suggest that, in this AD mouse model, dysfunction of large intracranial, extracerebral arteries important for brain perfusion is mediated by reduced NO bioavailability rather than by CAA. This finding supports the growing body of evidence highlighting the therapeutic importance of targeting the cerebrovasculature in AD.

  10. Apigenin modulates the expression levels of pro-inflammatory mediators to reduce the human insulin amyloid-induced oxidant damages in SK-N-MC cells.

    PubMed

    Amini, R; Yazdanparast, R; Ghaffari, S H

    2015-06-01

    Amyloid depositions of proteins play crucial roles in a wide variety of degenerative disorders called amyloidosis. Although the exact mechanisms involved in amyloid-mediated cytotoxicity remain unknown, increased formation of reactive oxygen species (ROS) and nitrogen species and overproduction of pro-inflammatory cytokines are believed to play key roles in the process. In that regard, we investigated the effect of apigenin, a common dietary flavonoid with high antioxidant and anti-inflammatory properties on potential factors involved in cytotoxicity of human insulin amyloids. Pretreatment of SK-N-MC neuroblastoma cells with apigenin increased cell viability and reduced the apoptosis induced by insulin fibrils. In addition, apigenin attenuated insulin fibril-induced ROS production and lipid peroxidation. Our result also demonstrated that pretreatment of the fibril-affected cells with apigenin caused an increase in catalase activity and the intracellular glutathione content along with reduction in nitric oxide production and nuclear factor κB, tumor necrosis factor α, and interleukin 6 gene expression based on real-time polymerase chain reaction evaluation. In accordance with these results, apigenin could be a promising candidate in the design of natural-based drugs for treatment or prevention of amyloid-related disorders.

  11. Green tea aroma fraction reduces β-amyloid peptide-induced toxicity in Caenorhabditis elegans transfected with human β-amyloid minigene.

    PubMed

    Takahashi, Atsushi; Watanabe, Tatsuro; Fujita, Takashi; Hasegawa, Toshio; Saito, Michio; Suganuma, Masami

    2014-01-01

    Green tea is a popular world-wide beverage with health benefits that include preventive effects on cancer as well as cardiovascular, liver and Alzheimer's diseases (AD). This study will examine the preventive effects on AD of a unique aroma of Japanese green tea. First, a transgenic Caenorhabditis elegans (C. elegans) CL4176 expressing human β-amyloid peptide (Aβ) was used as a model of AD. A hexane extract of processed green tea was further fractionated into volatile and non-volatile fractions, named roasty aroma and green tea aroma fractions depending on their aroma, by microscale distillation. Both hexane extract and green tea aroma fraction were found to inhibit Aβ-induced paralysis, while only green tea aroma fraction extended lifespan in CL4176. We also found that green tea aroma fraction has antioxidant activity. This paper indicates that the green tea aroma fraction is an additional component for prevention of AD.

  12. Diet rich in date palm fruits improves memory, learning and reduces beta amyloid in transgenic mouse model of Alzheimer's disease.

    PubMed

    Subash, Selvaraju; Essa, Musthafa Mohamed; Braidy, Nady; Awlad-Thani, Kathyia; Vaishnav, Ragini; Al-Adawi, Samir; Al-Asmi, Abdullah; Guillemin, Gilles J

    2015-01-01

    At present, the treatment options available to delay the onset or slow down the progression of Alzheimer's disease (AD) are not effective. Recent studies have suggested that diet and lifestyle factors may represent protective strategies to minimize the risk of developing AD. Date palm fruits are a good source of dietary fiber and are rich in total phenolics and natural antioxidants, such as anthocyanins, ferulic acid, protocatechuic acid and caffeic acid. These polyphenolic compounds have been shown to be neuroprotective in different model systems. We investigated whether dietary supplementation with 2% and 4% date palm fruits (grown in Oman) could reduce cognitive and behavioral deficits in a transgenic mouse model for AD (amyloid precursor protein [APPsw]/Tg2576). The experimental groups of APP-transgenic mice from the age of 4 months were fed custom-mix diets (pellets) containing 2% and 4% date fruits. We assessed spatial memory and learning ability, psychomotor coordination, and anxiety-related behavior in all the animals at the age of 4 months and after 14 months of treatment using the Morris water maze test, rota-rod test, elevated plus maze test, and open-field test. We have also analyzed the levels of amyloid beta (Aβ) protein (1-40 and 1-42) in plasma of control and experimental animals. Standard diet-fed Tg mice showed significant memory deficits, increased anxiety-related behavior, and severe impairment in spatial learning ability, position discrimination learning ability and motor coordination when compared to wild-type on the same diet and Tg mice fed 2% and 4% date supplementation at the age of 18 months. The levels of both Aβ proteins were significantly lowered in date fruits supplemented groups than the Tg mice without the diet supplement. The neuroprotective effect offered by 4% date fruits diet to AD mice is higher than 2% date fruits diet. Our results suggest that date fruits dietary supplementation may have beneficial effects in lowering the

  13. Diet rich in date palm fruits improves memory, learning and reduces beta amyloid in transgenic mouse model of Alzheimer's disease

    PubMed Central

    Subash, Selvaraju; Essa, Musthafa Mohamed; Braidy, Nady; Awlad-Thani, Kathyia; Vaishnav, Ragini; Al-Adawi, Samir; Al-Asmi, Abdullah; Guillemin, Gilles J.

    2015-01-01

    Background: At present, the treatment options available to delay the onset or slow down the progression of Alzheimer's disease (AD) are not effective. Recent studies have suggested that diet and lifestyle factors may represent protective strategies to minimize the risk of developing AD. Date palm fruits are a good source of dietary fiber and are rich in total phenolics and natural antioxidants, such as anthocyanins, ferulic acid, protocatechuic acid and caffeic acid. These polyphenolic compounds have been shown to be neuroprotective in different model systems. Objective: We investigated whether dietary supplementation with 2% and 4% date palm fruits (grown in Oman) could reduce cognitive and behavioral deficits in a transgenic mouse model for AD (amyloid precursor protein [APPsw]/Tg2576). Materials and Methods: The experimental groups of APP-transgenic mice from the age of 4 months were fed custom-mix diets (pellets) containing 2% and 4% date fruits. We assessed spatial memory and learning ability, psychomotor coordination, and anxiety-related behavior in all the animals at the age of 4 months and after 14 months of treatment using the Morris water maze test, rota-rod test, elevated plus maze test, and open-field test. We have also analyzed the levels of amyloid beta (Aβ) protein (1–40 and 1–42) in plasma of control and experimental animals. Results: Standard diet-fed Tg mice showed significant memory deficits, increased anxiety-related behavior, and severe impairment in spatial learning ability, position discrimination learning ability and motor coordination when compared to wild-type on the same diet and Tg mice fed 2% and 4% date supplementation at the age of 18 months. The levels of both Aβ proteins were significantly lowered in date fruits supplemented groups than the Tg mice without the diet supplement. The neuroprotective effect offered by 4% date fruits diet to AD mice is higher than 2% date fruits diet. Conclusions: Our results suggest that date

  14. Orally Administrated Cinnamon Extract Reduces β-Amyloid Oligomerization and Corrects Cognitive Impairment in Alzheimer's Disease Animal Models

    PubMed Central

    Farfara, Dorit; Benromano, Tali; Scherzer-Attali, Roni; Peled, Sivan; Vassar, Robert; Segal, Daniel; Gazit, Ehud; Frenkel, Dan; Ovadia, Michael

    2011-01-01

    An increasing body of evidence indicates that accumulation of soluble oligomeric assemblies of β-amyloid polypeptide (Aβ) play a key role in Alzheimer's disease (AD) pathology. Specifically, 56 kDa oligomeric species were shown to be correlated with impaired cognitive function in AD model mice. Several reports have documented the inhibition of Aβ plaque formation by compounds from natural sources. Yet, evidence for the ability of common edible elements to modulate Aβ oligomerization remains an unmet challenge. Here we identify a natural substance, based on cinnamon extract (CEppt), which markedly inhibits the formation of toxic Aβ oligomers and prevents the toxicity of Aβ on neuronal PC12 cells. When administered to an AD fly model, CEppt rectified their reduced longevity, fully recovered their locomotion defects and totally abolished tetrameric species of Aβ in their brain. Furthermore, oral administration of CEppt to an aggressive AD transgenic mice model led to marked decrease in 56 kDa Aβ oligomers, reduction of plaques and improvement in cognitive behavior. Our results present a novel prophylactic approach for inhibition of toxic oligomeric Aβ species formation in AD through the utilization of a compound that is currently in use in human diet. PMID:21305046

  15. Monoacylated Cellular Prion Proteins Reduce Amyloid-β-Induced Activation of Cytoplasmic Phospholipase A2 and Synapse Damage

    PubMed Central

    West, Ewan; Osborne, Craig; Nolan, William; Bate, Clive

    2015-01-01

    Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) and the loss of synapses. Aggregation of the cellular prion protein (PrPC) by Aβ oligomers induced synapse damage in cultured neurons. PrPC is attached to membranes via a glycosylphosphatidylinositol (GPI) anchor, the composition of which affects protein targeting and cell signaling. Monoacylated PrPC incorporated into neurons bound “natural Aβ”, sequestering Aβ outside lipid rafts and preventing its accumulation at synapses. The presence of monoacylated PrPC reduced the Aβ-induced activation of cytoplasmic phospholipase A2 (cPLA2) and Aβ-induced synapse damage. This protective effect was stimulus specific, as treated neurons remained sensitive to α-synuclein, a protein associated with synapse damage in Parkinson’s disease. In synaptosomes, the aggregation of PrPC by Aβ oligomers triggered the formation of a signaling complex containing the cPLA2.a process, disrupted by monoacylated PrPC. We propose that monoacylated PrPC acts as a molecular sponge, binding Aβ oligomers at the neuronal perikarya without activating cPLA2 or triggering synapse damage. PMID:26043272

  16. A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease.

    PubMed

    Deane, Rashid; Singh, Itender; Sagare, Abhay P; Bell, Robert D; Ross, Nathan T; LaRue, Barbra; Love, Rachal; Perry, Sheldon; Paquette, Nicole; Deane, Richard J; Thiyagarajan, Meenakshisundaram; Zarcone, Troy; Fritz, Gunter; Friedman, Alan E; Miller, Benjamin L; Zlokovic, Berislav V

    2012-04-01

    In Alzheimer disease (AD), amyloid β peptide (Aβ) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aβ binding to the V domain of RAGE and inhibited Aβ40- and Aβ42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APPsw/0 mice overexpressing human Aβ-precursor protein, a transgenic mouse model of AD with established Aβ pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aβ40 and Aβ42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aβ40 and Aβ42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APPsw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aβ-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD.

  17. Have winter fuel payments reduced excess winter mortality in England and Wales?

    PubMed

    Iparraguirre, J

    2015-03-01

    The historical series of excess winter mortality (EWM) in England and Wales presents a negative trend. Winter fuel payments (WFPs) are the most important benefits for people aged 65 or over directly related to Winter Mortality in the UK. This study presents a time series analysis of the direct effect of WFPs on EWM in England and Wales. We find a significant structural break in trend and volatility in the EWM series in England and Wales in 1999-2000. After controlling for a number of covariates, an ARIMA-X model finds that WFPs can account for almost half of the reduction in EWM in England and Wales since 1999/2000. Almost half of the reduction in EWM since 1999/2000 is attributable to WFPs. © The Author 2014. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  18. Gad67 haploinsufficiency reduces amyloid pathology and rescues olfactory memory deficits in a mouse model of Alzheimer's disease.

    PubMed

    Wang, Yue; Wu, Zheng; Bai, Yu-Ting; Wu, Gang-Yi; Chen, Gong

    2017-10-10

    Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, affecting millions of people worldwide. Although dysfunction of multiple neurotransmitter systems including cholinergic, glutamatergic and GABAergic systems has been associated with AD progression the underlying mechanisms remain elusive. We and others have recently found that GABA content is elevated in AD brains and linked to cognitive deficits in AD mouse models. The glutamic acid decarboxylase 67 (GAD67) is the major enzyme converting glutamate into GABA and has been implied in a number of neurological disorders such as epilepsy and schizophrenia. However, whether Gad67 is involved in AD pathology has not been well studied. Here, we investigate the functional role of GAD67 in an AD mouse model with Gad67 haploinsufficiency that is caused by replacing one allele of Gad67 with green fluorescent protein (GFP) gene during generation of GAD67-GFP mice. To genetically reduce GAD67 in AD mouse brains, we crossed the Gad67 haploinsufficient mice (GAD67-GFP(+/-)) with 5xFAD mice (harboring 5 human familial AD mutations in APP and PS1 genes) to generate a new line of bigenic mice. Immunostaining, ELISA, electrophysiology and behavior test were applied to compare the difference between groups. We found that reduction of GAD67 resulted in a significant decrease of amyloid β production in 5xFAD mice. Concurrently, the abnormal astrocytic GABA and tonic GABA currents, as well as the microglial reactivity were significantly reduced in the 5xFAD mice with Gad67 haploinsufficiency. Importantly, the olfactory memory deficit of 5xFAD mice was rescued by Gad67 haploinsufficiency. Our results demonstrate that GAD67 plays an important role in AD pathology, suggesting that GAD67 may be a potential drug target for modulating the progress of AD.

  19. Ablation of the microglial protein DOCK2 reduces amyloid burden in a mouse model of Alzheimer's disease.

    PubMed

    Cimino, Patrick J; Yang, Yue; Li, Xianwu; Hemingway, Jake F; Cherne, Makenzie K; Khademi, Shawn B; Fukui, Yoshinori; Montine, Kathleen S; Montine, Thomas J; Keene, C Dirk

    2013-04-01

    Alzheimer's disease (AD) neuropathology is characterized by innate immune activation primarily through prostaglandin E2 (PGE2) signaling. Dedicator of cytokinesis 2 (DOCK2) is a guanyl nucleotide exchange factor expressed exclusively in microglia in the brain and is regulated by PGE2 receptor EP2. DOCK2 modulates microglia cytokine secretion, phagocytosis, and paracrine neurotoxicity. EP2 ablation in experimental AD results in reduced oxidative damage and amyloid beta (Aβ) burden. This discovery led us to hypothesize that genetic ablation of DOCK2 would replicate the anti-Aβ effects of loss of EP2 in experimental AD. To test this hypothesis, we crossed mice that lacked DOCK2 (DOCK2-/-), were hemizygous for DOCK2 (DOCK2+/-), or that expressed two DOCK2 genes (DOCK2+/+) with APPswe-PS1Δe9 mice (a model of AD). While we found no DOCK2-dependent differences in cortex or in hippocampal microglia density or morphology in APPswe-PS1Δe9 mice, cerebral cortical and hippocampal Aβ plaque area and size were significantly reduced in 10-month-old APPswe-PS1Δe9/DOCK2-/- mice compared with APPswe-PS1Δe9/DOCK2+/+ controls. DOCK2 hemizygous APPswe-PS1Δe9 mice had intermediate Aβ plaque levels. Interestingly, soluble Aβ42 was not significantly different among the three genotypes, suggesting the effects were mediated specifically in fibrillar Aβ. In combination with earlier cell culture results, our in vivo results presented here suggest DOCK2 contributes to Aβ plaque burden via regulation of microglial innate immune function and may represent a novel therapeutic target for AD.

  20. Multifunctional Liposomes Reduce Brain β-Amyloid Burden and Ameliorate Memory Impairment in Alzheimer's Disease Mouse Models

    PubMed Central

    Balducci, Claudia; Mancini, Simona; Minniti, Stefania; La Vitola, Pietro; Zotti, Margherita; Sancini, Giulio; Mauri, Mario; Cagnotto, Alfredo; Colombo, Laura; Fiordaliso, Fabio; Grigoli, Emanuele; Salmona, Mario; Snellman, Anniina; Haaparanta-Solin, Merja; Forloni, Gianluigi; Re, Francesca

    2014-01-01

    Alzheimer's disease is characterized by the accumulation and deposition of plaques of β-amyloid (Aβ) peptide in the brain. Given its pivotal role, new therapies targeting Aβ are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of Aβ assemblies and evaluated their efficiency in reducing the Aβ burden in Alzheimer's disease mouse models. Liposomes were bifunctionalized with a peptide derived from the apolipoprotein-E receptor-binding domain for blood–brain barrier targeting and with phosphatidic acid for Aβ binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, Aβ assemblies in vitro (EM experiments). Administration of bifunctionalized liposomes to APP/presenilin 1 transgenic mice (aged 10 months) for 3 weeks (three injections per week) decreased total brain-insoluble Aβ1–42 (−33%), assessed by ELISA, and the number and total area of plaques (−34%) detected histologically. Also, brain Aβ oligomers were reduced (−70.5%), as assessed by SDS-PAGE. Plaque reduction was confirmed in APP23 transgenic mice (aged 15 months) either histologically or by PET imaging with [11C]Pittsburgh compound B (PIB). The reduction of brain Aβ was associated with its increase in liver (+18%) and spleen (+20%). Notably, the novel-object recognition test showed that the treatment ameliorated mouse impaired memory. Finally, liposomes reached the brain in an intact form, as determined by confocal microscopy experiments with fluorescently labeled liposomes. These data suggest that bifunctionalized liposomes destabilize brain Aβ aggregates and promote peptide removal across the blood–brain barrier and its peripheral clearance. This all-in-one multitask therapeutic device can be considered as a candidate for the treatment of Alzheimer's disease. PMID:25319699

  1. Multifunctional liposomes reduce brain β-amyloid burden and ameliorate memory impairment in Alzheimer's disease mouse models.

    PubMed

    Balducci, Claudia; Mancini, Simona; Minniti, Stefania; La Vitola, Pietro; Zotti, Margherita; Sancini, Giulio; Mauri, Mario; Cagnotto, Alfredo; Colombo, Laura; Fiordaliso, Fabio; Grigoli, Emanuele; Salmona, Mario; Snellman, Anniina; Haaparanta-Solin, Merja; Forloni, Gianluigi; Masserini, Massimo; Re, Francesca

    2014-10-15

    Alzheimer's disease is characterized by the accumulation and deposition of plaques of β-amyloid (Aβ) peptide in the brain. Given its pivotal role, new therapies targeting Aβ are in demand. We rationally designed liposomes targeting the brain and promoting the disaggregation of Aβ assemblies and evaluated their efficiency in reducing the Aβ burden in Alzheimer's disease mouse models. Liposomes were bifunctionalized with a peptide derived from the apolipoprotein-E receptor-binding domain for blood-brain barrier targeting and with phosphatidic acid for Aβ binding. Bifunctionalized liposomes display the unique ability to hinder the formation of, and disaggregate, Aβ assemblies in vitro (EM experiments). Administration of bifunctionalized liposomes to APP/presenilin 1 transgenic mice (aged 10 months) for 3 weeks (three injections per week) decreased total brain-insoluble Aβ1-42 (-33%), assessed by ELISA, and the number and total area of plaques (-34%) detected histologically. Also, brain Aβ oligomers were reduced (-70.5%), as assessed by SDS-PAGE. Plaque reduction was confirmed in APP23 transgenic mice (aged 15 months) either histologically or by PET imaging with [(11)C]Pittsburgh compound B (PIB). The reduction of brain Aβ was associated with its increase in liver (+18%) and spleen (+20%). Notably, the novel-object recognition test showed that the treatment ameliorated mouse impaired memory. Finally, liposomes reached the brain in an intact form, as determined by confocal microscopy experiments with fluorescently labeled liposomes. These data suggest that bifunctionalized liposomes destabilize brain Aβ aggregates and promote peptide removal across the blood-brain barrier and its peripheral clearance. This all-in-one multitask therapeutic device can be considered as a candidate for the treatment of Alzheimer's disease.

  2. An ScFv Intrabody Against the Non-Amyloid Component of Alpha Synuclein Reduces Intracellular Aggregation and Toxicity

    PubMed Central

    Lynch, Sandra M.; Zhou, Chun; Messer, Anne

    2008-01-01

    Summary Prevention of abnormal misfolding and aggregation of alpha-synuclein (α-syn) protein in vulnerable neurons should be a viable therapeutic strategy for reducing pathogenesis in Parkinson’s disease (PD). The non-amyloid component (NAC) region of α-syn shows strong tendencies to form β-sheet structures, and deletion of this region has been shown to reduce aggregation and toxicity in vitro and in vivo. Binding of a molecular species to this region may mimic effects of such deletions. Single-chain Fv antibodies (scFvs) retain the binding specificity of antibodies, and when genetically manipulated to create high-diversity libraries, allow in vitro selection against peptides. Accordingly, we used a yeast surface display library of an entire naïve repertoire of human scFv antibodies to select for binding to a NAC peptide. Candidate scFvs (after transfer to mammalian expression vectors), were screened for viability in a neuronal cell line by transient co-transfection with A53T mutant α-syn. This provided a ranking of the protective efficacies of the initial panel of intracellular antibodies (intrabodies). High steady-state expression levels and apparent conformational epitope binding appeared more important than in vitro affinity in these assays. None of the scFvs selected matched the sequences of previously-reported anti- α-syn scFvs. A stable cell line expressing the most effective intrabody, NAC32, showed highly significant reductions of abnormal aggregation in two separate models. Recently, intrabodies have shown promising anti-aggregation and neuroprotective effects against misfolded mutant huntingtin protein. The NAC32 study extends such work significantly, utilizing information about the pathogenic capacity of a specific α-syn region to offer a new generation of in vitro-derived antibody fragments, both for further engineering as direct therapeutics and as tools for rational drug design for PD. PMID:18237741

  3. Evaluating the effectiveness of a smartphone app to reduce excessive alcohol consumption: protocol for a factorial randomised control trial.

    PubMed

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

    2016-07-08

    Excessive alcohol consumption is a leading cause of death and morbidity worldwide and interventions to help people reduce their consumption are needed. Interventions delivered by smartphone apps have the potential to help harmful and hazardous drinkers reduce their consumption of alcohol. However, there has been little evaluation of the effectiveness of existing smartphone interventions. A systematic review, amongst other methodologies, identified promising modular content that could be delivered by an app: self-monitoring and feedback; action planning; normative feedback; cognitive bias re-training; and identity change. This protocol reports a factorial randomised controlled trial to assess the comparative potential of these five intervention modules to reduce excessive alcohol consumption. A between-subject factorial randomised controlled trial. Hazardous and harmful drinkers aged 18 or over who are making a serious attempt to reduce their drinking will be randomised to one of 32 (2(5)) experimental conditions after downloading the 'Drink Less' app. Participants complete baseline measures on downloading the app and are contacted after 1-month with a follow-up questionnaire. The primary outcome measure is change in past week consumption of alcohol. Secondary outcome measures are change in AUDIT score, app usage data and usability ratings for the app. A factorial between-subjects ANOVA will be conducted to assess main and interactive effects of the five intervention modules for the primary and secondary outcome measures. This study will establish the extent to which the five intervention modules offered in this app can help reduce hazardous and harmful drinking. This is the first step in optimising and understanding what component parts of an app could help to reduce excessive alcohol consumption. The findings from this study will be used to inform the content of a future integrated treatment app and evaluated against a minimal control in a definitive randomised

  4. Reducing Amyloid Plaque Burden via Ex Vivo Gene Delivery of an Aβ-Degrading Protease: A Novel Therapeutic Approach to Alzheimer Disease

    PubMed Central

    Hemming, Matthew L; Patterson, Michaela; Reske-Nielsen, Casper; Lin, Ling; Isacson, Ole; Selkoe, Dennis J

    2007-01-01

    Background Understanding the mechanisms of amyloid-β protein (Aβ) production and clearance in the brain has been essential to elucidating the etiology of Alzheimer disease (AD). Chronically decreasing brain Aβ levels is an emerging therapeutic approach for AD, but no such disease-modifying agents have achieved clinical validation. Certain proteases are responsible for the catabolism of brain Aβ in vivo, and some experimental evidence suggests they could be used as therapeutic tools to reduce Aβ levels in AD. The objective of this study was to determine if enhancing the clearance of Aβ in the brain by ex vivo gene delivery of an Aβ-degrading protease can reduce amyloid plaque burden. Methods and Findings We generated a secreted form of the Aβ-degrading protease neprilysin, which significantly lowers the levels of naturally secreted Aβ in cell culture. We then used an ex vivo gene delivery approach utilizing primary fibroblasts to introduce this soluble protease into the brains of β-amyloid precursor protein (APP) transgenic mice with advanced plaque deposition. Brain examination after cell implantation revealed robust clearance of plaques at the site of engraftment (72% reduction, p = 0.0269), as well as significant reductions in plaque burden in both the medial and lateral hippocampus distal to the implantation site (34% reduction, p = 0.0020; and 55% reduction, p = 0.0081, respectively). Conclusions Ex vivo gene delivery of an Aβ-degrading protease reduces amyloid plaque burden in transgenic mice expressing human APP. These results support the use of Aβ-degrading proteases as a means to therapeutically lower Aβ levels and encourage further exploration of ex vivo gene delivery for the treatment of Alzheimer disease. PMID:17760499

  5. Excess boron reduces polyphenol oxidase activities in embryo and endosperm of maize seed during germination.

    PubMed

    Olçer, Hillya; Kocaçaliskan, Ismail

    2007-01-01

    The effects of increasing concentrations of boron (0, 0.1, 1, 10 and 20 mM) as boric acid on the rate of germination and polyphenol oxidase activities in embryo and endosperm tissues of maize seeds (Zea mays L. cv. Arifiye) were studied. The germination percentage of maize seeds was not affected by boron concentrations up to 10 mM, and decreased by 20 mM. Distilled water and lower boron concentrations (0.1 and 1 mM) increased polyphenol oxidase activities at the beginning of germination up to 12 h whereas its excess levels (10 and 20 mM) decreased polyphenol oxidase activities in embryos and endosperm during germination. Polyphenol oxidase activities with o-diphenolic substrates (caffeic acid, catechol and dopa) were found to be higher than with a monophenolic substrat (tyrosine) in both embryos and endosperms. Further, caffeic acid oxidizing polyphenol oxidase was found to show more activity in embryos of the seeds germinating in distilled water when compared to other substrates.

  6. The consumption of low glycemic meals reduces abdominal obesity in subjects with excess body weight.

    PubMed

    de Assis Costa, J; de Cássia Gonçalves Alfenas, R

    2012-01-01

    To evaluate the effect of the glycemic index (GI) on food intake, anthropometric measurements and body composition in subjects with excess body weight. Crossover study, in which 17 subjects participated in two study sessions (high GI or low GI). Two daily meals were consumed in laboratory for 30 consecutive days in each session. Subjects also consumed under free living conditions 3 daily isocaloric servings of fruits, presenting the same GI as the session in which they were participating. At each 15 days, subjects were submitted to body composition (lean mass and fatty mass) and anthropometric indexes (weight, height, body mass index, waist circumference (WC), hip circumference, hip-waist relation (WHC)) assessment. Habitual food intake was assessed before and at the end of each session. Subjects were instructed to maintain the same level of physical activity during the study. There was a significant reduction on WC and WHC after the low GI session. The other parameters did not differ between the treatments applied in this study. These results suggest that the consumption of low GI foods may favor the prevention and control abdominal obesity and the associated metabolic diseases.

  7. Excess nitrate loads to coastal waters reduces nitrate removal efficiency: mechanism and implications for coastal eutrophication.

    PubMed

    Lunau, Mirko; Voss, Maren; Erickson, Matthew; Dziallas, Claudia; Casciotti, Karen; Ducklow, Hugh

    2013-05-01

    Terrestrial ecosystems are becoming increasingly nitrogen-saturated due to anthropogenic activities, such as agricultural loading with artificial fertilizer. Thus, more and more reactive nitrogen is entering streams and rivers, primarily as nitrate, where it is eventually transported towards the coastal zone. The assimilation of nitrate by coastal phytoplankton and its conversion into organic matter is an important feature of the aquatic nitrogen cycle. Dissolved reactive nitrogen is converted into a particulate form, which eventually undergoes nitrogen removal via microbial denitrification. High and unbalanced nitrate loads to the coastal zone may alter planktonic nitrate assimilation efficiency, due to the narrow stochiometric requirements for nutrients typically shown by these organisms. This implies a cascade of changes for the cycling of other elements, such as carbon, with unknown consequences at the ecosystem level. Here, we report that the nitrate removal efficiency (NRE) of a natural phytoplankton community decreased under high, unbalanced nitrate loads, due to the enhanced recycling of organic nitrogen and subsequent production and microbial transformation of excess ammonium. NRE was inversely correlated with the amount of nitrate present, and mechanistically controlled by dissolved organic nitrogen (DON), and organic carbon (Corg) availability. These findings have important implications for the management of nutrient runoff to coastal zones.

  8. Excessive dietary intake of vitamin A reduces skull bone thickness in mice.

    PubMed

    Lind, Thomas; Öhman, Caroline; Calounova, Gabriela; Rasmusson, Annica; Andersson, Göran; Pejler, Gunnar; Melhus, Håkan

    2017-01-01

    Calvarial thinning and skull bone defects have been reported in infants with hypervitaminosis A. These findings have also been described in humans, mice and zebrafish with loss-of-function mutations in the enzyme CYP26B1 that degrades retinoic acid (RA), the active metabolite of vitamin A, indicating that these effects are indeed caused by too high levels of vitamin A and that evolutionary conserved mechanisms are involved. To explore these mechanisms, we have fed young mice excessive doses of vitamin A for one week and then analyzed the skull bones using micro computed tomography, histomorphometry, histology and immunohistochemistry. In addition, we have examined the effect of RA on gene expression in osteoblasts in vitro. Compared to a standard diet, a high dietary intake of vitamin A resulted in a rapid and significant reduction in calvarial bone density and suture diastasis. The bone formation rate was almost halved. There was also increased staining of tartrate resistant acid phosphatase in osteocytes and an increased perilacunar matrix area, indicating osteocytic osteolysis. Consistent with this, RA induced genes associated with bone degradation in osteoblasts in vitro. Moreover, and in contrast to other known bone resorption stimulators, vitamin A induced osteoclastic bone resorption on the endocranial surfaces.

  9. Can Organic Materials Reduce Excess Nutrient Leaching from Manure-Rich Paddock Soils?

    PubMed

    Parvage, Mohammed Masud; Ulén, Barbro; Kirchmann, Holger

    2017-01-01

    Horse paddocks have been identified as a significant contributor of animal waste nutrients to natural waters; thus, modified paddock management is needed. Because chemical amendments pose a health risk to horses, an alternative for reducing nutrient translocation from manure is to add available organic residues to the soil. To examine the feasibility of outdoor use of organic materials to reduce nutrient losses from paddock soils, three commonly available organic materials (peat, wheat straw, and wood chips) were tested for their nutrient retention capacities in batch experiments followed by leaching experiments in an in-house lysimeter station using artificial rainfall. Results showed that the grounded peat and wood chips retained some phosphorus (P), whereas grounded wheat straw released P to the solution. In leaching experiments, peat reduced nitrogen (N) losses by 40% but increased P and carbon (C) losses severalfold. Wheat straw was ineffective in reducing P, N, or C losses and in some cases increased the losses. Wood chips effectively reduced P and C losses, by 70 and 40%, respectively, but not N losses. It was concluded that, among the three organic materials, only the wood chips can be used outdoors to reduce nutrient losses from paddock soils. Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.

  10. Asiaticoside ameliorates β-amyloid-induced learning and memory deficits in rats by inhibiting mitochondrial apoptosis and reducing inflammatory factors

    PubMed Central

    Zhang, Zhuo; Li, Xiaobin; Li, Duo; Luo, Mao; Li, Yongjie; Song, Li; Jiang, Xian

    2017-01-01

    The present study aimed to investigate the effects of asiaticoside (AS) on the pathology and associated mechanisms of β-amyloid (Aβ)-induced Alzheimer's disease (AD) in rats. An AD rat model was established by lateral intracerebroventricular injection of Aβ 1–42 oligomers. Learning and memory function were evaluated by Morris water maze (MWM) test. In addition, hematoxylin and eosin (H&E) staining, transmission electron microscopy (TEM), immunohistochemistry, ELISA and western blot analysis were performed to evaluate the disease pathogenesis. The results indicated that AS exerted protective effects in rats treated with Aβ oligomers, in a dose-dependent manner, as evidenced by the improved learning and memory function in the MWM test. In addition, H&E staining of hippocampal tissue showed that the histological structure was damaged in the model group, which was restored by AS treatment. Aβ deposition was dramatically increased in the model group, and the pathological changes were reversed by AS treatment. TEM revealed that the subcellular structure was injured by Aβ oligomers, however, the structure was ameliorated by AS treatment. Furthermore, AS was found to reduce the elevated levels of pro-inflammatory cytokines, interleukin-6 and tumor necrosis factor-α, in the brains of Aβ-treated rats. In addition, AS treatment resulted in a significant decrease in the expression of caspases-3, whereas the expression of B-cell lymphoma-2 was significantly increased, in these Aβ-treated rats. According to the findings of the observed study, AS has a marked protective effect on Aβ-induced AD pathology, and the underlying mechanism may be associated with the alleviation of the mitochondrial injuries, the anti-inflammatory activities, and the influence on the expression levels of apoptosis-associated proteins. PMID:28352309

  11. N-terminal region of myelin basic protein reduces fibrillar amyloid-β deposition in Tg-5xFAD mice.

    PubMed

    Ou-Yang, Ming-Hsuan; Xu, Feng; Liao, Mei-Chen; Davis, Judianne; Robinson, John K; Van Nostrand, William E

    2015-02-01

    Alzheimer's disease is a progressive neurodegenerative disorder that is characterized by extensive deposition of fibrillar amyloid-β (Aβ) in the brain. Previously, myelin basic protein (MBP) was identified to be a potent inhibitor to Aβ fibril formation, and this inhibitory activity was localized to the N-terminal residues 1-64, a fragment designated MBP1. Here, we show that the modest neuronal expression of a fusion protein of the biologically active MBP1 fragment and the enhanced green fluorescent protein (MBP1-EGFP) significantly improved the performance of spatial learning memory in Tg-5xFAD mice, a model of pathologic Aβ accumulation in brain. The levels of insoluble Aβ and fibrillar amyloid were significantly reduced in bigenic Tg-5xFAD/Tg-MBP1-EGFP mice. Quantitative stereological analysis revealed that the reduction in amyloid was because of a reduction in the size of fibrillar plaques rather than a decrease in plaque numbers. The current findings support previous studies showing that MBP1 inhibits Aβ fibril formation in vitro and demonstrate the ability of MBP1 to reduce Aβ pathology and improve behavioral performance.

  12. Cilostazol Upregulates Autophagy via SIRT1 Activation: Reducing Amyloid-β Peptide and APP-CTFβ Levels in Neuronal Cells

    PubMed Central

    Lee, Hye Rin; Shin, Hwa Kyoung; Park, So Youn; Kim, Hye Young; Bae, Sun Sik; Lee, Won Suk; Rhim, Byung Yong; Hong, Ki Whan; Kim, Chi Dae

    2015-01-01

    Autophagy is a vital pathway for the removal of β-amyloid peptide (Aβ) and the aggregated proteins that cause Alzheimer’s disease (AD). We previously found that cilostazol induced SIRT1 expression and its activity in neuronal cells, and thus, we hypothesized that cilostazol might stimulate clearances of Aβ and C-terminal APP fragment β subunit (APP-CTFβ) by up-regulating autophagy.When N2a cells were exposed to soluble Aβ1–42, protein levels of beclin-1, autophagy-related protein5 (Atg5), and SIRT1 decreased significantly. Pretreatment with cilostazol (10–30 μM) or resveratrol (20 μM) prevented these Aβ1–42 evoked suppressions. LC3-II (a marker of mammalian autophagy) levels were significantly increased by cilostazol, and this increase was reduced by 3-methyladenine. To evoke endogenous Aβ overproduction, N2aSwe cells (N2a cells stably expressing human APP containing the Swedish mutation) were cultured in medium with or without tetracycline (Tet+ for 48 h and then placed in Tet- condition). Aβ and APP-CTFβ expressions were increased after 12~24 h in Tet- condition, and these increased expressions were significantly reduced by pretreating cilostazol. Cilostazol-induced reductions in the expressions of Aβ and APP-CTFβ were blocked by bafilomycin A1 (a blocker of autophagosome to lysosome fusion). After knockdown of the SIRT1 gene (to ~40% in SIRT1 protein), cilostazol failed to elevate the expressions of beclin-1, Atg5, and LC3-II, indicating that cilostazol increases these expressions by up-regulating SIRT1. Further, decreased cell viability induced by Aβ was prevented by cilostazol, and this inhibition was reversed by 3-methyladenine, indicating that the protective effect of cilostazol against Aβ induced neurotoxicity is, in part, ascribable to the induction of autophagy. In conclusion, cilostazol modulates autophagy by increasing the activation of SIRT1, and thereby enhances Aβ clearance and increases cell viability. PMID:26244661

  13. Rho-associated protein kinase 1 (ROCK1) is increased in Alzheimer's disease and ROCK1 depletion reduces amyloid-β levels in brain.

    PubMed

    Henderson, Benjamin W; Gentry, Erik G; Rush, Travis; Troncoso, Juan C; Thambisetty, Madhav; Montine, Thomas J; Herskowitz, Jeremy H

    2016-08-01

    Alzheimer's disease (AD) is the leading cause of dementia and mitigating amyloid-β (Aβ) levels may serve as a rational therapeutic avenue to slow AD progression. Pharmacologic inhibition of the Rho-associated protein kinases (ROCK1 and ROCK2) is proposed to curb Aβ levels, and mechanisms that underlie ROCK2's effects on Aβ production are defined. How ROCK1 affects Aβ generation remains a critical barrier. Here, we report that ROCK1 protein levels were elevated in mild cognitive impairment due to AD (MCI) and AD brains compared to controls. Aβ42 oligomers marginally increased ROCK1 and ROCK2 protein levels in neurons but strongly induced phosphorylation of Lim kinase 1 (LIMK1), suggesting that Aβ42 activates ROCKs. RNAi depletion of ROCK1 or ROCK2 suppressed endogenous Aβ40 production in neurons, and Aβ40 levels were reduced in brains of ROCK1 heterozygous knock-out mice compared to wild-type littermate controls. ROCK1 knockdown decreased amyloid precursor protein (APP), and treatment with bafilomycin accumulated APP levels in neurons depleted of ROCK1. These observations suggest that reduction of ROCK1 diminishes Aβ levels by enhancing APP protein degradation. Collectively, these findings support the hypothesis that both ROCK1 and ROCK2 are therapeutic targets to combat Aβ production in AD. Mitigating amyloid-β (Aβ) levels is a rational strategy for Alzheimer's disease (AD) treatment, however, therapeutic targets with clinically available drugs are lacking. We hypothesize that Aβ accumulation in mild cognitive impairment because of AD (MCI) and AD activates the RhoA/ROCK pathway which in turn fuels production of Aβ. Escalation of this cycle over the course of many years may contribute to the buildup of amyloid pathology in MCI and/or AD. © 2016 International Society for Neurochemistry.

  14. Can appropriate diagnosis and treatment of childhood asthma reduce excessive antibiotic usage?

    PubMed

    Gedik, Ahmet Hakan; Cakir, Erkan; Ozkaya, Emin; Ari, Engin; Nursoy, Mustafa

    2014-01-01

    This study compared the frequency of antibiotic usage and the number of asthma episodes before and after the diagnosis and treatment of pediatric asthma patients who were followed up by specialists. Included in this study were 334 patients (211 males and 123 females) of 2-16 years of age who were diagnosed with asthma and followed up for at least 1 year in our clinic. The frequency of antibiotic usage and the number of asthma episodes in the year prior to diagnosis and treatment were compared to these same variables after 1 year of follow-up by specialists. The median age was 84 months (range: 24-192) and 212 (63%) children were at school or in day care centers. Atopy and a family history of asthma were present in 200 (60%) of the patients, and 137 (41%) reported that at least one member of their household smoked. Antibiotics were used a median number of 7 times [interquartile range (IQR) = 6] in the year before the asthma diagnosis, and 2 times (IQR = 3) during the year after treatment (p < 0.001). The mean number of asthma episodes before diagnosis, i.e. 4 (IQR = 8) was reduced to 0 (IQR = 2) in the year after treatment when the patients were followed up by specialists (p < 0.001). This study shows that appropriate diagnosis and treatment of childhood asthma significantly reduce the frequency of antibiotic usage and the number of asthmatic episodes. © 2014 S. Karger AG, Basel.

  15. Excessive zinc intake increases systemic blood pressure and reduces renal blood flow via kidney angiotensin II in rats.

    PubMed

    Kasai, Miyoko; Miyazaki, Takashi; Takenaka, Tsuneo; Yanagisawa, Hiroyuki; Suzuki, Hiromichi

    2012-12-01

    This study investigated the effects of excess zinc intake on the mean arterial pressure (MAP), renal blood flow (RBF), inulin clearance (IC), serum zinc level, serum angiotensin-converting enzyme (ACE) activity, and kidney angiotensin II (AT II) levels in rats. Experiments were performed on male Sprague-Dawley rats maintained for 4 weeks on a diet containing either 5 mg/100 g (control group), 50 mg/100 g (Zn50 group), or 200 mg/100 g (Zn200 group) zinc carbonate. Serum zinc levels significantly increased to 126.5 % in the Zn50 group and 198.1 % in the Zn200 group compared with controls. MAP significantly increased to 107.8 % in the Zn50 group and 114.5 % in the Zn200 group again compared with controls. Although the difference in serum ACE activity was independent of the serum zinc levels, the kidney AT II levels increased significantly to 137.2 % in the Zn50 group and 174.4 % in the Zn200 group compared with the controls. RBF was decreased significantly to 74.4 % in the Zn50 group and 69.7 % in the Zn200 group compared with the controls. IC values were significantly decreased to 69.6 % in the Zn50 group and 52.7 % in the Zn200 group as compared with control levels. Combined together, these results show that excessive Zn intake reduced IC and RBF and increased MAP and kidney AT II levels, suggesting that excessive Zn intake reduces renal function.

  16. Chronic treatment with lithium and pretreatment with excess inositol reduce inositol pool size in astrocytes by different mechanisms.

    PubMed

    Wolfson, M; Hertz, E; Belmaker, R H; Hertz, L

    1998-03-16

    Chronic treatment with a lithium salt is the classical treatment for manic-depressive disorder. It is hypothesized that the therapeutic action of lithium is caused by its inhibition of inositol phosphatases which leads to a relative deficiency of inositol and, therefore, an impairment of inositol recycling and production of precursor for the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). However, peculiarly enough, treatment with high doses of inositol also has an antidepressant effect. In the present work, we have studied the acute and chronic effects of lithium and of excess inositol, in separation or together, on accumulation of 50 microM [3H]inositol (a physiologically relevant concentration) into primary cultures of mouse astrocytes. Two parameters were investigated: (1) rate of unidirectional uptake across the cell membrane (measured during short-term exposure to the radioisotope), and (2) magnitude of the intracellular pool of inositol, equilibrating with extracellular inositol (measured during long-term exposure to the radioisotope). Inositol uptake was highly concentrative and occurred with a Km of approximately 500 microM and a Vmax of 1.5 nmol/min/mg protein. The uptake rate was not affected by either acute or chronic treatment with LiCl (or both), but it was substantially reduced ('down-regulated') after pretreatment with a high concentration of inositol. The inositol pool size was decreased to a similar extent as the uptake rate by previous exposure to excess inositol. In spite of the fact that inositol uptake rate was unaffected by lithium, the magnitude of the inositol pool was significantly decreased by chronic treatment with a pharmacologically relevant concentration of LiCl (1 mM), but not by treatment with lower concentrations. This decrease is likely to reflect a reduction in either inositol synthesis or replenishment of inositol from IP3, due to the inhibition of inositol phosphatases by the lithium ion. In agreement

  17. Expression of neprilysin in skeletal muscle reduces amyloid burden in a transgenic mouse model of Alzheimer disease.

    PubMed

    Liu, Yinxing; Studzinski, Christa; Beckett, Tina; Guan, Hanjun; Hersh, Matthew A; Murphy, M Paul; Klein, Ronald; Hersh, Louis B

    2009-08-01

    Neprilysin (NEP) is a zinc metallopeptidase that efficiently degrades the amyloid beta (Abeta) peptides believed to be involved in the etiology of Alzheimer disease (AD). The focus of this study was to develop a new and tractable therapeutic approach for treating AD using NEP gene therapy. We have introduced adeno-associated virus (AAV) expressing the mouse NEP gene into the hindlimb muscle of 6-month-old human amyloid precursor protein (hAPP) (3X-Tg-AD) mice, an age which correlates with early stage AD. Overexpression of NEP in muscle decreased brain soluble Abeta peptide levels by approximately 60% and decreased amyloid deposits by approximately 50%, with no apparent adverse effects. Expression of NEP on muscle did not affect the levels of a number of other physiological peptides known to be in vitro substrates. These findings demonstrate that peripheral expression of NEP and likely other peptidases represents an alternative to direct administration into brain and illustrates the potential for using NEP expression in muscle for the prevention and treatment of AD.

  18. Reversal of paralysis and reduced inflammation from peripheral administration of β-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis.

    PubMed

    Grant, Jacqueline L; Ghosn, Eliver Eid Bou; Axtell, Robert C; Herges, Katja; Kuipers, Hedwich F; Woodling, Nathan S; Andreasson, Katrin; Herzenberg, Leonard A; Herzenberg, Leonore A; Steinman, Lawrence

    2012-08-01

    β-Amyloid 42 (Aβ42) and β-amyloid 40 (Aβ40), major components of senile plaque deposits in Alzheimer's disease, are considered neurotoxic and proinflammatory. In multiple sclerosis, Aβ42 is up-regulated in brain lesions and damaged axons. We found, unexpectedly, that treatment with either Aβ42 or Aβ40 peptides reduced motor paralysis and brain inflammation in four different models of experimental autoimmune encephalomyelitis (EAE) with attenuation of motor paralysis, reduction of inflammatory lesions in the central nervous system (CNS), and suppression of lymphocyte activation. Aβ42 and Aβ40 treatments were effective in reducing ongoing paralysis induced with adoptive transfer of either autoreactive T helper 1 (T(H)1) or T(H)17 cells. High-dimensional 14-parameter flow cytometry of peripheral immune cell populations after in vivo Aβ42 and Aβ40 treatment revealed substantial modulations in the percentage of lymphoid and myeloid subsets during EAE. Major proinflammatory cytokines and chemokines were reduced in the blood after Aβ peptide treatment. Protection conferred by Aβ treatment did not require its delivery to the brain: Adoptive transfer with lymphocytes from donors treated with Aβ42 attenuated EAE in wild-type recipient mice, and Aβ deposition in the brain was not detected in treated EAE mice by immunohistochemical analysis. In contrast to the improvement in EAE with Aβ treatment, EAE was worse in mice with genetic deletion of the amyloid precursor protein. Therefore, in the absence of Aβ, there is exacerbated clinical EAE disease progression. Because Aβ42 and Aβ40 ameliorate experimental autoimmune inflammation targeting the CNS, we might now consider its potential anti-inflammatory role in other neuropathological conditions.

  19. Valproic acid and its congener propylisopropylacetic acid reduced the amount of soluble amyloid-β oligomers released from 7PA2 cells.

    PubMed

    Williams, Robin S B; Bate, Clive

    2017-09-22

    The amyloid hypothesis of Alzheimer's disease suggests that synaptic degeneration and pathology is caused by the accumulation of amyloid-β (Aβ) peptides derived from the amyloid precursor protein (APP). Subsequently, soluble Aβ oligomers cause the loss of synaptic proteins from neurons, a histopathological feature of Alzheimer's disease that correlates with the degree of dementia. In this study, the production of toxic forms of Aβ was examined in vitro using 7PA2 cells stably transfected with human APP. We show that conditioned media from 7PA2 cells containing Aβ oligomers caused synapse degeneration as measured by the loss of synaptic proteins, including synaptophysin and cysteine-string protein, from cultured neurons. Critically, conditioned media from 7PA2 cells treated with valproic acid (2-propylpentanoic acid (VPA)) or propylisopropylacetic acid (PIA) did not cause synapse damage. Treatment with VPA or PIA did not significantly affect total Aβ42 concentrations; rather these drugs selectively reduced the concentrations of Aβ42 oligomers in conditioned media. In contrast, treatment significantly increased the concentrations of Aβ42 monomers in conditioned media. VPA or PIA treatment reduced the concentrations of APP within lipid rafts, membrane compartments associated with Aβ production. These effects of VPA and PIA were reversed by the addition of platelet-activating factor, a bioactive phospholipid produced following activation of phospholipase A2, an enzyme sensitive to VPA and PIA. Collectively these data suggest that VPA and PIA reduce Aβ oligomers through inhibition of phospholipase A2 and suggest a novel therapeutic approach to Alzheimer's treatment. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

  20. Amyloid neuropathies.

    PubMed

    Adams, David; Lozeron, Pierre; Lacroix, Catherine

    2012-10-01

    As amyloid neuropathies have benefited from recent major progress, this review is timely and relevant. The main recent articles on amyloid neuropathy cover its description, methods for diagnosis and therapies. Varied clinical presentations are described in transthyretin (TTR)-familial amyloidosis with polyneuropathy (FAP) and light chain amyloid neuropathy. Mass spectrometry is able to identify the biochemical nature of amyloidogenic protein in nerve biopsy and skin biopsy samples for diagnosis of small fiber polyneuropathy. Both nerve biopsy and TTR gene sequencing are important to identify sporadic cases of amyloid neuropathy. Nerve biopsy is useful in demonstrating the amyloid origin of neuropathies developing after domino liver transplant recipients. Liver transplantation improves long-term survival in Met30 TTR-FAP. Factors recognized as leading to cardiomyopathy progression or heart involvement after liver transplantation are late disease onset and fibril composition. Combined heart and liver transplantation is recommended in severe restrictive cardiomyopathy. Antiamyloid drugs are emerging: tafamidis, a TTR stabilizer, showed in a phase III controlled study its ability to slow stage 1 FAP progression. Other strategies are emerging for TTR-FAP (combination doxycycline-tauroursodeoxycholic acid, small interfering RNA, antisense oligonucleotide, monoclonal antibody antiserum amyloid P component). For light chain neuropathy, intensive chemotherapy may be helpful. There is better recognition of amyloid neuropathies, and hope for enrolling patients with FAP in future clinical trials testing new antiamyloid drugs.

  1. Efficacy of humidity retention bags for the reduced adsorption and improved cleaning of tissue proteins including prion-associated amyloid to surgical stainless steel surfaces.

    PubMed

    Secker, T J; Pinchin, H E; Hervé, R C; Keevil, C W

    2015-01-01

    Increasing drying time adversely affects attachment of tissue proteins and prion-associated amyloid to surgical stainless steel, and reduces the efficacy of commercial cleaning chemistries. This study tested the efficacy of commercial humidity retention bags to reduce biofouling on surgical stainless steel and to improve subsequent cleaning. Surgical stainless steel surfaces were contaminated with ME7-infected brain homogenates and left to dry for 15 to 1,440 min either in air, in dry polythene bags or within humidity retention bags. Residual contamination pre/post cleaning was analysed using Thioflavin T/SYPRO Ruby dual staining and microscope analysis. An increase in biofouling was observed with increased drying time in air or in sealed dry bags. Humidity retention bags kept both protein and prion-associated amyloid minimal across the drying times both pre- and post-cleaning. Therefore, humidity bags demonstrate a cheap, easy to implement solution to improve surgical instrument reprocessing and to potentially reduce associated hospital acquired infections.

  2. Administrations of human adult ischemia-tolerant mesenchymal stem cells and factors reduce amyloid beta pathology in a mouse model of Alzheimer's disease.

    PubMed

    Harach, Taoufiq; Jammes, Fabien; Muller, Charles; Duthilleul, Nicolas; Cheatham, Victoria; Zufferey, Valentin; Cheatham, David; Lukasheva, Yelizaveta A; Lasser, Theo; Bolmont, Tristan

    2017-03-01

    The impact of human adult ischemia-tolerant mesenchymal stem cells (hMSCs) and factors (stem cell factors) on cerebral amyloid beta (Aβ) pathology was investigated in a mouse model of Alzheimer's disease (AD). To this end, hMSCs were administered intravenously to APPPS1 transgenic mice that normally develop cerebral Aβ. Quantitative reverse transcriptase polymerase chain reaction biodistribution revealed that intravenously delivered hMSCs were readily detected in APPPS1 brains 1 hour following administration, and dropped to negligible levels after 1 week. Notably, intravenously injected hMSCs that migrated to the brain region were localized in the cerebrovasculature, but they also could be observed in the brain parenchyma particularly in the hippocampus, as revealed by immunohistochemistry. A single hMSC injection markedly reduced soluble cerebral Aβ levels in APPPS1 mice after 1 week, although increasing several Aβ-degrading enzymes and modulating a panel of cerebral cytokines, suggesting an amyloid-degrading and anti-inflammatory impact of hMSCs. Furthermore, 10 weeks of hMSC treatment significantly reduced cerebral Aβ plaques and neuroinflammation in APPPS1 mice, without increasing cerebral amyloid angiopathy or microhemorrhages. Notably, a repeated intranasal delivery of soluble factors secreted by hMSCs in culture, in the absence of intravenous hMSC injection, was also sufficient to diminish cerebral amyloidosis in the mice. In conclusion, this preclinical study strongly underlines that cerebral amyloidosis is amenable to therapeutic intervention based on peripheral applications of hMSC or hMSC factors, paving the way for a novel therapy for Aβ amyloidosis and associated pathologies observed in AD. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Pyruvate prevents the development of age-dependent cognitive deficits in a mouse model of Alzheimer's disease without reducing amyloid and tau pathology.

    PubMed

    Isopi, Elisa; Granzotto, Alberto; Corona, Carlo; Bomba, Manuela; Ciavardelli, Domenico; Curcio, Michele; Canzoniero, Lorella M T; Navarra, Riccardo; Lattanzio, Rossano; Piantelli, Mauro; Sensi, Stefano L

    2015-09-01

    Amyloid-β (Aβ) deposition and tau-dependent pathology are key features of Alzheimer's disease (AD). However, to date, approaches aimed at counteracting these two pathogenic factors have produced only modest therapeutic outcomes. More effective therapies should therefore consider additional pathogenic factors like energy production failure, hyperexcitability and excitotoxicity, oxidative stress, deregulation of metal ion homeostasis, and neuroinflammation. Pyruvate is an energy substrate associated with neuroprotective properties. In this study, we evaluated protective effects of long-term administration of pyruvate in 3xTg-AD mice, a preclinical AD model that develops amyloid-β- and tau-dependent pathology. Chronic (9 months) treatment with pyruvate inhibited short and long-term memory deficits in 6 and 12 months old 3xTg-AD mice as assessed with the Morris water maze test. Pyruvate had no effects on intraneuronal amyloid-β accumulation and, surprisingly, the molecule increased deposition of phosphorylated tau. Pyruvate did not change aerobic or anaerobic metabolisms but decreased lipid peroxidation, counteracted neuronal hyperexcitability, decreased baseline levels of oxidative stress, and also reduced reactive oxygen species-driven elevations of intraneuronal Zn(2+) as well as glutamate receptor-mediated deregulation of intraneuronal Ca(2+). Thus, pyruvate promotes beneficial cognitive effects without affecting Aβ and tau pathology. The molecule mainly promotes a reduction of hyperexcitability, oxidative stress while favors the regulation of intraneuronal Ca(2+) and Zn(2+) homeostasis rather than acting as energy substrate. Pyruvate can be therefore a valuable, safe, and affordable pharmacological tool to be associated with classical anti-Aβ and tau drugs to counteract the development and progression of AD-related cognitive deficits and neuronal loss. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Erythropoietin improves memory function with reducing endothelial dysfunction and amyloid-beta burden in Alzheimer's disease models.

    PubMed

    Lee, Soon-Tae; Chu, Kon; Park, Jung-Eun; Jung, Keun-Hwa; Jeon, Daejong; Lim, Ji-Youn; Lee, Sang Kun; Kim, Manho; Roh, Jae-Kyu

    2012-01-01

    Neurovascular degeneration contributes to the pathogenesis of Alzheimer's disease (AD). Because erythropoietin (EPO) promotes endothelial regeneration, we investigated the therapeutic effects of EPO in animal models of AD. In aged Tg2576 mice, EPO receptors (EPORs) were expressed in the cortex and hippocampus. Tg2576 mice were treated with daily injection of EPO (5000 IU/kg/day) for 5 days. At 14 days, EPO improved contextual memory as measured by fear-conditioning test. EPO enhanced endothelial proliferation and the level of synaptophysin expression in the brain. EPO also increased capillary density, and decreased the level of the receptor for advanced glycation endproducts (RAGE) in the brain, while decreasing in the amount of amyloid plaque and amyloid-β (Aβ). In cultured human endothelial cells, EPO enhanced angiogenesis and suppressed the expression of the RAGE. These results show that EPO improves memory and ameliorates endothelial degeneration induced by Aβ in AD models. This pre-clinical evidence suggests that EPO may be useful for the treatment of AD.

  5. Enhancing the Capacity of School Nurses to Reduce Excessive Anxiety in Children: Development of the CALM Intervention.

    PubMed

    Drake, Kelly L; Stewart, Catherine E; Muggeo, Michela A; Ginsburg, Golda S

    2015-08-01

    Excessive anxiety is among the most common psychiatric problems facing youth. Because anxious youth tend to have somatic complaints, many seek help from the school nurse. Thus, school nurses are in an ideal position to provide early intervention. This study addresses this problem and describes the plans to develop and test a new intervention (Child Anxiety Learning Modules; CALM), delivered by school nurses, to reduce child anxiety and improve academic functioning. An iterative development process including consultation with an expert panel, two open trials, and a pilot randomized controlled study comparing CALM to usual care is proposed. Feedback will be solicited from all participants during each phase and data on outcome measures will be provided by children, parents, teachers, and independent evaluators. Data will be collected on intervention satisfaction and feasibility. Primary outcomes that include child anxiety symptoms, classroom behavior, and school performance (e.g., attendance, grades, standardized test scores) will be collected at pre- and post-interventions and at a 3-month follow-up evaluation. Pediatric anxiety is a common problem that school nurses frequently encounter. Consequently, they are well positioned to play a key role in enhancing access to behavioral health interventions to reduce anxiety and may therefore make a significant positive public health impact. © 2015 Wiley Periodicals, Inc.

  6. Human Umbilical Cord Stem Cell Xenografts Improve Cognitive Decline and Reduce the Amyloid Burden in a Mouse Model of Alzheimer’s Disease

    PubMed Central

    Boutajangout, Allal; Noorwali, Abdulwahab; Atta, Hazem; Wisniewski, Thomas

    2017-01-01

    Introduction Alzheimer’s disease (AD) is the most common cause of dementia. The search for new treatments is made more urgent given its increasing prevalence resulting from the aging of the global population. Over the past 20 years, stem cell technologies have become an increasingly attractive option to both study and potentially treat neurodegenerative diseases. Several investigators reported a beneficial effect of different types of stem or progenitor cells on the pathology and cognitive function in AD models. Mouse models are one of the most important research tools for finding new treatment for AD. We aimed to explore the possible therapeutic potential of human umbilical cord mesenchymal stem cell xenografts in a transgenic (Tg) mouse model of AD. Methods APP/PS1 Tg AD model mice received human umbilical cord stem cells, directly injected into the carotid artery. To test the efficacy of the umbilical cord stem cells in this AD model, behavioral tasks (sensorimotor and cognitive tests) and immunohistochemical quantitation of the pathology was performed. Results Treatment of the APP/PS1 AD model mice, with human umbilical cord stem cells, produced a reduction of the amyloid beta burden in the cortex and the hippocampus which correlated with a reduction of the cognitive loss. Conclusion Human umbilical cord mesenchymal stem cells appear to reduce AD pathology in a transgenic mouse model as documented by a reduction of the amyloid plaque burden compared to controls. This amelioration of pathology correlates with improvements on cognitive and sensorimotor tasks. PMID:27719629

  7. Human Umbilical Cord Stem Cell Xenografts Improve Cognitive Decline and Reduce the Amyloid Burden in a Mouse Model of Alzheimer's Disease.

    PubMed

    Boutajangout, Allal; Noorwali, Abdulwahab; Atta, Hazem; Wisniewski, Thomas

    2017-01-01

    Alzheimer's disease (AD) is the most common cause of dementia. The search for new treatments is made more urgent given its increasing prevalence resulting from the aging of the global population. Over the past 20 years, stem cell technologies have become an increasingly attractive option to both study and potentially treat neurodegenerative diseases. Several investigators reported a beneficial effect of different types of stem or progenitor cells on the pathology and cognitive function in AD models. Mouse models are one of the most important research tools for finding new treatment for AD. We aimed to explore the possible therapeutic potential of human umbilical cord mesenchymal stem cell xenografts in a transgenic (Tg) mouse model of AD. APP/PS1 Tg AD model mice received human umbilical cord stem cells, directly injected into the carotid artery. To test the efficacy of the umbilical cord stem cells in this AD model, behavioral tasks (sensorimotor and cognitive tests) and immunohistochemical quantitation of the pathology was performed. Treatment of the APP/PS1 AD model mice, with human umbilical cord stem cells, produced a reduction of the amyloid beta burden in the cortex and the hippocampus which correlated with a reduction of the cognitive loss. Human umbilical cord mesenchymal stem cells appear to reduce AD pathology in a transgenic mouse model as documented by a reduction of the amyloid plaque burden compared to controls. This amelioration of pathology correlates with improvements on cognitive and sensorimotor tasks.

  8. Brain pyroglutamate amyloid-β is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic.

    PubMed

    Hook, Gregory; Yu, Jin; Toneff, Thomas; Kindy, Mark; Hook, Vivian

    2014-01-01

    Pyroglutamate amyloid-β peptides (pGlu-Aβ) are particularly pernicious forms of amyloid-β peptides (Aβ) present in Alzheimer's disease (AD) brains. pGlu-Aβ peptides are N-terminally truncated forms of full-length Aβ peptides (flAβ(1-40/42)) in which the N-terminal glutamate is cyclized to pyroglutamate to generate pGlu-Aβ(3-40/42). β-secretase cleavage of amyloid-β precursor protein (AβPP) produces flAβ(1-40/42), but it is not yet known whether the β-secretase BACE1 or the alternative β-secretase cathepsin B (CatB) participate in the production of pGlu-Aβ. Therefore, this study examined the effects of gene knockout of these proteases on brain pGlu-Aβ levels in transgenic AβPPLon mice, which express AβPP isoform 695 and have the wild-type (wt) β-secretase activity found in most AD patients. Knockout or overexpression of the CatB gene reduced or increased, respectively, pGlu-Aβ(3-40/42), flAβ(1-40/42), and pGlu-Aβ plaque load, but knockout of the BACE1 gene had no effect on those parameters in the transgenic mice. Treatment of AβPPLon mice with E64d, a cysteine protease inhibitor of CatB, also reduced brain pGlu-Aβ(3-42), flAβ(1-40/42), and pGlu-Aβ plaque load. Treatment of neuronal-like chromaffin cells with CA074Me, an inhibitor of CatB, resulted in reduced levels of pGlu-Aβ(3-40) released from the activity-dependent, regulated secretory pathway. Moreover, CatB knockout and E64d treatment has been previously shown to improve memory deficits in the AβPPLon mice. These data illustrate the role of CatB in producing pGlu-Aβ and flAβ that participate as key factors in the development of AD. The advantages of CatB inhibitors, especially E64d and its derivatives, as alternatives to BACE1 inhibitors in treating AD patients are discussed.

  9. Reduced ovarian glyoxalase-I activity by dietary glycotoxins and androgen excess: a causative link to polycystic ovarian syndrome.

    PubMed

    Kandaraki, Eleni; Chatzigeorgiou, Antonis; Piperi, Christina; Palioura, Eleni; Palimeri, Sotiria; Korkolopoulou, Penelope; Koutsilieris, Michael; Papavassiliou, Athanasios G

    2012-10-24

    Glyoxalase detoxification system composed of glyoxalase (GLO)-I and GLO-II is ubiquitously expressed and implicated in the protection against cellular damage because of cytotoxic metabolites such as advanced glycation end products (AGEs). Recently, ovarian tissue has emerged as a new target of excessive AGE deposition and has been associated with either a high AGE diet in experimental animals or hyperandrogenic disorders such as polycystic ovarian syndrome (PCOS) in humans. This study was designed to investigate the impact of dietary AGEs and androgens in rat ovarian GLO-I activity of normal nonandrogenized (NAN, group A, n = 18) and androgenized prepubertal (AN) rats (group B, n = 29). Both groups were further randomly assigned, either to a high-AGE (HA) or low-AGE (LA) diet for 3 months. The activity of ovarian GLO-I was significantly reduced in normal NAN animals fed an HA diet compared with an LA diet (p = 0.006). Furthermore, GLO-I activity was markedly reduced in AN animals compared with NAN (p ≤ 0.001) when fed with the corresponding diet type. In addition, ovarian GLO-I activity was positively correlated with the body weight gain (r(s) = 0.533, p < 0.001), estradiol (r(s) = 0.326, p = 0.033) and progesterone levels (r(s) = 0.500, p < 0.001). A negative correlation was observed between GLO-I activity and AGE expression in the ovarian granulosa cell layer of all groups with marginal statistical significance (r(s) = -0.263, p = 0.07). The present data demonstrate that ovarian GLO-I activity may be regulated by dietary composition and androgen levels. Modification of ovarian GLO-I activity, observed for the first time in this androgenized prepubertal rat model, may present a contributing factor to the reproductive dysfunction characterizing PCOS.

  10. Reduced Ovarian Glyoxalase-I Activity by Dietary Glycotoxins and Androgen Excess: A Causative Link to Polycystic Ovarian Syndrome

    PubMed Central

    Kandaraki, Eleni; Chatzigeorgiou, Antonis; Piperi, Christina; Palioura, Eleni; Palimeri, Sotiria; Korkolopoulou, Penelope; Koutsilieris, Michael; Papavassiliou, Athanasios G

    2012-01-01

    Glyoxalase detoxification system composed of glyoxalase (GLO)-I and GLO-II is ubiquitously expressed and implicated in the protection against cellular damage because of cytotoxic metabolites such as advanced glycation end products (AGEs). Recently, ovarian tissue has emerged as a new target of excessive AGE deposition and has been associated with either a high AGE diet in experimental animals or hyperandrogenic disorders such as polycystic ovarian syndrome (PCOS) in humans. This study was designed to investigate the impact of dietary AGEs and androgens in rat ovarian GLO-I activity of normal nonandrogenized (NAN, group A, n = 18) and androgenized prepubertal (AN) rats (group B, n = 29). Both groups were further randomly assigned, either to a high-AGE (HA) or low-AGE (LA) diet for 3 months. The activity of ovarian GLO-I was significantly reduced in normal NAN animals fed an HA diet compared with an LA diet (p = 0.006). Furthermore, GLO-I activity was markedly reduced in AN animals compared with NAN (p ≤ 0.001) when fed with the corresponding diet type. In addition, ovarian GLO-I activity was positively correlated with the body weight gain (rs = 0.533, p < 0.001), estradiol (rs = 0.326, p = 0.033) and progesterone levels (rs = 0.500, p < 0.001). A negative correlation was observed between GLO-I activity and AGE expression in the ovarian granulosa cell layer of all groups with marginal statistical significance (rs = −0.263, p = 0.07). The present data demonstrate that ovarian GLO-I activity may be regulated by dietary composition and androgen levels. Modification of ovarian GLO-I activity, observed for the first time in this androgenized prepubertal rat model, may present a contributing factor to the reproductive dysfunction characterizing PCOS. PMID:22859292

  11. Microbial Manipulation of the Amyloid Fold

    PubMed Central

    DePas, William H.

    2012-01-01

    Microbial biofilms are encased in a protein, DNA and polysaccharide matrix that protects the community, promotes interactions with the environment, and helps cells to adhere together. The protein component of these matrices is often a remarkably stable, β-sheet-rich polymer called amyloid. Amyloids form ordered, self-templating fibers that are highly aggregative, making them a valuable biofilm component. Some eukaryotic proteins inappropriately adopt the amyloid fold and these misfolded protein aggregates disrupt normal cellular proteostasis, which can cause significant cytotoxicity. Indeed, until recently amyloids were considered solely the result of protein misfolding. However, research over the past decade has revealed how various organisms have capitalized on the amyloid fold by developing sophisticated biogenesis pathways that coordinate gene expression, protein folding, and secretion so that amyloid-related toxicities are minimized. How microbes manipulate amyloids, by augmenting their advantageous properties and by reducing their undesirable properties, will be the subject of this review. PMID:23108148

  12. Reduction of low-density lipoprotein receptor-related protein (LRP1) in hippocampal neurons does not proportionately reduce, or otherwise alter, amyloid deposition in APPswe/PS1dE9 transgenic mice

    PubMed Central

    2012-01-01

    Introduction The low-density lipoprotein receptor-related protein (LRP1) and its family members have been implicated in the pathogenesis of Alzheimer's disease. Multiple susceptibility factors converge to metabolic pathways that involve LRP1, including modulation of the processing of amyloid precursor protein (APP) and the clearance of Aβ peptide. Methods We used the Cre-lox system to lower LRP1 levels in hippocampal neurons of mice that develop Alzheimer-type amyloid by crosses between mice that express Cre recombinase under the transcriptional control of the GFAP promoter, mice that harbor loxp sites in the LRP1 gene, and the APPswe/PS1dE9 transgenic model. We compared amyloid plaque numbers in APPswe/PS1dE9 mice lacking LRP1 expression in hippocampus (n = 13) to mice with normal levels of LRP1 (n = 12). Student t-test was used to test whether there were significant differences in plaque numbers and amyloid levels between the groups. A regression model was used to fit two regression lines for these groups, and to compare the rates of Aβ accumulation. Results Immunohistochemical analyses demonstrated efficient elimination of LRP1 expression in the CA fields and dentate gyrus of the hippocampus. Within hippocampus, we observed no effect on the severity of amyloid deposition, the rate of Aβ40/42 accumulation, or the architecture of amyloid plaques when LRP1 levels were reduced. Conclusions Expression of LRP1 by neurons in proximity to senile amyloid plaques does not appear to play a major role in modulating the formation of these proximal deposits or in the appearance of the associated neuritic pathology. PMID:22537779

  13. Reduced Efficacy of Anti-Aβ Immunotherapy in a Mouse Model of Amyloid Deposition and Vascular Cognitive Impairment Comorbidity.

    PubMed

    Weekman, Erica M; Sudduth, Tiffany L; Caverly, Carly N; Kopper, Timothy J; Phillips, Oliver W; Powell, Dave K; Wilcock, Donna M

    2016-09-21

    Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia behind Alzheimer's disease (AD). It is estimated that 40% of AD patients also have some form of VCID. One promising therapeutic for AD is anti-Aβ immunotherapy, which uses antibodies against Aβ to clear it from the brain. While successful in clearing Aβ and improving cognition in mice, anti-Aβ immunotherapy failed to reach primary cognitive outcomes in several different clinical trials. We hypothesized that one potential reason the anti-Aβ immunotherapy clinical trials were unsuccessful was due to this high percentage of VCID comorbidity in the AD population. We used our unique model of VCID-amyloid comorbidity to test this hypothesis. We placed 9-month-old wild-type and APP/PS1 mice on either a control diet or a diet that induces hyperhomocysteinemia (HHcy). After being placed on the diet for 3 months, the mice then received intraperotineal injections of either IgG2a control or 3D6 for another 3 months. While we found that treatment of our comorbidity model with 3D6 resulted in decreased total Aβ levels, there was no cognitive benefit of the anti-Aβ immunotherapy in our AD/VCID mice. Further, microhemorrhages were increased by 3D6 in the APP/PS1/control but further increased in an additive fashion when 3D6 was administered to the APP/PS1/HHcy mice. This suggests that the use of anti-Aβ immunotherapy in patients with both AD and VCID would be ineffective on cognitive outcomes. Despite significant mouse model data demonstrating both pathological and cognitive efficacy of anti-Aβ immunotherapy for the treatment of Alzheimer's disease, clinical trial outcomes have been underwhelming, failing to meet any primary endpoints. We show here that vascular cognitive impairment and dementia (VCID) comorbidity eliminates cognitive efficacy of anti-Aβ immunotherapy, despite amyloid clearance. Further, cerebrovascular adverse events of the anti-Aβ immunotherapy are

  14. Deferiprone Reduces Amyloid-β and Tau Phosphorylation Levels but not Reactive Oxygen Species Generation in Hippocampus of Rabbits Fed a Cholesterol-Enriched Diet

    PubMed Central

    Prasanthi, Jaya R.P.; Schrag, Matthew; Dasari, Bhanu; Marwarha, Gurdeep; Kirsch, Wolff M.; Ghribi, Othman

    2013-01-01

    Accumulation of amyloid-β (Aβ) peptide and the hyperphosphorylation of tau protein are major hallmarks of Alzheimer’s disease (AD). The causes of AD are not well known but a number of environmental and dietary factors are suggested to increase the risk of developing AD. Additionally, altered metabolism of iron may have a role in the pathogenesis of AD. We have previously demonstrated that cholesterol-enriched diet causes AD-like pathology with iron deposition in rabbit brain. However, the extent to which chelation of iron protects against this pathology has not been determined. In this study, we administered the iron chelator deferiprone in drinking water to rabbits fed with a 2% cholesterol diet for 12 weeks. We found that deferiprone (both at 10 and 50 mg/kg/day) significantly decreased levels of Aβ40 and Aβ42 as well as BACE1, the enzyme that initiates cleavage of amyloid-β protein precursor to yield Aβ. Deferiprone also reduced the cholesterol diet-induced increase in phosphorylation of tau but failed to reduce reactive oxygen species generation. While deferiprone treatment was not associated with any change in brain iron levels, it was associated with a significant reduction in plasma iron and cholesterol levels. These results demonstrate that deferiprone confers important protection against hypercholesterolemia-induced AD pathology but the mechanism(s) may involve reduction in plasma iron and cholesterol levels rather than chelation of brain iron. We propose that adding an antioxidant therapy to deferiprone may be necessary to fully protect against cholesterol-enriched diet-induced AD-like pathology. PMID:22406440

  15. The Kunitz-protease inhibitor domain in amyloid precursor protein reduces cellular mitochondrial enzymes expression and function.

    PubMed

    Chua, Li-Min; Lim, Mei-Li; Wong, Boon-Seng

    2013-08-09

    Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) and this can be contributed by aberrant metabolic enzyme function. But, the mechanism causing this enzymatic impairment is unclear. Amyloid precursor protein (APP) is known to be alternatively spliced to produce three major isoforms in the brain (APP695, APP751, APP770). Both APP770 and APP751 contain the Kunitz Protease Inhibitory (KPI) domain, but the former also contain an extra OX-2 domain. APP695 on the other hand, lacks both domains. In AD, up-regulation of the KPI-containing APP isoforms has been reported. But the functional contribution of this elevation is unclear. In the present study, we have expressed and compared the effect of the non-KPI containing APP695 and the KPI-containing APP751 on mitochondrial function. We found that the KPI-containing APP751 significantly decreased the expression of three major mitochondrial metabolic enzymes; citrate synthase, succinate dehydrogenase and cytochrome c oxidase (COX IV). This reduction lowers the NAD(+)/NADH ratio, COX IV activity and mitochondrial membrane potential. Overall, this study demonstrated that up-regulation of the KPI-containing APP isoforms is likely to contribute to the impairment of metabolic enzymes and mitochondrial function in AD.

  16. Non-fibrillar amyloid-{beta} peptide reduces NMDA-induced neurotoxicity, but not AMPA-induced neurotoxicity

    SciTech Connect

    Niidome, Tetsuhiro; Goto, Yasuaki; Kato, Masaru; Wang, Pi-Lin; Goh, Saori; Tanaka, Naoki; Akaike, Akinori; Kihara, Takeshi; Sugimoto, Hachiro

    2009-09-04

    Amyloid-{beta} peptide (A{beta}) is thought to be linked to the pathogenesis of Alzheimer's disease. Recent studies suggest that A{beta} has important physiological roles in addition to its pathological roles. We recently demonstrated that A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity, but the relationship between A{beta}42 assemblies and their neuroprotective effects remains largely unknown. In this study, we prepared non-fibrillar and fibrillar A{beta}42 based on the results of the thioflavin T assay, Western blot analysis, and atomic force microscopy, and examined the effects of non-fibrillar and fibrillar A{beta}42 on glutamate-induced neurotoxicity. Non-fibrillar A{beta}42, but not fibrillar A{beta}42, protected hippocampal neurons from glutamate-induced neurotoxicity. Furthermore, non-fibrillar A{beta}42 decreased both neurotoxicity and increases in the intracellular Ca{sup 2+} concentration induced by N-methyl-D-aspartate (NMDA), but not by {alpha}-amino-3-hydrozy-5-methyl-4-isoxazole propionic acid (AMPA). Our results suggest that non-fibrillar A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity through regulation of the NMDA receptor.

  17. Icariside II Effectively Reduces Spatial Learning and Memory Impairments in Alzheimer’s Disease Model Mice Targeting Beta-Amyloid Production

    PubMed Central

    Yan, Lingli; Deng, Yuanyuan; Gao, Jianmei; Liu, Yuangui; Li, Fei; Shi, Jingshan; Gong, Qihai

    2017-01-01

    Icariside II (ICS II) is a broad-spectrum anti-cancer natural compound extracted from Herba Epimedii Maxim. Recently, the role of ICS II has been investigated in central nervous system, especially have a neuroprotective effect in Alzheimer’s disease (AD). In this study, we attempted to investigate the effects of ICS II, on cognitive deficits and beta-amyloid (Aβ) production in APPswe/PS1dE9 (APP/PS1) double transgenic mice. It was found that chronic ICS II administrated not only effectively ameliorated cognitive function deficits, but also inhibited neuronal degeneration and reduced the formation of plaque burden. ICS II significantly suppressed Aβ production via promoting non-amyloidogenic APP cleavage process by up-regulating a disintegrin and metalloproteinase domain 10 (ADAM10) expression, inhibited amyloidogenic APP processing pathway by down-regulating amyloid precursor protein (APP) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1) expression in APP/PS1 transgenic mice. Meanwhile, ICS II attenuated peroxisome proliferator-activated receptor-γ (PPARγ) degradation as well as inhibition of eukaryotic initiation factor α phosphorylation (p-eIF2α) and PKR endoplasmic reticulum regulating kinase phosphorylation (p-PERK). Moreover, phosphodiesterase type 5 inhibitors (PDE5-Is) have recently emerged as a possible therapeutic target for cognitive enhancement via inhibiting Aβ levels, and we also found that ICS II markedly decreased phosphodiesterase-5A (PDE5A) expression. In conclusion, the present study demonstrates that ICS II could attenuate spatial learning and memory impairments in APP/PS1 transgenic mice. This protection appears to be due to the increased ADAM10 expression and decreased expression of both APP and BACE1, resulting in inhibition of Aβ production in the hippocampus and cortex. Inhibition of PPARγ degradation and PERK/eIF2α phosphorylation are involved in the course, therefore suggesting that ICS II might be a promising

  18. Mitochondria-targeted catalase reduces abnormal APP processing, amyloid β production and BACE1 in a mouse model of Alzheimer's disease: implications for neuroprotection and lifespan extension.

    PubMed

    Mao, Peizhong; Manczak, Maria; Calkins, Marcus J; Truong, Quang; Reddy, Tejaswini P; Reddy, Arubala P; Shirendeb, Ulziibat; Lo, Herng-Hsiang; Rabinovitch, Peter S; Reddy, P Hemachandra

    2012-07-01

    The purpose of this study was to investigate the protective effects of the mitochondria-targeted antioxidant catalase (MCAT) and lifespan extension in mice that express amyloid beta (Aβ). Using immunoblotting and immunostaining analyses, we measured the production of full-length amyloid precursor protein (APP), soluble APPα, C-terminal fragments CTF99 and CTF83, monomeric and oligomeric Aβ, Aβ deposits and beta site amyloid precursor protein cleaving enzyme 1 (BACE1), in different stages of disease progression in MCAT/AβPP and AβPP mice. Using quantitative reverse transcriptase polymerase chain reaction and immunostaining analyses, we studied the expression of catalase, BACE1, the Alzheimer's disease (AD) markers, synaptophysin, APP, neprilysin, insulin-degrading enzyme and transthyretin in MCAT, AβPP, MCAT/AβPP and wild-type (WT) mice. Using the high pressure liquid chromatography analysis of 8-hydroxy-2-deoxyguanosine, we measured oxidative DNA damage in the cerebral cortical tissues from MCAT, AβPP, MCAT/AβPP and WT mice. We found that the AβPP transgenic mice that carried the human MCAT gene lived 5 months longer than did the AβPP mice. We also found that the overexpression of MCAT in the brain sections from the MCAT/AβPP transgenic mice significantly correlated with a reduction in the levels of full-length APP, CTF99, BACE1, Aβ levels (40 and 42), Aβ deposits and oxidative DNA damage relative to the brain sections from the AβPP mice. Interestingly, we found significantly increased levels of soluble APPα and CTF83 in the MCAT/AβPP mice, relative to the AβPP mice. These data provide direct evidence that oxidative stress plays a primary role in AD etiopathology and that in MCAT mice express Aβ, MCAT prevents abnormal APP processing, reduces Aβ levels and enhances Aβ-degrading enzymes in mice at different ages, corresponding to different stages of disease progression. These findings indicate that mitochondria-targeted molecules may be an

  19. [Amyloid goiter].

    PubMed

    Hrívó, A; Péter, I; Bánkúti, B; Péley, G; Baska, F; Besznyák, I

    1999-03-21

    Amyloid goitre is at an extremely rare occurrence. Authors review the origin of disease and its symptoms, diagnostic and therapeutic tools. The disease may be due to either primary or secondary systemic or local amyloidosis. Diagnosis may be made even before surgery on anamnestic data, on very rapid growth of thyroid glands, on diffuse appearance, on other symptoms of systemic amyloidosis, on findings of iconographic procedures and on detection of amyloid in aspirates. Final diagnosis is based on histology. Surgical therapy is aiming at avoidance of the existing and the threatening consequences of expanding mass. The outcome is independent from thyroid surgery, it is related to other manifestations of amyloidosis. Concerning with the present case the chronic superior vena cava syndrome and chylous pleural effusion as first described symptoms and asymptomatic hyperthyroxinaemia is emphasised. Neither other organ involvement, nor primary amyloidogenous molecula was found during the 18 months follow up, so patient has secondary and localised amyloidosis.

  20. Enhancing the Capacity of School Nurses to Reduce Excessive Anxiety in Children: Development of the CALM Intervention

    ERIC Educational Resources Information Center

    Drake, Kelly L.; Stewart, Catherine E.; Muggeo, Michela A.; Ginsburg, Golda S.

    2015-01-01

    Problem: Excessive anxiety is among the most common psychiatric problems facing youth. Because anxious youth tend to have somatic complaints, many seek help from the school nurse. Thus, school nurses are in an ideal position to provide early intervention. This study addresses this problem and describes the plans to develop and test a new…

  1. Rescue of Early bace-1 and Global DNA Demethylation by S-Adenosylmethionine Reduces Amyloid Pathology and Improves Cognition in an Alzheimer’s Model

    PubMed Central

    Do Carmo, Sonia; Hanzel, Cecilia E.; Jacobs, Marie L.; Machnes, Ziv; Iulita, M. Florencia; Yang, Jingyun; Yu, Lei; Ducatenzeiler, Adriana; Danik, Marc; Breuillaud, Lionel S.; Bennett, David A.; Szyf, Moshe; Cuello, A. Claudio

    2016-01-01

    General DNA hypomethylation is associated with Alzheimer’s disease (AD), but it is unclear when DNA hypomethylation starts or plays a role in AD pathology or whether DNA re-methylation would rescue early amyloid-related cognitive impairments. In an APP transgenic mouse model of AD-like amyloid pathology we found that early intraneuronal amyloid beta build-up is sufficient to unleash a global and beta-site amyloid precursor protein cleaving enzyme 1 (bace-1) DNA demethylation in AD-vulnerable brain regions. S-adenosylmethionine administration at these early stages abolished this hypomethylation, diminished the amyloid pathology and restored cognitive capabilities. To assess a possible human significance of findings, we examined the methylation at 12 CpGs sites in the bace-1 promoter, using genome-wide DNA methylation data from 740 postmortem human brains. Thus, we found significant associations of bace-1 promoter methylation with β-amyloid load among persons with AD dementia, and PHFtau tangle density. Our results support a plausible causal role for the earliest amyloid beta accumulation to provoke DNA hypomethylation, influencing AD pathological outcomes. PMID:27681803

  2. Rescue of Early bace-1 and Global DNA Demethylation by S-Adenosylmethionine Reduces Amyloid Pathology and Improves Cognition in an Alzheimer's Model.

    PubMed

    Do Carmo, Sonia; Hanzel, Cecilia E; Jacobs, Marie L; Machnes, Ziv; Iulita, M Florencia; Yang, Jingyun; Yu, Lei; Ducatenzeiler, Adriana; Danik, Marc; Breuillaud, Lionel S; Bennett, David A; Szyf, Moshe; Cuello, A Claudio

    2016-09-29

    General DNA hypomethylation is associated with Alzheimer's disease (AD), but it is unclear when DNA hypomethylation starts or plays a role in AD pathology or whether DNA re-methylation would rescue early amyloid-related cognitive impairments. In an APP transgenic mouse model of AD-like amyloid pathology we found that early intraneuronal amyloid beta build-up is sufficient to unleash a global and beta-site amyloid precursor protein cleaving enzyme 1 (bace-1) DNA demethylation in AD-vulnerable brain regions. S-adenosylmethionine administration at these early stages abolished this hypomethylation, diminished the amyloid pathology and restored cognitive capabilities. To assess a possible human significance of findings, we examined the methylation at 12 CpGs sites in the bace-1 promoter, using genome-wide DNA methylation data from 740 postmortem human brains. Thus, we found significant associations of bace-1 promoter methylation with β-amyloid load among persons with AD dementia, and PHFtau tangle density. Our results support a plausible causal role for the earliest amyloid beta accumulation to provoke DNA hypomethylation, influencing AD pathological outcomes.

  3. Does Usage of an eHealth Intervention Reduce the Risk of Excessive Gestational Weight Gain? Secondary Analysis From a Randomized Controlled Trial.

    PubMed

    Graham, Meredith Leigh; Strawderman, Myla S; Demment, Margaret; Olson, Christine Marie

    2017-01-09

    Excessive gestational weight gain (GWG) contributes to the development of obesity in mother and child. Internet-based interventions have the potential for delivering innovative and interactive options for prevention of excessive GWG to large numbers of people. The objective of this study was to create a novel measure of Internet-based intervention usage patterns and examine whether usage of an Internet-based intervention is associated with reduced risk of excessive GWG. The website featured blogs, local resources, articles, frequently asked questions (FAQs), and events that were available to women in both the intervention and control arm. Weekly reminders to use the website and to highlight new content were emailed to participants in both arms. Only intervention arm participants had access to the weight gain tracker and diet and physical activity goal-setting tools. A total of 1335 (898 intervention and 437 control) relatively diverse and healthy pregnant women were randomly assigned to the intervention arm or control arm. Usage patterns were examined for both intervention and control arm participants using latent class analysis. Regression analyses were used to estimate the association between usage patterns and three GWG outcomes: excessive total GWG, excessive GWG rate, and GWG. Five usage patterns best characterized the usage of the intervention by intervention arm participants. Three usage patterns best characterized control arm participants' usage. Control arm usage patterns were not associated with excessive GWG, whereas intervention arm usage patterns were associated with excessive GWG. The control and intervention arm usage pattern characterization is a unique methodological contribution to process evaluations for self-directed Internet-based interventions. In the intervention arm some usage patterns were associated with GWG outcomes. ClinicalTrials.gov; Clinical Trials Number: NCT01331564; https://clinicaltrials.gov/ct2/show/NCT01331564 (Archived by Web

  4. Does Usage of an eHealth Intervention Reduce the Risk of Excessive Gestational Weight Gain? Secondary Analysis From a Randomized Controlled Trial

    PubMed Central

    Strawderman, Myla S; Demment, Margaret; Olson, Christine Marie

    2017-01-01

    Background Excessive gestational weight gain (GWG) contributes to the development of obesity in mother and child. Internet-based interventions have the potential for delivering innovative and interactive options for prevention of excessive GWG to large numbers of people. Objective The objective of this study was to create a novel measure of Internet-based intervention usage patterns and examine whether usage of an Internet-based intervention is associated with reduced risk of excessive GWG. Methods The website featured blogs, local resources, articles, frequently asked questions (FAQs), and events that were available to women in both the intervention and control arm. Weekly reminders to use the website and to highlight new content were emailed to participants in both arms. Only intervention arm participants had access to the weight gain tracker and diet and physical activity goal-setting tools. A total of 1335 (898 intervention and 437 control) relatively diverse and healthy pregnant women were randomly assigned to the intervention arm or control arm. Usage patterns were examined for both intervention and control arm participants using latent class analysis. Regression analyses were used to estimate the association between usage patterns and three GWG outcomes: excessive total GWG, excessive GWG rate, and GWG. Results Five usage patterns best characterized the usage of the intervention by intervention arm participants. Three usage patterns best characterized control arm participants’ usage. Control arm usage patterns were not associated with excessive GWG, whereas intervention arm usage patterns were associated with excessive GWG. Conclusions The control and intervention arm usage pattern characterization is a unique methodological contribution to process evaluations for self-directed Internet-based interventions. In the intervention arm some usage patterns were associated with GWG outcomes. ClinicalTrial ClinicalTrials.gov; Clinical Trials Number: NCT01331564

  5. Review of Interventions to Reduce Ultraviolet Tanning: Need for Treatments Targeting Excessive Tanning, an Emerging Addictive Behavior.

    PubMed

    Stapleton, Jerod L; Hillhouse, Joel; Levonyan-Radloff, Kristine; Manne, Sharon L

    2017-06-22

    Millions of Americans engage in tanning each year, defined as intentional ultraviolet radiation (UVR) exposure in the form of sunbathing or the use of indoor tanning beds. An emerging body of research suggests that UVR has addictive properties and some tanners engage in excessive tanning. This article provides an overview of the evidence of tanning addiction and a systematic review of existing tanning interventions with the goal of evaluating their potential to impact addicted tanners. Our search identified 24 intervention studies that were summarized and discussed according to 3 primary themes. First, there is a dearth of tanning interventions that target excessive tanning or are designed as treatments for tanning addiction. Second, tanning interventions are primarily educational interventions designed to increase knowledge of the risks of tanning. Third, there are notable aspects of existing tanning interventions that are relevant to addiction science, including the use of brief motivational and cognitive-behavioral-based interventions. Future directions are considered including recommendations for utilizing the existing evidence base to formulate interventions targeting excessive tanners. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  6. Tau elevations in the brain extracellular space correlate with reduced amyloid-β levels and predict adverse clinical outcomes after severe traumatic brain injury.

    PubMed

    Magnoni, Sandra; Esparza, Thomas J; Conte, Valeria; Carbonara, Marco; Carrabba, Giorgio; Holtzman, David M; Zipfel, Greg J; Stocchetti, Nino; Brody, David L

    2012-04-01

    Axonal injury is believed to be a major determinant of adverse outcomes following traumatic brain injury. However, it has been difficult to assess acutely the severity of axonal injury in human traumatic brain injury patients. We hypothesized that microdialysis-based measurements of the brain extracellular fluid levels of tau and neurofilament light chain, two low molecular weight axonal proteins, could be helpful in this regard. To test this hypothesis, 100 kDa cut-off microdialysis catheters were placed in 16 patients with severe traumatic brain injury at two neurological/neurosurgical intensive care units. Tau levels in the microdialysis samples were highest early and fell over time in all patients. Initial tau levels were >3-fold higher in patients with microdialysis catheters placed in pericontusional regions than in patients in whom catheters were placed in normal-appearing right frontal lobe tissue (P = 0.005). Tau levels and neurofilament light-chain levels were positively correlated (r = 0.6, P = 0.013). Neurofilament light-chain levels were also higher in patients with pericontusional catheters (P = 0.04). Interestingly, initial tau levels were inversely correlated with initial amyloid-β levels measured in the same samples (r = -0.87, P = 0.000023). This could be due to reduced synaptic activity in areas with substantial axonal injury, as amyloid-β release is closely coupled with synaptic activity. Importantly, high initial tau levels correlated with worse clinical outcomes, as assessed using the Glasgow Outcome Scale 6 months after injury (r = -0.6, P = 0.018). Taken together, our data add support for the hypothesis that axonal injury may be related to long-term impairments following traumatic brain injury. Microdialysis-based measurement of tau levels in the brain extracellular space may be a useful way to assess the severity of axonal injury acutely in the intensive care unit. Further studies with larger numbers of

  7. A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease

    PubMed Central

    Deane, Rashid; Singh, Itender; Sagare, Abhay P.; Bell, Robert D.; Ross, Nathan T.; LaRue, Barbra; Love, Rachal; Perry, Sheldon; Paquette, Nicole; Deane, Richard J.; Thiyagarajan, Meenakshisundaram; Zarcone, Troy; Fritz, Gunter; Friedman, Alan E.; Miller, Benjamin L.; Zlokovic, Berislav V.

    2012-01-01

    In Alzheimer disease (AD), amyloid β peptide (Aβ) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aβ binding to the V domain of RAGE and inhibited Aβ40- and Aβ42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APPsw/0 mice overexpressing human Aβ-precursor protein, a transgenic mouse model of AD with established Aβ pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aβ40 and Aβ42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aβ40 and Aβ42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APPsw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aβ-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD. PMID:22406537

  8. Personalized health planning with integrative health coaching to reduce obesity risk among women gaining excess weight during pregnancy.

    PubMed

    Yang, Nancy Y; Wroth, Shelley; Parham, Catherine; Strait, Melva; Simmons, Leigh Ann

    2013-07-01

    Health coaching is an emerging behavioral intervention to improve outcomes in chronic disease management and prevention; however, no studies have investigated its utility in postpartum women who have gained excess weight during pregnancy. A 32-year-old primigravida woman who was overweight at conception and gained 23 lbs more than Institute of Medicine recommendations for her pre-pregnancy body mass index participated in a 6-month personalized health planning with integrative health coaching (PHPIHC) intervention. The intervention included a baseline health risk assessment review with a healthcare provider and eight biweekly, 30-minute telephonic health coaching sessions. The participant demonstrated improvement in physical activity, energy expenditure, knowledge, and confidence to engage in healthpromoting behaviors. Although the participant did not reach the target weight by completion of the health coaching sessions, follow up 8 months later indicated she achieved the target goal (within 5% of prepregnancy weight). This case report suggests that PHP-IHC can support postpartum women in returning to pre-pregnancy weight after gaining excess gestational weight. Future research and clinical trials are needed to determine the best timing, length, and medium (online, in-person, telephonic) of PHP-IHC for postpartum women.

  9. AMYLOID NEUROPATHIES

    PubMed Central

    Shin, Susan C.; Robinson-Papp, Jessica

    2012-01-01

    Peripheral neuropathy is a common complication of many of the systemic amyloidoses. Although the cause of neuropathy is not entirely clear, it is likely related to amyloid deposition within the nerve. This may lead to focal, multifocal, or diffuse neuropathies involving sensory, motor and/or autonomic fibers. The presenting symptoms depend on the distribution of nerves affected. One of the most common phenotypes is sensorimotor polyneuropathy, which is characterized by symptoms of neuropathic pain, numbness, and in advanced cases weakness. Symptoms begin in the feet and ultimately progress to the proximal legs and hands. The most common focal neuropathy is a median neuropathy at the wrist, or clinically known as carpal tunnel syndrome. Carpal tunnel symptoms may include pain and sensory disturbances in the lateral palm and fingers; hand weakness may ensue if the focal neuropathy is severe. Autonomic neuropathy may affect a variety of organ systems such as the cardiovascular, gastrointestinal, and genitourinary systems. Symptoms may be non-specific making the diagnosis of autonomic neuropathy more difficult to identify. However, it is important to recognize and distinguish autonomic neuropathy from diseases of the end-organs themselves. This chapter reviews the inherited and acquired amyloidoses that affect the peripheral nervous system including familial amyloid polyneuropathy, and primary, secondary and senile amyloidosis. We emphasize the clinical presentation of the neurologic aspects of these diseases, physical examination findings, appropriate diagnostic evaluation, treatment and prognosis. PMID:23239211

  10. Amyloid neuropathies.

    PubMed

    Shin, Susan C; Robinson-Papp, Jessica

    2012-01-01

    Peripheral neuropathy is a common complication of many of the systemic amyloidoses. Although the cause of neuropathy is not entirely clear, it is likely related to amyloid deposition within the nerve. This may lead to focal, multifocal, or diffuse neuropathies involving sensory, motor and/or autonomic fibers. The presenting symptoms depend on the distribution of nerves affected. One of the most common phenotypes is sensorimotor polyneuropathy, which is characterized by symptoms of neuropathic pain, numbness, and in advanced cases weakness. Symptoms begin in the feet and ultimately progress to the proximal legs and hands. The most common focal neuropathy is a median neuropathy at the wrist, clinically known as carpal tunnel syndrome. Carpal tunnel symptoms may include pain and sensory disturbances in the lateral palm and fingers; hand weakness may ensue if the focal neuropathy is severe. Autonomic neuropathy may affect a variety of organ systems such as the cardiovascular, gastrointestinal, and genitourinary systems. Symptoms may be non-specific making the diagnosis of autonomic neuropathy more difficult to identify. However, it is important to recognize and distinguish autonomic neuropathy from diseases of the end-organs themselves. This article reviews the inherited and acquired amyloidoses that affect the peripheral nervous system including familial amyloid polyneuropathy, and primary, secondary and senile amyloidosis. We emphasize the clinical presentation of the neurologic aspects of these diseases, physical examination findings, appropriate diagnostic evaluation, treatment and prognosis. © 2012 Mount Sinai School of Medicine.

  11. Natural polyphenols binding to amyloid: a broad class of compounds to treat different human amyloid diseases.

    PubMed

    Ngoungoure, Viviane L Ndam; Schluesener, Jan; Moundipa, Paul F; Schluesener, Hermann

    2015-01-01

    Polyphenols are a large group of phytonutrients found in herbal beverages and foods. They have manifold biological activities, including antioxidative, antimicrobial, and anti-inflammatory properties. Interestingly, some polyphenols bind to amyloid and substantially ameliorate amyloid diseases. Misfolding, aggregation, and accumulation of amyloid fibrils in tissues or organs leads to a group of disorders, called amyloidoses. Prominent diseases are Alzheimer's, Parkinson's, and Huntington's disease, but there are other, less well-known diseases wherein accumulation of misfolded protein is a prominent feature. Amyloidoses are a major burden to public health. In particular, Alzheimer's disease shows a strong increase in patient numbers. Accelerated development of effective therapies for amyloidoses is a necessity. A viable strategy can be the prevention or reduction of protein misfolding, thus reducing amyloid build-up by restoring the cellular aggretome. Amyloid-binding polyphenols affect amyloid formation on various levels, e.g. by inhibiting fibril formation or steering oligomer formation into unstructured, nontoxic pathways. Consequently, preclinical studies demonstrate reduction of amyloid-formation by polyphenols. Amyloid-binding polyphenols might be suitable lead structures for development of imaging agents for early detection of disease and monitoring amyloid deposition. Intake of dietary polyphenols might be relevant to the prevention of amyloidoses. Nutraceutical strategies might be a way to reduce amyloid diseases.

  12. Histamine H3 Inverse Agonist BF 2649 or Antagonist with Partial H4 Agonist Activity Clobenpropit Reduces Amyloid Beta Peptide-Induced Brain Pathology in Alzheimer's Disease.

    PubMed

    Patnaik, Ranjana; Sharma, Aruna; Skaper, Stephen D; Muresanu, Dafin F; Lafuente, José Vicente; Castellani, Rudy J; Nozari, Ala; Sharma, Hari S

    2017-08-31

    Alzheimer's disease (AD) is one of the leading causes for disability and death affecting millions of people worldwide. Thus, novel therapeutic strategies are needed to reduce brain pathology associated with AD. In view of increasing awareness regarding involvement of histaminergic pathways in AD, we explored the role of one H3 receptor inverse agonist BF 2649 and one selective H3 receptor antagonist with partial H4 agonist activity in amyloid beta peptide (AβP) infusion-induced brain pathology in a rat model. AD-like pathology was produced by administering AβP (1-40) intracerebroventricular (i.c.v.) in the left lateral ventricle (250 ng/10 μl, once daily) for 4 weeks. Control rats received saline. In separate group of rats, either BF 2649 (1 mg/kg, i.p.) or clobenpropit (1 mg/kg, i.p.) was administered once daily for 1 week after 3 weeks of AβP administration. After 30 days, blood-brain barrier (BBB) breakdown, edema formation, neuronal, glial injuries, and AβP deposits were examined in the brain. A significant reduction in AβP deposits along with marked reduction in neuronal or glial reactions was seen in the drug-treated group. The BBB breakdown to Evans blue albumin and radioiodine in the cortex, hippocampus, hypothalamus, and cerebellum was also significantly reduced in these drug-treated groups. Clobenpropit showed superior effects than the BF2649 in reducing brain pathology in AD. Taken together, our observations are the first to show that blockade of H3 and stimulation of H4 receptors are beneficial for the treatment of AD pathology, not reported earlier.

  13. Rebamipide reduces amyloid-β 1-42 (Aβ42) production and ameliorates Aβ43-lowered cell viability in cultured SH-SY5Y human neuroblastoma cells.

    PubMed

    Fukui, Kenta; Yachi, Kazuma; Yoshida, Hidemi; Tanji, Kunikazu; Matsumiya, Tomoh; Hayakari, Ryo; Tsuruga, Kazushi; Tanaka, Hiroshi; Imaizumi, Tadaatsu

    2017-06-03

    Amyloid-beta (Aβ) peptides, Aβ 1-42 (Aβ42) and Aβ43, in particular, have been implicated in the pathophysiology of neurodegenerative disease such as Alzheimer's disease (AD). Rebamipide (REB), a gastrointestinal protective drug, can cross the blood-brain barrier after oral administration; however, the effects of REB on neuronal cells have not yet been reported. In this study, we investigated the effects of REB on Aβ43-induced cytotoxicity (monomers, 10μM) in cultured SH-SY5Y human neuroblastoma cells. Addition of REB (10-1000nM) into the media partially ameliorated the reduced cell viability observed after Aβ43 treatment, which was determined by the MTT assay. REB reduced the levels of intracellular Aβ oligomers (100-150kDa) that were formed from the exogenous addition of Aβ43 monomers. In addition, REB (30nM) reduced endogenous Aβ42 secretion, which was analyzed by the enzyme-linked immunosorbent assay. Furthermore, REB enhanced the expression of tumor necrosis factor-α-converting enzyme/a disintegrin and metalloproteinase-17, neprilysin, matrix-metalloproteinase-14 (MMP-14)/membrane type-1 MMP, cyclooxygenase-2, and sirtuin 1, even in cells challenged with Aβ43. These results suggest that REB improves the cell viability by inducing genes that regulate Aβ levels and also genes that are cytoprotective. The secondary use of REB may have potential in the prevention of Aβ-mediated diseases, particularly AD. Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  14. Increased efflux of amyloid-β peptides through the blood-brain barrier by muscarinic acetylcholine receptor inhibition reduces pathological phenotypes in mouse models of brain amyloidosis.

    PubMed

    Paganetti, Paolo; Antoniello, Katia; Devraj, Kavi; Toni, Nicolas; Kieran, Dairin; Madani, Rime; Pihlgren, Maria; Adolfsson, Oskar; Froestl, Wolfgang; Schrattenholz, André; Liebner, Stefan; Havas, Daniel; Windisch, Manfred; Cirrito, John R; Pfeifer, Andrea; Muhs, Andreas

    2014-01-01

    The formation and accumulation of toxic amyloid-β peptides (Aβ) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating Aβ homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Aβ or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain Aβ burden in AβPPPS1, hAβPPSL, and AβPP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced Aβ peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Aβ in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Aβ in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Aβ peptide in pre-plaque mhAβPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of Aβ peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Aβ transport across the Blood Brain Brain (BBB). Thus increased Aβ clearance through the BBB may contribute to reduced Aβ burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects.

  15. Cortical bone loss caused by glucocorticoid excess requires RANKL production by osteocytes and is associated with reduced OPG expression in mice.

    PubMed

    Piemontese, Marilina; Xiong, Jinhu; Fujiwara, Yuko; Thostenson, Jeff D; O'Brien, Charles A

    2016-09-01

    Glucocorticoid excess is a major cause of low bone mass and fractures. Glucocorticoid administration decreases cortical thickness and increases cortical porosity in mice, and these changes are associated with increased osteoclast number at the endocortical surface. Receptor activator of NF-κB ligand (RANKL) produced by osteocytes is required for osteoclast formation in cancellous bone as well as the increase in cortical bone resorption caused by mechanical unloading or dietary calcium deficiency. However, whether osteocyte-derived RANKL also participates in the increase in bone resorption caused by glucocorticoid excess is unknown. To address this question, we examined the effects of prednisolone on cortical bone of mice lacking RANKL production in osteocytes. Prednisolone administration increased osteoclast number at the endocortical surface, increased cortical porosity, and reduced cortical thickness in control mice, but none of these effects occurred in mice lacking RANKL in osteocytes. Prednisolone administration did not alter RANKL mRNA abundance but did reduce osteoprotegerin (OPG) mRNA abundance in osteocyte-enriched cortical bone. Similarly, dexamethasone suppressed OPG but did not increase RANKL production in cortical bone organ cultures and primary osteoblasts. These results demonstrate that RANKL produced by osteocytes is required for the cortical bone loss caused by glucocorticoid excess but suggest that the changes in endocortical resorption are driven by reduced OPG rather than elevated RANKL expression.

  16. Minocycline reduces inflammatory parameters in the brain structures and serum and reverses memory impairment caused by the administration of amyloid β (1-42) in mice.

    PubMed

    Garcez, Michelle Lima; Mina, Francielle; Bellettini-Santos, Tatiani; Carneiro, Franciellen Gonçalves; Luz, Aline Pereira; Schiavo, Gustavo Luis; Andrighetti, Matheus Scopel; Scheid, Maylton Grégori; Bolfe, Renan Pereira; Budni, Josiane

    2017-03-21

    Alzheimer's disease (AD) is a neurodegenerative disorder and the most common type of age-related dementia. Cognitive decline, beta-amyloid (Aβ) accumulation, neurofibrillary tangles, and neuroinflammation are the main pathophysiological characteristics of AD. Minocycline is a tetracycline derivative with anti-inflammatory properties that has a neuroprotective effect. The aim of this study was to evaluate the effect of minocycline on memory, neurotrophins and neuroinflammation in an animal model of AD induced by the administration of Aβ (1-42) oligomer. Male BALB/c mice were treated with minocycline (50mg/kg) via the oral route for a total of 17days, 24h after intracerebroventricular administration of Aβ (1-42) oligomer. At the end of this period, was performed the radial maze test, and 24h after the last minocycline administration, serum was collected and the cortex and hippocampus were dissected for biochemical analysis. The administration of minocycline reversed the memory impairment caused by Aβ (1-42). In the hippocampus, minocycline reversed the increases in the levels of interleukin (IL-1β), Tumor Necrosis Factor- alpha (TNF-α) and, IL-10 caused by Aβ (1-42). In the cortex, AD-like model increase the levels of IL-1β, TNF-α and, IL-4. Minocycline treatment reversed this. In the serum, Aβ (1-42) increased the levels of IL-1β and IL-4, and minocycline was able to reverse this action, but not to reverse the decrease of IL-10 levels. Minocycline also reversed the increase in the levels of Brain-derived neurotrophic factor (BDNF) in the hippocampus caused by Aβ (1-42), and reduced Nerve Growth Factor (NGF) increases in the total cortex. Therefore, our results indicate that minocycline causes improvements in the spatial memory, and cytokine levels were correlated with this effect in the brain it. Besides this, minocycline reduced BDNF and NGF levels, highlighting the promising effects of minocycline in treating AD-like dementia.

  17. Telmisartan reduces progressive accumulation of cellular amyloid beta and phosphorylated tau with inflammatory responses in aged spontaneously hypertensive stroke resistant rat.

    PubMed

    Kurata, Tomoko; Lukic, Violeta; Kozuki, Miki; Wada, Daisuke; Miyazaki, Kazunori; Morimoto, Nobutoshi; Ohta, Yasuyuki; Deguchi, Kentaro; Ikeda, Yoshio; Kamiya, Tatsushi; Abe, Koji

    2014-01-01

    In addition to reducing the level of blood pressure (BP), telmisartan was expected to show the long-term neuroprotective effects preventing accumulation of cellular amyloid beta peptide (Aβ) and phosphorylated tau (pτ) by ameliorating neuroinflammation. We examined effects of telmisartan on cellular Aβ and pτ with inflammatory responses in the brain of a spontaneously hypertensive stroke resistant (SHR-SR) rat by giving either telmisartan at 0 (vehicle), .3 mg/kg/day or 3 mg/kg/day, orally, from 3 months of age and performed immunohistologic analysis at 6, 12, and 18 months. Compared with normotensive Wistar rats, numbers of Aβ- and pτ-positive neurons in the cerebral cortex progressively increased with age until 18 months in the SHR-SR rats, as did the numbers of ionized calcium-binding adapter molecule 1 (Iba-1)-positive microglia, tumor necrosis factor alpha (TNF-α)-positive neurons, and monocyte chemotactic protein 1 (MCP-1)-positive neurons. Low-dose telmisartan significantly decreased the numbers of Aβ- and pτ-positive neuron as well as the numbers of TNF-α-positive neurons, Iba-1-positive microglia, and MCP-1-positive neurons at 6, 12, and 18 months. High-dose telmisartan reduced BP and showed a further reduction of cellular Aβ and pτ. The present study suggests that accumulation of cellular Aβ and pτ and the inflammatory responses were decreased via improving metabolic syndrome with low-dose telmisartan and improving both metabolic syndrome and hypertension with high-dose telmisartan. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  18. Amyloidreduces the expression of neuronal FAIM-L, thereby shifting the inflammatory response mediated by TNFα from neuronal protection to death

    PubMed Central

    Carriba, P; Jimenez, S; Navarro, V; Moreno-Gonzalez, I; Barneda-Zahonero, B; Moubarak, R S; Lopez-Soriano, J; Gutierrez, A; Vitorica, J; Comella, J X

    2015-01-01

    The brains of patients with Alzheimer's disease (AD) present elevated levels of tumor necrosis factor-α (TNFα), a cytokine that has a dual function in neuronal cells. On one hand, TNFα can activate neuronal apoptosis, and on the other hand, it can protect these cells against amyloid-β (Aβ) toxicity. Given the dual behavior of this molecule, there is some controversy regarding its contribution to the pathogenesis of AD. Here we examined the relevance of the long form of Fas apoptotic inhibitory molecule (FAIM) protein, FAIM-L, in regulating the dual function of TNFα. We detected that FAIM-L was reduced in the hippocampi of patients with AD. We also observed that the entorhinal and hippocampal cortex of a mouse model of AD (PS1M146LxAPP751sl) showed a reduction in this protein before the onset of neurodegeneration. Notably, cultured neurons treated with the cortical soluble fractions of these animals showed a decrease in endogenous FAIM-L, an effect that is mimicked by the treatment with Aβ-derived diffusible ligands (ADDLs). The reduction in the expression of FAIM-L is associated with the progression of the neurodegeneration by changing the inflammatory response mediated by TNFα in neurons. In this sense, we also demonstrate that the protection afforded by TNFα against Aβ toxicity ceases when endogenous FAIM-L is reduced by short hairpin RNA (shRNA) or by treatment with ADDLs. All together, these results support the notion that levels of FAIM-L contribute to determine the protective or deleterious effect of TNFα in neuronal cells. PMID:25675299

  19. Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease.

    PubMed

    Kounnas, Maria Z; Danks, Anne M; Cheng, Soan; Tyree, Curtis; Ackerman, Elizabeth; Zhang, Xulun; Ahn, Kwangwook; Nguyen, Phuong; Comer, Dan; Mao, Long; Yu, Chengzhi; Pleynet, David; Digregorio, Paul J; Velicelebi, Gonul; Stauderman, Kenneth A; Comer, William T; Mobley, William C; Li, Yue-Ming; Sisodia, Sangram S; Tanzi, Rudolph E; Wagner, Steven L

    2010-09-09

    Alzheimer's disease (AD) is characterized pathologically by the abundance of senile plaques and neurofibrillary tangles in the brain. We synthesized over 1200 novel gamma-secretase modulator (GSM) compounds that reduced Abeta(42) levels without inhibiting epsilon-site cleavage of APP and Notch, the generation of the APP and Notch intracellular domains, respectively. These compounds also reduced Abeta(40) levels while concomitantly elevating levels of Abeta(38) and Abeta(37). Immobilization of a potent GSM onto an agarose matrix quantitatively recovered Pen-2 and to a lesser degree PS-1 NTFs from cellular extracts. Moreover, oral administration (once daily) of another potent GSM to Tg 2576 transgenic AD mice displayed dose-responsive lowering of plasma and brain Abeta(42); chronic daily administration led to significant reductions in both diffuse and neuritic plaques. These effects were observed in the absence of Notch-related changes (e.g., intestinal proliferation of goblet cells), which are commonly associated with repeated exposure to functional gamma-secretase inhibitors (GSIs). 2010 Elsevier Inc. All rights reserved.

  20. A controlled intervention to promote a healthy body image, reduce eating disorder risk and prevent excessive exercise among trainee health education and physical education teachers.

    PubMed

    Yager, Zali; O'Dea, Jennifer

    2010-10-01

    This study examined the impact of two interventions on body image, eating disorder risk and excessive exercise among 170 (65% female) trainee health education and physical education (HE&PE) teachers of mean (standard deviation) age 21.6 (2.3) who were considered an 'at-risk' population for poor body image and eating disorders. In the first year of the study, the control group cohort (n = 49 females, 20 males) received the regular didactic health education curriculum; in the second year of the study, the Intervention 1 cohort (n = 31 females, 21 males) received a self-esteem and media literacy health education program and in the third year of the study, the Intervention 2 cohort (n = 30 females, 19 males) received a combined self-esteem, media literacy and dissonance program using online and computer-based activities. Intervention 2 produced the best results, with males improving significantly in self-esteem, body image and drive for muscularity. Intervention 2 females improved significantly on Eating Disorders Inventory Drive for Thinness, Eating Disorder Examination and excessive exercise. The improvements were consistent at 6-month follow-up for females. It is feasible to promote body image, reduce body dissatisfaction and reduce excessive exercise among trainee HE&PE teachers via a health education curriculum.

  1. Traditional Chinese Nootropic Medicine Radix Polygalae and Its Active Constituent Onjisaponin B Reduce β-Amyloid Production and Improve Cognitive Impairments

    PubMed Central

    Li, Xiaohang; Cui, Jin; Yu, Yang; Li, Wei; Hou, Yujun; Wang, Xin; Qin, Dapeng; Zhao, Cun; Yao, Xinsheng; Zhao, Jian; Pei, Gang

    2016-01-01

    Decline of cognitive function is the hallmark of Alzheimer’s disease (AD), regardless of the pathological mechanism. Traditional Chinese medicine has been used to combat cognitive impairments and has been shown to improve learning and memory. Radix Polygalae (RAPO) is a typical and widely used herbal medicine. In this study, we aimed to follow the β-amyloid (Aβ) reduction activity to identify active constituent(s) of RAPO. We found that Onjisaponin B of RAPO functioned as RAPO to suppress Aβ production without direct inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and γ-secretase activities. Our mechanistic study showed that Onjisaponin B promoted the degradation of amyloid precursor protein (APP). Further, oral administration of Onjisaponin B ameliorated Aβ pathology and behavioral defects in APP/PS1 mice. Taken together, our results indicate that Onjisaponin B is effective against AD, providing a new therapeutic agent for further drug discovery. PMID:26954017

  2. Traditional Chinese Nootropic Medicine Radix Polygalae and Its Active Constituent Onjisaponin B Reduce β-Amyloid Production and Improve Cognitive Impairments.

    PubMed

    Li, Xiaohang; Cui, Jin; Yu, Yang; Li, Wei; Hou, Yujun; Wang, Xin; Qin, Dapeng; Zhao, Cun; Yao, Xinsheng; Zhao, Jian; Pei, Gang

    2016-01-01

    Decline of cognitive function is the hallmark of Alzheimer's disease (AD), regardless of the pathological mechanism. Traditional Chinese medicine has been used to combat cognitive impairments and has been shown to improve learning and memory. Radix Polygalae (RAPO) is a typical and widely used herbal medicine. In this study, we aimed to follow the β-amyloid (Aβ) reduction activity to identify active constituent(s) of RAPO. We found that Onjisaponin B of RAPO functioned as RAPO to suppress Aβ production without direct inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and γ-secretase activities. Our mechanistic study showed that Onjisaponin B promoted the degradation of amyloid precursor protein (APP). Further, oral administration of Onjisaponin B ameliorated Aβ pathology and behavioral defects in APP/PS1 mice. Taken together, our results indicate that Onjisaponin B is effective against AD, providing a new therapeutic agent for further drug discovery.

  3. Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces amyloid-β plaques.

    PubMed

    Kim, J-Y; Kim, D H; Kim, J H; Lee, D; Jeon, H B; Kwon, S-J; Kim, S M; Yoo, Y J; Lee, E H; Choi, S J; Seo, S W; Lee, J I; Na, D L; Yang, Y S; Oh, W; Chang, J W

    2012-04-01

    Presently, co-culture of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) with BV2 microglia under amyloid-β42 (Aβ42) exposure induced a reduction of Aβ42 in the medium as well as an overexpression of the Aβ-degrading enzyme neprilysin (NEP) in microglia. Cytokine array examinations of co-cultured media revealed elevated release of soluble intracellular adhesion molecule-1 (sICAM-1) from hUCB-MSCs. Administration of human recombinant ICAM-1 in BV2 cells and wild-type mice brains induced NEP expression in time- and dose-dependent manners. In co-culturing with BV2 cells under Aβ42 exposure, knockdown of ICAM-1 expression on hUCB-MSCs by small interfering RNA (siRNA) abolished the induction of NEP in BV2 cells as well as reduction of added Aβ42 in the co-cultured media. By contrast, siRNA-mediated inhibition of the sICAM-1 receptor, lymphocyte function-associated antigen-1 (LFA-1), on BV2 cells reduced NEP expression by ICAM-1 exposure. When hUCB-MSCs were transplanted into the hippocampus of a 10-month-old transgenic mouse model of Alzheimer's disease for 10, 20, or 40 days, NEP expression was increased in the mice brains. Moreover, Aβ42 plaques in the hippocampus and other regions were decreased by active migration of hUCB-MSCs toward Aβ deposits. These data suggest that hUCB-MSC-derived sICAM-1 decreases Aβ plaques by inducing NEP expression in microglia through the sICAM-1/LFA-1 signaling pathway.

  4. Icariside II, a Broad-Spectrum Anti-cancer Agent, Reverses Beta-Amyloid-Induced Cognitive Impairment through Reducing Inflammation and Apoptosis in Rats

    PubMed Central

    Deng, Yuanyuan; Long, Long; Wang, Keke; Zhou, Jiayin; Zeng, Lingrong; He, Lianzi; Gong, Qihai

    2017-01-01

    Beta-amyloid (Aβ) deposition, associated neuronal apoptosis and neuroinflammation are considered as the important factors which lead to cognitive deficits in Alzheimer’s disease (AD). Icariside II (ICS II), an active flavonoid compound derived from Epimedium brevicornum Maxim, has been extensively used to treat erectile dysfunction, osteoporosis and dementia in traditional Chinese medicine. Recently, ICS II attracts great interest due to its broad-spectrum anti-cancer property. ICS II shows an anti-inflammatory potential both in cancer treatment and cerebral ischemia-reperfusion. It is not yet clear whether the anti-inflammatory effect of ICS II could delay progression of AD. Therefore, the current study aimed to investigate the effects of ICS II on the behavioral deficits, Aβ levels, neuroinflammatory responses and apoptosis in Aβ25-35-treated rats. We found that bilateral hippocampal injection of Aβ25-35 induced cognitive impairment, neuronal damage, along with increase of Aβ, inflammation and apoptosis in hippocampus of rats. However, treatment with ICS II 20 mg/kg could improve the cognitive deficits, ameliorate neuronal death, and reduce the levels of Aβ in the hippocampus. Furthermore, ICS II could suppress microglial and astrocytic activation, inhibit expression of IL-1β, TNF-α, COX-2, and iNOS mRNA and protein, and attenuate the Aβ induced Bax/Bcl-2 ratio elevation and caspase-3 activation. In conclusion, these results showed that ICS II could reverse Aβ-induced cognitive deficits, possibly via the inhibition of neuroinflammation and apoptosis, which suggested a potential protective effect of ICS II on AD. PMID:28210222

  5. Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer's disease.

    PubMed

    D'Andrea, M R; Nagele, R G; Wang, H Y; Peterson, P A; Lee, D H

    2001-02-01

    Amyloid has recently been shown to accumulate intracellularly in the brains of patients with Alzheimer's disease (AD), yet amyloid plaques are generally thought to arise from gradual extracellular amyloid deposition. We have investigated the possibility of a link between these two apparently conflicting observations. Immunohistochemistry and digital image analysis was used to examine the detailed localization of beta-amyloid(42) (A beta 42), a major component of amyloid plaques, in the entorhinal cortex and hippocampus of AD brains. A beta 42 first selectively accumulates in the perikaryon of pyramidal cells as discrete, granules that appear to be cathepsin D-positive, suggesting that they may represent lysosomes or lysosome-derived structures. AD brain regions abundantly populated with pyramidal neurones exhibiting excessive A beta 42 accumulations also contained evidence of neuronal lysis. Lysis of these A beta 42-burdened neurones apparently resulted in a local, radial dispersion of their cytoplasmic contents, including A beta 42 and lysosomal enzymes, into the surrounding extracellular space. A nuclear remnant was found at the dense core of many amyloid plaques, strengthening the idea that each amyloid plaque represents the end product of a single neuronal cell lysis. The inverse relationship between the amyloid plaque density and pyramidal cell density in the AD brain regions also supports this possibility, as does the close correlation between plaque size and the size of local pyramidal cells. Our findings suggest that excessive intracellular accumulation of A beta 42-positive material in pyramidal cells can result in cell lysis, and that cell lysis is an important source of amyloid plaques and neuronal loss in AD brains.

  6. Agrimonia pilosa Ledeb., Cinnamomum cassia Blume, and Lonicera japonica Thunb. protect against cognitive dysfunction and energy and glucose dysregulation by reducing neuroinflammation and hippocampal insulin resistance in β-amyloid-infused rats.

    PubMed

    Park, Sunmin; Kang, Suna; Kim, Da Sol; Moon, Bo Rerum

    2017-02-01

    The water extracts of Cinnamomum cassia Blume bark (CCB; Lauraceae), Lonicera japonica Thunb. flower (LJT; Caprifoliaceae), and Agrimonia pilosa Ledeb. leaves (APL; Rosaceae) prevented amyloid-β (25-35)-induced cell death in PC12 cells in our preliminary study. We evaluated whether long-term oral consumption of CCB, LJT, and APL improves cognitive dysfunction and glucose homeostasis in rats with experimentally induced AD-type dementia. Male rats received hippocampal CA1 infusions of amyloid-β (25-35, AD) or amyloid-β (35-25, non-plaque forming, normal-controls, Non-AD-CON), at a rate of 3.6 nmol/day for 14 days. AD rats were divided into four groups receiving either 2% lyophilized water extracts of CCB, LJT, or APL or 2% dextrin (AD-CON) in high-fat diets (43% energy as fat). Hippocampal amyloid-β deposition, tau phosphorylation, and expressions of tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS) (neruoinflammation markers) were increased, and insulin signaling decreased in AD-CON. CCB, LJT, and APL all prevented hippocampal amyloid-β accumulation and enhanced hippocampal insulin signaling. CCB, LJT, and APL decreased TNF-α and iNOS in the hippocampus and especially APL exhibited the greatest decrease. AD-CON exhibited cognitive dysfunction in passive avoidance and water maze tests, whereas CCB, LJT, and APL protected against cognitive dysfunction, and APL was most effective and was similar to Non-AD-CON. AD-CON had less fat oxidation as an energy fuel, but it was reversed by CCB, LJT, and especially APL. APL-treated rats had less visceral fat than AD-CON rats. AD-CON rats exhibited impaired insulin sensitivity and increased insulin secretion during oral glucose tolerance test compared with Non-AD-CON, but CCB and APL prevented the impairment. These results supported that APL, LJT, and CCB effectively prevent the cognitive dysfunction and the impairment of energy and glucose homeostasis induced by amyloid-β deposition by reducing

  7. Copper Abolishes the β-Sheet Secondary Structure of Preformed Amyloid Fibrils of Amyloid-β42

    PubMed Central

    House, Emily; Mold, Matthew; Collingwood, Joanna; Baldwin, Alex; Goodwin, Steven; Exley, Christopher

    2010-01-01

    The observation of the co-deposition of metals and amyloid-β42 (Aβ42) in brain tissue in Alzheimer’s disease prompted myriad investigations into the role played by metals in the precipitation of this peptide. Copper is bound by monomeric Aβ42 and upon precipitation of the copper-peptide complex thereby prevents Aβ42 from adopting a β-sheet secondary structure. Copper is also bound by β-sheet conformers of Aβ42, and herein we have investigated how this interaction affects the conformation of the precipitated peptide. Copper significantly reduced the thioflavin T fluorescence of aged, fibrillar Aβ42 with, for example, a 20-fold excess of the metal resulting in a ca 90% reduction in thioflavin T fluorescence. Transmission electron microscopy showed that copper significantly reduced the quantities of amyloid fibrils while Congo red staining and polarized light demonstrated a copper-induced abolition of apple-green birefringence. Microscopy under cross-polarized light also revealed the first observation of spherulites of Aβ42. The size and appearance of these amyloid structures were found to be very similar to spherulites identified in Alzheimer’s disease tissue. The combined results of these complementary methods strongly suggested that copper abolished the β-sheet secondary structure of pre-formed, aged amyloid fibrils of Aβ42. Copper may protect against the presence of β-sheets of Aβ42 in vivo, and its binding by fibrillar Aβ42 could have implications for Alzheimer’s disease therapy. PMID:19749401

  8. Retrospective study to investigate the possible relationship between excess blood loss at caesarean section and reduced intra-operative oxytocin dose.

    PubMed

    Pearson, Greg A; Pepper, Warwick; Russell, Robin; MacKenzie, I Z

    2016-01-01

    To investigate a possible relationship between the oxytocin dose at caesarean section and blood loss. Retrospective analysis of computerised data for all caesarean sections in a UK maternity unit delivering 6000 women annually during 1995-2009 and thus for seven years before and after the 2001 recommended change in oxytocin dose. Validation of computerised and hand-checked clinical data for 1996 and 2006 was performed and annual frequency of blood loss >1000 ml was observed. Validation showed most variables recorded were similar for both acquisition methods. For 17,405 (98.9%) caesarean sections with blood loss recorded, excess or severe loss occurred in 127 (1.6%) of 7177 cases during 1995-2001 compared with 362 (4.0%) of 9035 during 2003-2009 (OR 2.317, CI 1.888-2.843). It was significantly more frequent with multiple than singleton pregnancies (OR 1.946, CI 1.417-2.673), with general than neuraxial anaesthesia (OR 4.296, CI 3.479-5.305) and with non-longitudinal than longitudinal fetal lie (OR 1.942, CI 1.501-2.512). Excluding these three groups, excess blood loss was still more frequent during 2003-2009 than 1995-2001 (OR 3.181, CI 2.374-4.263). Oxytocin given during labour did not influence the frequency of excess blood loss. The increased rate of excess blood loss at caesarean section during the latter period could be the result of the reduced oxytocin dose. If similar observations are made by others, this possible relationship should be investigated with appropriate objective randomised studies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  9. Multiple low-dose infusions of human umbilical cord blood cells improve cognitive impairments and reduce amyloid-β-associated neuropathology in Alzheimer mice.

    PubMed

    Darlington, Donna; Deng, Juan; Giunta, Brian; Hou, Huayan; Sanberg, Cyndy D; Kuzmin-Nichols, Nicole; Zhou, Hua-Dong; Mori, Takashi; Ehrhart, Jared; Sanberg, Paul R; Tan, Jun

    2013-02-01

    Alzheimer's disease (AD) is the most common progressive age-related dementia in the elderly and the fourth major cause of disability and mortality in that population. The disease is pathologically characterized by deposition of β-amyloid plaques neurofibrillary tangles in the brain. Current strategies for the treatment of AD are symptomatic only. As such, they are less than efficacious in terms of significantly slowing or halting the underlying pathophysiological progression of the disease. Modulation by cell therapy may be new promising disease-modifying therapy. Recently, we showed reduction in amyloid-β (Aβ) levels/β-amyloid plaques and associated astrocytosis following low-dose infusions of mononuclear human umbilical cord blood cells (HUCBCs). Our current study extended our previous findings by examining cognition via (1) the rotarod test, (2) a 2-day version of the radial-arm water maze test, and (3) a subsequent observation in an open pool platform test to characterize the effects of monthly peripheral HUCBC infusion (1×10(6) cells/μL) into the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) from 6 to 12 months of age. We show that HUCBC therapy correlates with decreased (1) cognitive impairment, (2) Aβ levels/β-amyloid plaques, (3) amyloidogenic APP processing, and (4) reactive microgliosis after a treatment of 6 or 10 months. As such, this report lays the groundwork for an HUCBC therapy as potentially novel alternative to oppose AD at the disease-modifying level.

  10. Reduced pathology and improved behavioral performance in Alzheimer’s disease mice vaccinated with HSV amplicons expressing amyloid-beta and interleukin-4

    PubMed Central

    Frazer, Maria E.; Hughes, Jennifer E.; Mastrangelo, Michael A.; Tibbens, Jennifer L.; Federoff, Howard J.; Bowers, William J.

    2008-01-01

    Immunotherapeutics designed to dissolve existing amyloid plaques or to interrupt amyloid-beta (Aβ) accumulation may be feasible for treatment and/or prevention of Alzheimer’s disease (AD). “Shaping” immune responses elicited against Aβ is requisite to generate an efficacious and safe outcome by minimizing the possibility of deleterious inflammatory reactions in the brain as observed in clinical testing of Aβ peptide/adjuvant-based modalities. Herpes Simplex Virus (HSV)-based amplicons can co-express multiple antigens and/or immunomodulatory genes due to their large genetic size capacity, thereby facilitating antigen-specific immune response shaping. We have constructed an amplicon (HSVIEAβCMVIL-4) that co-delivers Aβ1-42 with interleukin-4, a cytokine that promotes the generation of Th2-like T cell responses, which are favored in the setting of AD immunotherapy. Triple-transgenic AD (3xTg-AD) mice, which progressively develop both amyloid and neurofibrillary tangle pathology, were vaccinated thrice with HSVIEAβCMVIL-4, or a set of control amplicon vectors. Increased Th2-related, Aβ-specific antibodies, improved learning and memory functioning, and prevention of AD-related amyloid and tau pathological progression were observed in HSVIEAβCMVIL-4 vaccinated mice as compared to the other experimental groups. Our study underscores the potential of Aβ immunotherapy for AD and highlights the potency of amplicons to facilitate immune response modulation to a disease-relevant antigen. PMID:18388924

  11. St. John's Wort reduces beta-amyloid accumulation in a double transgenic Alzheimer's disease mouse model-role of P-glycoprotein.

    PubMed

    Brenn, Anja; Grube, Markus; Jedlitschky, Gabriele; Fischer, Andrea; Strohmeier, Barbara; Eiden, Martin; Keller, Markus; Groschup, Martin H; Vogelgesang, Silke

    2014-01-01

    The adenosine triphosphate-binding cassette transport protein P-glycoprotein (ABCB1) is involved in the export of beta-amyloid from the brain into the blood, and there is evidence that age-associated deficits in cerebral P-glycoprotein content may be involved in Alzheimer's disease pathogenesis. P-glycoprotein function and expression can be pharmacologically induced by a variety of compounds including extracts of Hypericum perforatum (St. John's Wort). To clarify the effect of St. John's Wort on the accumulation of beta-amyloid and P-glycoprotein expression in the brain, St. John's Wort extract (final hyperforin concentration 5%) was fed to 30-day-old male C57BL/6J-APP/PS1(+/-) mice over a period of 60 or 120 days, respectively. Age-matched male C57BL/6J-APP/PS1(+/-) mice receiving a St. John's Wort-free diet served as controls. Mice receiving St. John's Wort extract showed (i) significant reductions of parenchymal beta-amyloid 1-40 and 1-42 accumulation; and (ii) moderate, but statistically significant increases in cerebrovascular P-glycoprotein expression. Thus, the induction of cerebrovascular P-glycoprotein may be a novel therapeutic strategy to protect the brain from beta-amyloid accumulation, and thereby impede the progression of Alzheimer's disease.

  12. Factors Influencing Usability of a Smartphone App to Reduce Excessive Alcohol Consumption: Think Aloud and Interview Studies.

    PubMed

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

    2017-01-01

    Interventions delivered by smartphone apps have the potential to help drinkers reduce their consumption of alcohol. To optimize engagement and reduce the high rates of attrition associated with the use of digital interventions, it is necessary to ensure that an app's design and functionality is appropriate for its intended purposes and target population. To understand the usability of an app to help people reduce their alcohol consumption. The app, Drink Less, contains a core module focusing on goal setting, supplemented by five additional modules: self-monitoring and feedback, identity change, cognitive bias re-training, action planning, and social comparison. Two studies were conducted, a "think aloud" study performed with people using the app for the first time and a semistructured interview study performed after users had had access to the app for at least 2 weeks. A thematic analysis of the "think aloud" and interview transcripts was conducted by one coder and verified by a second. Twenty-four participants, half of whom were women and half from disadvantaged groups, took part in the two studies. Three main themes identified in the data were "Feeling lost and unsure of what to do next," "Make the app easy to use," and "Make the app beneficial and rewarding to use." These themes reflected participants' need for (i) guidance, particularly when first using the app or when entering data; (ii) the data entry process to be simple and the navigation intuitive; (iii) neither the amount of text nor range of options to be overwhelming; (iv) the app to reward them for effort and progress; and (v) it to be clear how the app could help alcohol reduction goals be reached. First-time and experienced users want an alcohol reduction app to be easy, rewarding, and beneficial to use. An easy-to-use app would reduce user burden, offer ongoing help, and be esthetically pleasing. A rewarding and beneficial app would provide positive reinforcement, give feedback about progress

  13. Mixed oligomers and monomeric amyloid-β disrupts endothelial cells integrity and reduces monomeric amyloid-β transport across hCMEC/D3 cell line as an in vitro blood-brain barrier model.

    PubMed

    Qosa, Hisham; LeVine, Harry; Keller, Jeffrey N; Kaddoumi, Amal

    2014-09-01

    Senile amyloid plaques are one of the diagnostic hallmarks of Alzheimer's disease (AD). However, the severity of clinical symptoms of AD is weakly correlated with the plaque load. AD symptoms severity is reported to be more strongly correlated with the level of soluble amyloid-β (Aβ) assemblies. Formation of soluble Aβ assemblies is stimulated by monomeric Aβ accumulation in the brain, which has been related to its faulty cerebral clearance. Studies tend to focus on the neurotoxicity of specific Aβ species. There are relatively few studies investigating toxic effects of Aβ on the endothelial cells of the blood-brain barrier (BBB). We hypothesized that a soluble Aβ pool more closely resembling the in vivo situation composed of a mixture of Aβ40 monomer and Aβ42 oligomer would exert higher toxicity against hCMEC/D3 cells as an in vitro BBB model than either component alone. We observed that, in addition to a disruptive effect on the endothelial cells integrity due to enhancement of the paracellular permeability of the hCMEC/D3 monolayer, the Aβ mixture significantly decreased monomeric Aβ transport across the cell culture model. Consistent with its effect on Aβ transport, Aβ mixture treatment for 24h resulted in LRP1 down-regulation and RAGE up-regulation in hCMEC/D3 cells. The individual Aβ species separately failed to alter Aβ clearance or the cell-based BBB model integrity. Our study offers, for the first time, evidence that a mixture of soluble Aβ species, at nanomolar concentrations, disrupts endothelial cells integrity and its own transport across an in vitro model of the BBB.

  14. Four-Week Consumption of Malaysian Honey Reduces Excess Weight Gain and Improves Obesity-Related Parameters in High Fat Diet Induced Obese Rats

    PubMed Central

    Kanyan Enchang, Francis; Nor Hussein, Fuzina

    2017-01-01

    Many studies revealed the potential of honey consumption in controlling obesity. However, no study has been conducted using Malaysian honey. In this study, we investigated the efficacy of two local Malaysian honey types: Gelam and Acacia honey in reducing excess weight gain and other parameters related to obesity. The quality of both honey types was determined through physicochemical analysis and contents of phenolic and flavonoid. Male Sprague-Dawley rats were induced to become obese using high fat diet (HFD) prior to introduction with/without honey or orlistat for four weeks. Significant reductions in excess weight gain and adiposity index were observed in rats fed with Gelam honey compared to HFD rats. Moreover, levels of plasma glucose, triglycerides, and cholesterol, plasma leptin and resistin, liver enzymes, renal function test, and relative organ weight in Gelam and Acacia honey treated groups were reduced significantly when compared to rats fed with HFD only. Similar results were also displayed in rats treated with orlistat, but with hepatotoxicity effects. In conclusion, consumption of honey can be used to control obesity by regulating lipid metabolism and appears to be more effective than orlistat. PMID:28246535

  15. Four-Week Consumption of Malaysian Honey Reduces Excess Weight Gain and Improves Obesity-Related Parameters in High Fat Diet Induced Obese Rats.

    PubMed

    Samat, Suhana; Kanyan Enchang, Francis; Nor Hussein, Fuzina; Wan Ismail, Wan Iryani

    2017-01-01

    Many studies revealed the potential of honey consumption in controlling obesity. However, no study has been conducted using Malaysian honey. In this study, we investigated the efficacy of two local Malaysian honey types: Gelam and Acacia honey in reducing excess weight gain and other parameters related to obesity. The quality of both honey types was determined through physicochemical analysis and contents of phenolic and flavonoid. Male Sprague-Dawley rats were induced to become obese using high fat diet (HFD) prior to introduction with/without honey or orlistat for four weeks. Significant reductions in excess weight gain and adiposity index were observed in rats fed with Gelam honey compared to HFD rats. Moreover, levels of plasma glucose, triglycerides, and cholesterol, plasma leptin and resistin, liver enzymes, renal function test, and relative organ weight in Gelam and Acacia honey treated groups were reduced significantly when compared to rats fed with HFD only. Similar results were also displayed in rats treated with orlistat, but with hepatotoxicity effects. In conclusion, consumption of honey can be used to control obesity by regulating lipid metabolism and appears to be more effective than orlistat.

  16. Genetic inhibition of phosphorylation of the translation initiation factor eIF2α does not block Aβ-dependent elevation of BACE1 and APP levels or reduce amyloid pathology in a mouse model of Alzheimer's disease.

    PubMed

    Sadleir, Katherine R; Eimer, William A; Kaufman, Randal J; Osten, Pavel; Vassar, Robert

    2014-01-01

    β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) initiates the production of β-amyloid (Aβ), the major constituent of amyloid plaques in Alzheimer's disease (AD). BACE1 is elevated ∼2-3 fold in AD brain and is concentrated in dystrophic neurites near plaques, suggesting BACE1 elevation is Aβ-dependent. Previously, we showed that phosphorylation of the translation initiation factor eIF2α de-represses translation of BACE1 mRNA following stress such as energy deprivation. We hypothesized that stress induced by Aβ might increase BACE1 levels by the same translational mechanism involving eIF2α phosphorylation. To test this hypothesis, we used three different genetic strategies to determine the effects of reducing eIF2α phosphorylation on Aβ-dependent BACE1 elevation in vitro and in vivo: 1) a two-vector adeno-associated virus (AAV) system to express constitutively active GADD34, the regulatory subunit of PP1c eIF2α phosphatase; 2) a non-phosphorylatable eIF2α S51A knockin mutation; 3) a BACE1-YFP transgene lacking the BACE1 mRNA 5' untranslated region (UTR) required for eIF2α translational regulation. The first two strategies were used in primary neurons and 5XFAD transgenic mice, while the third strategy was employed only in 5XFAD mice. Despite very effective reduction of eIF2α phosphorylation in both primary neurons and 5XFAD brains, or elimination of eIF2α-mediated regulation of BACE1-YFP mRNA translation in 5XFAD brains, Aβ-dependent BACE1 elevation was not decreased. Additionally, robust inhibition of eIF2α phosphorylation did not block Aβ-dependent APP elevation in primary neurons, nor did it reduce amyloid pathology in 5XFAD mice. We conclude that amyloid-associated BACE1 elevation is not caused by translational de-repression via eIF2α phosphorylation, but instead appears to involve a post-translational mechanism. These definitive genetic results exclude a role for eIF2α phosphorylation in Aβ-dependent BACE1 and APP elevation

  17. The cysteine protease inhibitor, E64d, reduces brain amyloid-β and improves memory deficits in Alzheimer’s disease animal models by inhibiting cathepsin B, but not BACE1, β-secretase activity

    PubMed Central

    Hook, Gregory; Hook, Vivian; Kindy, Mark

    2015-01-01

    The cysteine protease cathepsin B is a potential drug target for reducing brain amyloid-β peptides (Aβ) and improving memory in Alzheimer’s disease (AD), because reduction of cathepsin B in transgenic mice expressing human wild-type amyloid-β protein precursor (AβPP) results in significantly decreased brain Aβ. Cathepsin B cleaves the wild-type β-secretase site sequence in AβPP to produce Aβ and cathepsin B inhibitors administered to animal models expressing AβPP containing the wild-type β-secretase site sequence reduce brain Aβ in a manner consistent with β-secretase inhibition. But such inhibitors could act either by direct inhibition of cathepsin B β-secretase activity or by off-target inhibition of the other β-secretase, the aspartyl protease BACE1. To evaluate that issue, we orally administered a cysteine protease inhibitor, E64d, to normal guinea pigs or transgenic mice expressing human AβPP, both of which express the human wild-type β-secretase site sequence. In guinea pigs, oral E64d administration caused a dose-dependent reduction of up to 92% in brain, CSF and plasma of Aβ(40) and Aβ(42), a reduction of up to 50% in the C-terminal β-secretase fragment (CTFβ), and a 91% reduction in brain cathepsin B activity but increased brain BACE1 activity by 20%. In transgenic AD mice, oral E64d administration improved memory deficits and reduced brain Aβ(40) and Aβ(42), amyloid plaque, brain CTFβ, and brain cathepsin B activity but increased brain BACE1 activity. We conclude that E64d likely reduces brain Aβ by inhibiting cathepsin B and not BACE1 β-secretase activity and that E64d therefore may have potential for treating AD patients. PMID:21613740

  18. Divalent copper ion bound amyloid-β(40) and amyloid-β(42) alloforms are less preferred than divalent zinc ion bound amyloid-β(40) and amyloid-β(42) alloforms.

    PubMed

    Coskuner, Orkid

    2016-12-01

    Divalent copper and zinc ions bind to the amyloid-β(40) and amyloid-β(42) alloforms and affect their structural stability as well as their chemical and physical properties. Current literature debates the impact of copper ions on amyloid-β alloforms. Recently, we reported the structural and thermodynamic properties of apo amyloid-β and divalent zinc ion bound amyloid-β alloforms (see, Wise-Scira et al. in J Biol Inorg Chem 17:927-938, 2012 and Coskuner et al. in ACS Chem Neurosci 4: 310-320, 2013). In our search for understanding the impacts of transition metal ions on disordered amyloid-β, we also developed and reported new potential functions using quantum mechanics, which are required for high-quality molecular dynamics simulations of divalent copper ion bound amyloid-β alloforms (see, Wise and Coskuner in J Comput Chem 35:1278-1289, 2014). The structures and thermodynamic properties of the divalent copper ion bound amyloid-β(40) and amyloid-β(42) alloforms in an aqueous medium are studied. The secondary and tertiary structures of divalent copper ion bound amyloid-β(40) and amyloid-β(42) along with their thermodynamic properties including enthalpy, entropy, Gibbs free energy and potential of mean force surface are investigated. Results are compared to those for apo amyloid-β and divalent zinc ion bound amyloid-β alloforms. Results demonstrate that copper binding to Aβ alloforms is thermodynamically less preferred rather than zinc binding. Less compact structures of copper ion bound amyloid-β alloforms possess reduced stability in comparison to zinc ion bound amyloid-β alloforms. Cu(II) binding impacts the thermodynamic properties, secondary and tertiary structural properties of Aβ40 and Aβ42.

  19. Excessive Tanning

    PubMed Central

    Sansone, Lori A.

    2010-01-01

    Excessive tanning appears to be evident in about one quarter of regular sunbathers. Susceptible individuals are likely to be young Caucasians from Western societies. Despite ongoing education by the media to the public about the risks of excessive exposure to ultraviolet radiation and the availability of potent sunscreens, there seems to be a concurrent proliferation of tanning facilities. What might be potential psychological explanations for excessive or pathological tanning? Psychopathological explanations may exist on both Axes I and II and include substance use, obsessive-compulsive, body dysmorphic, and borderline personality disorders. While there is no known treatment for pathological sunbathing, we discuss several treatment interventions from the literature that have been successfully used for the general public. PMID:20622941

  20. Altered Theca and Cumulus Oocyte Complex Gene Expression, Follicular Arrest and Reduced Fertility in Cows with Dominant Follicle Follicular Fluid Androgen Excess

    PubMed Central

    Summers, Adam F.; Pohlmeier, William E.; Sargent, Kevin M.; Cole, Brizett D.; Vinton, Rebecca J.; Kurz, Scott G.; McFee, Renee M.; Cushman, Robert A.; Cupp, Andrea S.; Wood, Jennifer R.

    2014-01-01

    Aspiration of bovine follicles 12–36 hours after induced corpus luteum lysis serendipitously identified two populations of cows, one with High androstenedione (A4; >40 ng/ml; mean = 102) and another with Low A4 (<20 ng/ml; mean = 9) in follicular fluid. We hypothesized that the steroid excess in follicular fluid of dominant follicles in High A4 cows would result in reduced fertility through altered follicle development and oocyte maternal RNA abundance. To test this hypothesis, estrous cycles of cows were synchronized and ovariectomy was performed 36 hours later. HPLC MS/MS analysis of follicular fluid showed increased dehydroepiandrosterone (6-fold), A4 (158-fold) and testosterone (31-fold) in the dominant follicle of High A4 cows. However, estrone (3-fold) and estradiol (2-fold) concentrations were only slightly elevated, suggesting a possible inefficiency in androgen to estrogen conversion in High A4 cows. Theca cell mRNA expression of LHCGR, GATA6, CYP11A1, and CYP17A1 was greater in High A4 cows. Furthermore, abundance of ZAR1 was decreased 10-fold in cumulus oocyte complexes from High A4 cows, whereas NLRP5 abundance tended to be 19.8-fold greater (P = 0.07). There was a tendency for reduction in stage 4 follicles in ovarian cortex samples from High A4 cows suggesting that progression to antral stages were impaired. High A4 cows tended (P<0.07) to have a 17% reduction in calving rate compared with Low A4 cows suggesting reduced fertility in the High A4 population. These data suggest that the dominant follicle environment of High A4 cows including reduced estrogen conversion and androgen excess contributes to infertility in part through altered follicular and oocyte development. PMID:25330369

  1. Reducing environmental risk of excessively fertilized soils and improving cucumber growth by Caragana microphylla-straw compost application in long-term continuous cropping systems.

    PubMed

    Tian, Yongqiang; Wang, Qing; Zhang, Weihua; Gao, Lihong

    2016-02-15

    Continuous cropping is a common agricultural practice in the word. In China, farmers often apply excessive fertilizers to fields in an attempt to maintain yields in continuous cropping systems. However, this practice often results in high nutrient concentrations in soils, nutrient pollution in leaching water and more crop disease. Here, we investigated 8 different soils from continuously cropped cucumbers in Northern China that grouped into those with extremely high nutrient levels (EHNL) and those with lower nutrient levels (LNL). All soils were treated with Caragana microphylla-straw (CMS) compost addition, and then were used to measure soil physiochemical and microbial properties, leaching water quality, plant root growth and cucumber fruit yield. In general, the EHNL-soil showed higher nitrate, phosphorus and potassium concentrations in the leaching water compared to the LNL-soil. However, the CMS compost application increased soil nutrient and water holding capacities, total microbial biomass (bacteria and fungi), root length, plant biomass and fruit yields, but decreased nutrient concentrations in the leaching water from the EHNL-soil. In addition, the CMS compost decreased the number of Fusarium oxysporum f. sp. cucumerinum in soils with very high concentration of mineral nitrogen. Our results infer that CMS compost application was an effective method for reducing environmental risk of excessively fertilized soils.

  2. Functional amyloids in bacteria.

    PubMed

    Romero, Diego; Kolter, Roberto

    2014-06-01

    The term amyloidosis is used to refer to a family of pathologies altering the homeostasis of human organs. Despite having a name that alludes to starch content, the amyloid accumulations are made up of proteins that polymerize as long and rigid fibers. Amyloid proteins vary widely with respect to their amino acid sequences but they share similarities in their quaternary structure; the amyloid fibers are enriched in β-sheets arranged perpendicular to the axis of the fiber. This structural feature provides great robustness, remarkable stability, and insolubility. In addition, amyloid proteins specifically stain with certain dyes such as Congo red and thioflavin-T. The aggregation into amyloid fibers, however, it is not restricted to pathogenic processes, rather it seems to be widely distributed among proteins and polypeptides. Amyloid fibers are present in insects, fungi and bacteria, and they are important in maintaining the homeostasis of the organism. Such findings have motivated the use of the term "functional amyloid" to differentiate these amyloid proteins from their toxic siblings. This review focuses on systems that have evolved in bacteria that control the expression and assembly of amyloid proteins on cell surfaces, such that the robustness of amyloid proteins are used towards a beneficial end.

  3. Exercise reduces appetite and traffics excess nutrients away from energetically efficient pathways of lipid deposition during the early stages of weight regain

    PubMed Central

    Steig, Amy J.; Jackman, Matthew R.; Giles, Erin D.; Higgins, Janine A.; Johnson, Ginger C.; Mahan, Chad; Melanson, Edward L.; Wyatt, Holly R.; Eckel, Robert H.; Hill, James O.

    2011-01-01

    The impact of regular exercise on energy balance, fuel utilization, and nutrient availability, during weight regain was studied in obese rats, which had lost 17% of their weight by a calorie-restricted, low-fat diet. Weight reduced rats were maintained for 6 wk with and without regular treadmill exercise (1 h/day, 6 days/wk, 15 m/min). In vivo tracers and indirect calorimetry were then used in combination to examine nutrient metabolism during weight maintenance (in energy balance) and during the first day of relapse when allowed to eat ad libitum (relapse). An additional group of relapsing, sedentary rats were provided just enough calories to create the same positive energy imbalance as the relapsing, exercised rats. Exercise attenuated the energy imbalance by 50%, reducing appetite and increasing energy requirements. Expenditure increased beyond the energetic cost of the exercise bout, as exercised rats expended more energy to store the same nutrient excess in sedentary rats with the matched energy imbalance. Compared with sedentary rats with the same energy imbalance, exercised rats exhibited the trafficking of dietary fat toward oxidation and away from storage in adipose tissue, as well as a higher net retention of fuel via de novo lipogenesis in adipose tissue. These metabolic changes in relapse were preceded by an increase in the skeletal muscle expression of genes involved in lipid uptake, mobilization, and oxidation. Our observations reveal a favorable shift in fuel utilization with regular exercise that increases the energetic cost of storing excess nutrients during relapse and alterations in circulating nutrients that may affect appetite. The attenuation of the biological drive to regain weight, involving both central and peripheral aspects of energy homeostasis, may explain, in part, the utility of regular exercise in preventing weight regain after weight loss. PMID:21715696

  4. Exercise reduces appetite and traffics excess nutrients away from energetically efficient pathways of lipid deposition during the early stages of weight regain.

    PubMed

    Steig, Amy J; Jackman, Matthew R; Giles, Erin D; Higgins, Janine A; Johnson, Ginger C; Mahan, Chad; Melanson, Edward L; Wyatt, Holly R; Eckel, Robert H; Hill, James O; MacLean, Paul S

    2011-09-01

    The impact of regular exercise on energy balance, fuel utilization, and nutrient availability, during weight regain was studied in obese rats, which had lost 17% of their weight by a calorie-restricted, low-fat diet. Weight reduced rats were maintained for 6 wk with and without regular treadmill exercise (1 h/day, 6 days/wk, 15 m/min). In vivo tracers and indirect calorimetry were then used in combination to examine nutrient metabolism during weight maintenance (in energy balance) and during the first day of relapse when allowed to eat ad libitum (relapse). An additional group of relapsing, sedentary rats were provided just enough calories to create the same positive energy imbalance as the relapsing, exercised rats. Exercise attenuated the energy imbalance by 50%, reducing appetite and increasing energy requirements. Expenditure increased beyond the energetic cost of the exercise bout, as exercised rats expended more energy to store the same nutrient excess in sedentary rats with the matched energy imbalance. Compared with sedentary rats with the same energy imbalance, exercised rats exhibited the trafficking of dietary fat toward oxidation and away from storage in adipose tissue, as well as a higher net retention of fuel via de novo lipogenesis in adipose tissue. These metabolic changes in relapse were preceded by an increase in the skeletal muscle expression of genes involved in lipid uptake, mobilization, and oxidation. Our observations reveal a favorable shift in fuel utilization with regular exercise that increases the energetic cost of storing excess nutrients during relapse and alterations in circulating nutrients that may affect appetite. The attenuation of the biological drive to regain weight, involving both central and peripheral aspects of energy homeostasis, may explain, in part, the utility of regular exercise in preventing weight regain after weight loss.

  5. Curcumin could reduce the monomer of TTR with Tyr114Cys mutation via autophagy in cell model of familial amyloid polyneuropathy

    PubMed Central

    Li, Hui; Zhang, Yu; Cao, Li; Xiong, Ran; Zhang, Bei; Wu, Li; Zhao, Zongbo; Chen, Sheng-Di

    2014-01-01

    Transthyretin (TTR) familial amyloid polyneuropathy (FAP) is an autosomal dominant inherited neurodegenerative disorder caused by various mutations in the transthyretin gene. We aimed to identify the mechanisms underlying TTR FAP with Tyr114Cys (Y114C) mutation. Our study showed that TTR Y114C mutation led to an increase in monomeric TTR and impaired autophagy. Treatment with curcumin resulted in a significant decrease of monomeric TTR by recovering autophagy. Our research suggests that impairment of autophagy might be involved in the pathogenesis of TTR FAP with Y114C mutation, and curcumin might be a potential therapeutic approach for TTR FAP. PMID:25382970

  6. Regional cerebral blood flow estimated by early PiB uptake is reduced in mild cognitive impairment and associated with age in an amyloid-dependent manner.

    PubMed

    Gietl, Anton F; Warnock, Geoffrey; Riese, Florian; Kälin, Andrea M; Saake, Antje; Gruber, Esmeralda; Leh, Sandra E; Unschuld, Paul G; Kuhn, Felix P; Burger, Cyrill; Mu, Linjing; Seifert, Burkhardt; Nitsch, Roger M; Schibli, Roger; Ametamey, Simon M; Buck, Alfred; Hock, Christoph

    2015-04-01

    Early uptake of [(11)C]-Pittsburgh Compound B (ePiB, 0-6 minutes) estimates cerebral blood flow. We studied ePiB in 13 PiB-negative and 10 PiB-positive subjects with mild cognitive impairment (MCI, n = 23) and 11 PiB-positive and 74 PiB-negative cognitively healthy elderly control subjects (HCS, n = 85) in 6 bilateral volumes of interest: posterior cingulate cortex (PCC), hippocampus (hipp), temporoparietal region, superior parietal gyrus, parahippocampal gyrus (parahipp), and inferior frontal gyrus (IFG) for the associations with cognitive status, age, amyloid deposition, and apolipoprotein E ε4-allele. We observed no difference in ePiB between PiB-positive and -negative subjects and carriers and noncarriers. EPiB decreased with age in PiB-positive subjects in bilateral superior parietal gyrus, bilateral temporoparietal region, right IFG, right PCC, and left parahippocampal gyrus but not in PiB-negative subjects. MCI had lower ePiB than HCS (left PCC, left IFG, and left and right hipp). Lowest ePiB values were found in MCI of 70 years and older, who also displayed high cortical PiB binding. This suggests that lowered regional cerebral blood flow indicated by ePiB is associated with age in the presence but not in the absence of amyloid pathology.

  7. An amyloid lung

    PubMed Central

    Zundel, W. E.; Prior, A. P.

    1971-01-01

    A 55-year-old housewife died from an illness characterized by progressive respiratory incapacity. Changes were confined to the lungs and consisted of a diffuse infiltration by amyloid. No adequate cause was found for this amyloid, and we suggest that this is a case of primary alveolar septal amyloidosis. Images PMID:5559913

  8. MicroRNA-339-5p down-regulates protein expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects.

    PubMed

    Long, Justin M; Ray, Balmiki; Lahiri, Debomoy K

    2014-02-21

    Alzheimer disease (AD) results, in part, from the excess accumulation of the amyloid-β (Aβ) peptide as neuritic plaques in the brain. The short Aβ peptide is derived from the large transmembrane Aβ precursor protein (APP). The rate-limiting step in the production of Aβ from APP is mediated by the β-site APP-cleaving enzyme 1 (BACE1). Dysregulation of BACE1 levels leading to excess Aβ deposition is implicated in sporadic AD. Thus, elucidating the full complement of regulatory pathways that control BACE1 expression is key to identifying novel drug targets central to the Aβ-generating process. MicroRNAs (miRNAs) are expected to participate in this molecular network. Here, we identified a known miRNA, miR-339-5p, as a key contributor to this regulatory network. Two distinct miR-339-5p target sites were predicted in the BACE1 3'-UTR by in silico analyses. Co-transfection of miR-339-5p with a BACE1 3'-UTR reporter construct resulted in significant reduction in reporter expression. Mutation of both target sites eliminated this effect. Delivery of the miR-339-5p mimic also significantly inhibited expression of BACE1 protein in human glioblastoma cells and human primary brain cultures. Delivery of target protectors designed against the miR-339-5p BACE1 3'-UTR target sites in primary human brain cultures significantly elevated BACE1 expression. Finally, miR-339-5p levels were found to be significantly reduced in brain specimens isolated from AD patients as compared with age-matched controls. Therefore, miR-339-5p regulates BACE1 expression in human brain cells and is most likely dysregulated in at least a subset of AD patients making this miRNA a novel drug target.

  9. Excess rumen product anions in cattle. I. Blood clearance rates and reduced liver function from sublethal doses of volatile fatty acids, lactate and succinate.

    PubMed Central

    Bide, R W

    1983-01-01

    Blood clearance rates of volatile fatty acids, lactate and succinate were estimated in cattle following a single rapid intravenous injection of a Na-anion solution. Bromosulfophthalein was administered immediately before the anion to monitor the effects upon liver function, blood circulation, and dose equilibrium. Acetate, propionate, and valerate at doses up to 5 mmole/kg were cleared quickly from the blood by a first-order process without effects either upon the animal or bromosulfophthalein clearance. Injection of acetic acid solutions produced no effects. Butyrate was toxic at doses above 1 mmole/kg and progressively affected both the rate and progress of bromosulfophthalein clearance as the dose increased. Lactate and succinate were toxic and lethal at doses around 0.25 mmole/kg, and caused both reduced rates and altered progress of bromosulfophthalein clearance. The toxic reactions resulted in total collapse from loss of muscle tone. The butyrate and lactate effects were accentuated when the anion solutions were injected at low pH where a large portion of the anion would be unionized. Levels of butyrate, lactate and succinate in the rumens of feedlot cattle were high enough to provide toxic doses of these anions. The results are discussed in terms of the effects of excess rumen production of these anions upon the liver function and health of feedlot cattle. PMID:6883189

  10. Excess of Methyl Donor in the Perinatal Period Reduces Postnatal Leptin Secretion in Rat and Interacts with the Effect of Protein Content in Diet

    PubMed Central

    Giudicelli, Fanny; Brabant, Anne-Laure; Grit, Isabelle; Parnet, Patricia; Amarger, Valérie

    2013-01-01

    Methionine, folic acid, betaine and choline interact in the one-carbon metabolism which provides methyl groups for methylation reactions. An optimal intake of these nutrients during pregnancy is required for successful completion of fetal development and evidence is growing that they could be involved in metabolic long-term programming. However, the biological pathways involved in the action of these nutrients are still poorly known. This study investigated the interaction between methyl donors and protein content in maternal diet during the preconceptual, pregnancy and lactation periods and the consequences on the rat offspring in the short and long term. Methyl donor supplementation reduced leptin secretion in offspring, whereas insulin levels were mostly affected by protein restriction. The joint effect of protein restriction and methyl donor excess strongly impaired postnatal growth in both gender and long term weight gain in male offspring only, without affecting food intake. In addition, rats born from protein restricted and methyl donor supplemented dams gained less weight when fed a hypercaloric diet. Methylation of the leptin gene promoter in adipose tissue was increased in methyl donor supplemented groups but not affected by protein restriction only. These results suggest that maternal methyl donor supplementation may influence energy homeostasis in a gender-dependent manner, without affecting food intake. Moreover, we showed that macronutrients and micronutrients in maternal diet interact to influence the programming of the offspring. PMID:23840890

  11. Structures for amyloid fibrils.

    PubMed

    Makin, O Sumner; Serpell, Louise C

    2005-12-01

    Alzheimer's disease and Creutzfeldt-Jakob disease are the best-known examples of a group of diseases known as the amyloidoses. They are characterized by the extracellular deposition of toxic, insoluble amyloid fibrils. Knowledge of the structure of these fibrils is essential for understanding the process of pathology of the amyloidoses and for the rational design of drugs to inhibit or reverse amyloid formation. Structural models have been built using information from a wide variety of techniques, including X-ray diffraction, electron microscopy, solid state NMR and EPR. Recent advances have been made in understanding the architecture of the amyloid fibril. Here, we describe and compare postulated structural models for the mature amyloid fibril and discuss how the ordered structure of amyloid contributes to its stability.

  12. Selective intracellular release of copper and zinc ions from bis(thiosemicarbazonato) complexes reduces levels of Alzheimer disease amyloid-beta peptide.

    PubMed

    Donnelly, Paul S; Caragounis, Aphrodite; Du, Tai; Laughton, Katrina M; Volitakis, Irene; Cherny, Robert A; Sharples, Robyn A; Hill, Andrew F; Li, Qiao-Xin; Masters, Colin L; Barnham, Kevin J; White, Anthony R

    2008-02-22

    Copper and zinc play important roles in Alzheimer disease pathology with recent reports describing potential therapeutics based on modulation of metal bioavailability. We examined the ability of a range of metal bis(thiosemicarbazonato) complexes (MII(btsc), where M=CuII or ZnII) to increase intracellular metal levels in Chinese hamster ovary cells overexpressing amyloid precursor protein (APP-CHO) and the subsequent effect on extracellular levels of amyloid-beta peptide (Abeta). The CuII(btsc) complexes were engineered to be either stable to both a change in oxidation state and dissociation of metal or susceptible to intracellular reduction and dissociation of metal. Treatment of APP-CHO cells with stable complexes resulted in elevated levels of intracellular copper with no effect on the detected levels of Abeta. Treatment with complexes susceptible to intracellular reduction increased intracellular copper levels but also resulted in a dose-dependent reduction in the levels of monomeric Abeta. Treatment with less stable ZnII(btsc) complexes increased intracellular zinc levels with a subsequent dose-dependent depletion of monomeric Abeta levels. The increased levels of intracellular bioavailable copper and zinc initiated a signaling cascade involving activation of phosphoinositol 3-kinase and c-Jun N-terminal kinase. Inhibition of these enzymes prevented Abeta depletion induced by the MII(btsc) complexes. Inhibition of metalloproteases also partially restored Abeta levels, implicating metal-driven metalloprotease activation in the extracellular monomeric Abeta depletion. However, a role for alternative metal-induced Abeta metabolism has not been ruled out. These studies demonstrate that MII(btsc) complexes have potential for Alzheimer disease therapy.

  13. Fibril Fragmentation Enhances Amyloid Cytotoxicity*♦

    PubMed Central

    Xue, Wei-Feng; Hellewell, Andrew L.; Gosal, Walraj S.; Homans, Steve W.; Hewitt, Eric W.; Radford, Sheena E.

    2009-01-01

    Fibrils associated with amyloid disease are molecular assemblies of key biological importance, yet how cells respond to the presence of amyloid remains unclear. Cellular responses may not only depend on the chemical composition or molecular properties of the amyloid fibrils, but their physical attributes such as length, width, or surface area may also play important roles. Here, we report a systematic investigation of the effect of fragmentation on the structural and biological properties of amyloid fibrils. In addition to the expected relationship between fragmentation and the ability to seed, we show a striking finding that fibril length correlates with the ability to disrupt membranes and to reduce cell viability. Thus, despite otherwise unchanged molecular architecture, shorter fibrillar samples show enhanced cytotoxic potential than their longer counterparts. The results highlight the importance of fibril length in amyloid disease, with fragmentation not only providing a mechanism by which fibril load can be rapidly increased but also creating fibrillar species of different dimensions that can endow new or enhanced biological properties such as amyloid cytotoxicity. PMID:19808677

  14. Effects of lovastatin and pravastatin on amyloid processing and inflammatory response in TgCRND8 brain.

    PubMed

    Chauhan, Neelima B; Siegel, George J; Feinstein, Douglas L

    2004-10-01

    Previous studies suggest that treatment with statins reduce beta amyloid (Abeta) deposition in brains of mouse models of Alzheimer's disease (AD) and may reduce the prevalence of AD in humans. Since lipophilicity influences the biological efficacy of statins, we compared the effects of lovastatin, a lipophilic statin, to effects of the hydrophilic pravastatin on amyloid processing and inflammatory responses in brain. Three-month old TgCRND8 mice expressing mutant human amyloid precursor protein (mHuAPP) were treated daily with various doses of either statin. After 1 month, levels of cerebral soluble and fibrillar Abeta peptides, soluble sAPPalpha, and inflammatory cytokines were measured. Both statins caused dose-dependent reductions in total Abeta peptides with parallel increases in total sAPPalpha. At all doses, slightly greater effects were observed with lovastatin than with pravastatin. In contrast, only lovastatin significantly increased levels of IL-1beta and of TNFalpha in a dose-dependent manner. Lovastatin, but not pravastatin, decreased succinic dehydrogenase and increased lactate dehydrogenase activities in skeletal muscle and increased TUNEL staining in liver. Our data demonstrate that both statins shift the balance of APP processing from excessive beta-toward the normal alpha-cleavage while reducing the total amyloid burden in TgCRND8 brain and that lovastatin, but not pravastatin, potentiates cerebral inflammation and is associated with liver and muscle histotoxicity in these animals. These data show that pravastatin can reduce amyloid burden without potentiating inflammatory responses in brain and, therefore, may have a wider dose-range of safety than have lipophilic statins in the treatment or prevention of AD.

  15. Nanophotonics of protein amyloids

    NASA Astrophysics Data System (ADS)

    Bhattacharya, Mily; Mukhopadhyay, Samrat

    2014-04-01

    Technological breakthroughs in the super-resolution optical imaging techniques have enriched our current understanding of a range of biological systems and biomolecular processes at the nanoscopic spatial resolution. Protein amyloids are an important class of ordered protein assemblies consisting of misfolded proteins that are implicated in a wide range of devastating human diseases. In order to decipher the structural basis of the supramolecular protein assembly in amyloids and their detrimental interactions with the cell membranes, it is important to employ high-resolution optical imaging techniques. Additionally, amyloids could serve as novel biological nanomaterials for a variety of potential applications. In this review, we summarize a few examples of the utility of near-field scanning optical imaging methodologies to obtain a wealth of structural information into the nanoscale amyloid assembly. Although the near-field technologies were developed several decades ago, it is only recently that these methodologies are being applied and adapted for amyloid research to yield novel information pertaining to the exciting nanoscopic world of protein aggregates. We believe that the account on the nanophotonics of amyloids described in this review will be useful for the future studies on the biophysics of amyloids.

  16. Amyloid Fibrils from Hemoglobin

    PubMed Central

    Jayawardena, Nadishka; Kaur, Manmeet; Nair, Smitha; Malmstrom, Jenny; Goldstone, David; Negron, Leonardo; Gerrard, Juliet A.; Domigan, Laura J.

    2017-01-01

    Amyloid fibrils are a class of insoluble protein nanofibers that are formed via the self-assembly of a wide range of peptides and proteins. They are increasingly exploited for a broad range of applications in bionanotechnology, such as biosensing and drug delivery, as nanowires, hydrogels, and thin films. Amyloid fibrils have been prepared from many proteins, but there has been no definitive characterization of amyloid fibrils from hemoglobin to date. Here, nanofiber formation was carried out under denaturing conditions using solutions of apo-hemoglobin extracted from bovine waste blood. A characteristic amyloid fibril morphology was confirmed by transmission electron microscopy (TEM) and atomic force microscopy (AFM), with mean fibril dimensions of approximately 5 nm diameter and up to several microns in length. The thioflavin T assay confirmed the presence of β-sheet structures in apo-hemoglobin fibrils, and X-ray fiber diffraction showed the characteristic amyloid cross-β quaternary structure. Apo-hemoglobin nanofibers demonstrated high stability over a range of temperatures (−20 to 80 °C) and pHs (2–10), and were stable in the presence of organic solvents and trypsin, confirming their potential as nanomaterials with versatile applications. This study conclusively demonstrates the formation of amyloid fibrils from hemoglobin for the first time, and also introduces a cost-effective method for amyloid fibril manufacture using meat industry by-products. PMID:28398221

  17. Altered theca and cumulus oocyte complex gene expression, follicular arrest and reduced fertility in cows with dominant follicle follicular fluid androgen excess

    USDA-ARS?s Scientific Manuscript database

    To date, animal models with naturally occurring androgen excess have not been identified. Serendipitously, we discovered two subpopulations of cows with dramatically different follicular fluid androgen concentrations in dominant follicles within our research herd. In the cow, androstenedione is the...

  18. Peptide Detection of Fungal Functional Amyloids in Infected Tissue

    PubMed Central

    Garcia-Sherman, Melissa C.; Lysak, Nataliya; Filonenko, Alexandra; Richards, Hazel; Sobonya, Richard E.; Klotz, Stephen A.; Lipke, Peter N.

    2014-01-01

    Many fungal cell adhesion proteins form functional amyloid patches on the surface of adhering cells. The Candida albicans Agglutinin-like sequence (Als) adhesins are exemplars for this phenomenon, and have amyloid forming sequences that are conserved between family members. The Als5p amyloid sequence mediates amyloid fibril formation and is critical for cell adhesion and biofilm formation, and is also present in the related adhesins Als1p and Als3p. We have developed a fluorescent peptide probe containing the conserved Als amyloid-forming sequence. This peptide bound specifically to yeast expressing Als5p, but not to cells lacking the adhesin. The probe bound to both yeast and hyphal forms of C. albicans. Δals1/Δals3 single and double deletion strains exhibited reduced fluorescence, indicating that probe binding required expression of these proteins. Additionally, the Als peptide specifically stained fungal cells in abscesses in autopsy sections. Counterstaining with calcofluor white showed colocalization with the amyloid peptide. In addition, fungi in autopsy sections derived from the gastrointestinal tract showed colocalization of the amyloid-specific dye thioflavin T and the fluorescent peptide. Collectively, our data demonstrate that we can exploit amyloid sequence specificity for detection of functional amyloids in situ. PMID:24465872

  19. Contrasting effects of nanoparticle-protein attraction on amyloid aggregation.

    PubMed

    Radic, Slaven; Davis, Thomas P; Ke, Pu Chun; Ding, Feng

    2015-01-01

    Nanoparticles (NPs) have been experimentally found to either promote or inhibit amyloid aggregation of proteins, but the molecular mechanisms for such complex behaviors remain unknown. Using coarse-grained molecular dynamics simulations, we investigated the effects of varying the strength of nonspecific NP-protein attraction on amyloid aggregation of a model protein, the amyloid-beta peptide implicated in Alzheimer's disease. Specifically, with increasing NP-peptide attraction, amyloid aggregation on the NP surface was initially promoted due to increased local protein concentration on the surface and destabilization of the folded state. However, further increase of NP-peptide attraction decreased the stability of amyloid fibrils and reduced their lateral diffusion on the NP surface necessary for peptide conformational changes and self-association, thus prohibiting amyloid aggregation. Moreover, we found that the relative concentration between protein and NPs also played an important role in amyloid aggregation. With a high NP/protein ratio, NPs that intrinsically promote protein aggregation may display an inhibitive effect by depleting the proteins in solution while having a low concentration of the proteins on each NP's surface. Our coarse-grained molecular dynamics simulation study offers a molecular mechanism for delineating the contrasting and seemingly conflicting effects of NP-protein attraction on amyloid aggregation and highlights the potential of tailoring anti-aggregation nanomedicine against amyloid diseases.

  20. Peptide Amyloid Surface Display

    PubMed Central

    2015-01-01

    Homomeric self-assembly of peptides into amyloid fibers is a feature of many diseases. A central role has been suggested for the lateral fiber surface affecting gains of toxic function. To investigate this, a protein scaffold that presents a discrete, parallel β-sheet surface for amyloid subdomains up to eight residues in length has been designed. Scaffolds that present the fiber surface of islet amyloid polypeptide (IAPP) were prepared. The designs show sequence-specific surface effects apparent in that they gain the capacity to attenuate rates of IAPP self-assembly in solution and affect IAPP-induced toxicity in insulin-secreting cells. PMID:25541905

  1. Sulindac Sulfide Induces the Formation of Large Oligomeric Aggregates of the Alzheimer's Disease Amyloid-β Peptide Which Exhibit Reduced Neurotoxicity.

    PubMed

    Prade, Elke; Barucker, Christian; Sarkar, Riddhiman; Althoff-Ospelt, Gerhard; Lopez del Amo, Juan Miguel; Hossain, Shireen; Zhong, Yifei; Multhaup, Gerd; Reif, Bernd

    2016-03-29

    Alzheimer's disease is characterized by deposition of the amyloid β-peptide (Aβ) in brain tissue of affected individuals. In recent years, many potential lead structures have been suggested that can potentially be used for diagnosis and therapy. However, the mode of action of these compounds is so far not understood. Among these small molecules, the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide received a lot of attention. In this manuscript, we characterize the interaction between the monomeric Aβ peptide and the NSAID sulindac sulfide. We find that sulindac sulfide efficiently depletes the pool of toxic oligomers by enhancing the rate of fibril formation. In vitro, sulindac sulfide forms colloidal particles which catalyze the formation of fibrils. Aggregation is immediate, presumably by perturbing the supersaturated Aβ solution. We find that sulindac sulfide induced Aβ aggregates are structurally homogeneous. The C-terminal part of the peptide adopts a β-sheet structure, whereas the N-terminus is disordered. The salt bridge between D23 and K28 is present, similar as in wild type fibril structures. (13)C-(19)F transferred echo double resonance experiments suggest that sulindac sulfide colocalizes with the Aβ peptide in the aggregate.

  2. Structure-Based Design of Functional Amyloid Materials

    SciTech Connect

    Li, Dan; Jones, Eric M.; Sawaya, Michael R.; Furukawa, Hiroyasu; Luo, Fang; Ivanova, Magdalena; Sievers, Stuart A.; Wang, Wenyuan; Yaghi, Omar M.; Liu, Cong; Eisenberg, David S.

    2014-12-04

    We report that amyloid fibers, once exclusively associated with disease, are acquiring utility as a class of biological nanomaterials. We introduce a method that utilizes the atomic structures of amyloid peptides, to design materials with versatile applications. As a model application, we designed amyloid fibers capable of capturing carbon dioxide from flue gas, to address the global problem of excess anthropogenic carbon dioxide. By measuring dynamic separation of carbon dioxide from nitrogen, we show that fibers with designed amino acid sequences double the carbon dioxide binding capacity of the previously reported fiber formed by VQIVYK from Tau protein. In a second application, we designed fibers that facilitate retroviral gene transfer. Finally, by measuring lentiviral transduction, we show that designed fibers exceed the efficiency of polybrene, a commonly used enhancer of transduction. The same procedures can be adapted to the design of countless other amyloid materials with a variety of properties and uses.

  3. Structure-Based Design of Functional Amyloid Materials

    DOE PAGES

    Li, Dan; Jones, Eric M.; Sawaya, Michael R.; ...

    2014-12-04

    We report that amyloid fibers, once exclusively associated with disease, are acquiring utility as a class of biological nanomaterials. We introduce a method that utilizes the atomic structures of amyloid peptides, to design materials with versatile applications. As a model application, we designed amyloid fibers capable of capturing carbon dioxide from flue gas, to address the global problem of excess anthropogenic carbon dioxide. By measuring dynamic separation of carbon dioxide from nitrogen, we show that fibers with designed amino acid sequences double the carbon dioxide binding capacity of the previously reported fiber formed by VQIVYK from Tau protein. In amore » second application, we designed fibers that facilitate retroviral gene transfer. Finally, by measuring lentiviral transduction, we show that designed fibers exceed the efficiency of polybrene, a commonly used enhancer of transduction. The same procedures can be adapted to the design of countless other amyloid materials with a variety of properties and uses.« less

  4. Nonaccommodative convergence excess.

    PubMed

    von Noorden, G K; Avilla, C W

    1986-01-15

    Nonaccommodative convergence excess is a condition in which a patient has orthotropia or a small-angle esophoria or esotropia at distance and a large-angle esotropia at near, not significantly reduced by the addition of spherical plus lenses. The AC/A ratio, determined with the gradient method, is normal or subnormal. Tonic convergence is suspected of causing the convergence excess in these patients. Nonaccommodative convergence excess must be distinguished from esotropia with a high AC/A ratio and from hypoaccommodative esotropia. In 24 patients treated with recession of both medial recti muscles with and without posterior fixation or by posterior fixation alone, the mean correction of esotropia was 7.4 prism diopters at distance and 17 prism diopters at near.

  5. When amyloids become prions.

    PubMed

    Sabate, Raimon

    2014-01-01

    The conformational diseases, linked to protein aggregation into amyloid conformations, range from non-infectious neurodegenerative disorders, such as Alzheimer disease (AD), to highly infectious ones, such as human transmissible spongiform encephalopathies (TSEs). They are commonly known as prion diseases. However, since all amyloids could be considered prions (from those involved in cell-to-cell transmission to those responsible for real neuronal invasion), it is necessary to find an underlying cause of the different capacity to infect that each of the proteins prone to form amyloids has. As proposed here, both the intrinsic cytotoxicity and the number of nuclei of aggregation per cell could be key factors in this transmission capacity of each amyloid.

  6. When amyloids become prions

    PubMed Central

    Sabate, Raimon

    2014-01-01

    The conformational diseases, linked to protein aggregation into amyloid conformations, range from non-infectious neurodegenerative disorders, such as Alzheimer's disease (AD), to highly infectious ones, such as human transmissible spongiform encephalopathies (TSEs). They are commonly known as prion diseases. However, since all amyloids could be considered prions (from those involved in cell-to-cell transmission to those responsible for real neuronal invasion), it is necessary to find an underlying cause of the different capacity to infect that each of the proteins prone to form amyloids has. As proposed here, both the intrinsic cytotoxicity and the number of nuclei of aggregation per cell could be key factors in this transmission capacity of each amyloid. PMID:24831240

  7. Serum amyloid P inhibits granulocyte adhesion

    PubMed Central

    2013-01-01

    Background The extravasation of granulocytes (such as neutrophils) at a site of inflammation is a key aspect of the innate immune system. Signals from the site of inflammation upregulate granulocyte adhesion to the endothelium to initiate extravasation, and also enhance granulocyte adhesion to extracellular matrix proteins to facilitate granulocyte movement through the inflamed tissue. During the resolution of inflammation, other signals inhibit granulocyte adhesion to slow and ultimately stop granulocyte influx into the tissue. In a variety of inflammatory diseases such as acute respiratory distress syndrome, an excess infiltration of granulocytes into a tissue causes undesired collateral damage, and being able to reduce granulocyte adhesion and influx could reduce this damage. Results We found that serum amyloid P (SAP), a constitutive protein component of the blood, inhibits granulocyte spreading and granulocyte adhesion to extracellular matrix components. This indicates that in addition to granulocyte adhesion inhibitors that are secreted during the resolution of inflammation, a granulocyte adhesion inhibitor is present at all times in the blood. Although SAP affects adhesion, it does not affect the granulocyte adhesion molecules CD11b, CD62L, CD18, or CD44. SAP also has no effect on the production of hydrogen peroxide by resting or stimulated granulocytes, or N-formyl-methionine-leucine-phenylalanine (fMLP)-induced granulocyte migration. In mice treated with intratracheal bleomycin to induce granulocyte accumulation in the lungs, SAP injections reduced the number of granulocytes in the lungs. Conclusions We found that SAP, a constitutive component of blood, is a granulocyte adhesion inhibitor. We hypothesize that SAP allows granulocytes to sense whether they are in the blood or in a tissue. PMID:23324174

  8. Nucleofection of rat pheochromocytoma PC-12 cells with human mutated beta-amyloid precursor protein gene (APP-sw) leads to reduced viability, autophagy-like process, and increased expression and secretion of beta amyloid.

    PubMed

    Pająk, Beata; Kania, Elżbieta; Orzechowski, Arkadiusz

    2015-01-01

    Pheochromocytoma PC-12 cells are immune to physiological stimuli directed to evoke programmed cell death. Besides, metabolic inhibitors are incapable of sensitizing PC-12 cells to extrinsic or intrinsic apoptosis unless they are used in toxic concentrations. Surprisingly, these cells become receptive to cell deletion after human APP-sw gene expression. We observed reduced cell viability in GFP vector + APP-sw-nucleofected cells (drop by 36%) but not in GFP vector - or GFP vector + APP-wt-nucleofected cells. Lower viability was accompanied by higher expression of Aβ 1-16 and elevated secretion of Aβ 1-40 (in average 53.58 pg/mL). At the ultrastructural level autophagy-like process was demonstrated to occur in APP-sw-nucleofected cells with numerous autophagosomes and multivesicular bodies but without autolysosomes. Human APP-sw gene is harmful to PC-12 cells and cells are additionally driven to incomplete autophagy-like process. When stimulated by TRAIL or nystatin, CLU protein expression accompanies early phase of autophagy.

  9. Nucleofection of Rat Pheochromocytoma PC-12 Cells with Human Mutated Beta-Amyloid Precursor Protein Gene (APP-sw) Leads to Reduced Viability, Autophagy-Like Process, and Increased Expression and Secretion of Beta Amyloid

    PubMed Central

    Pająk, Beata; Kania, Elżbieta

    2015-01-01

    Pheochromocytoma PC-12 cells are immune to physiological stimuli directed to evoke programmed cell death. Besides, metabolic inhibitors are incapable of sensitizing PC-12 cells to extrinsic or intrinsic apoptosis unless they are used in toxic concentrations. Surprisingly, these cells become receptive to cell deletion after human APP-sw gene expression. We observed reduced cell viability in GFP vector + APP-sw-nucleofected cells (drop by 36%) but not in GFP vector − or GFP vector + APP-wt-nucleofected cells. Lower viability was accompanied by higher expression of Aβ 1-16 and elevated secretion of Aβ 1-40 (in average 53.58 pg/mL). At the ultrastructural level autophagy-like process was demonstrated to occur in APP-sw-nucleofected cells with numerous autophagosomes and multivesicular bodies but without autolysosomes. Human APP-sw gene is harmful to PC-12 cells and cells are additionally driven to incomplete autophagy-like process. When stimulated by TRAIL or nystatin, CLU protein expression accompanies early phase of autophagy. PMID:25821818

  10. Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer’s disease and apoE TR mouse cortex

    PubMed Central

    Arold, Stephen; Sullivan, Patrick; Bilousova, Tina; Teng, Edmond; Miller, Carol A.; Poon, Wayne W.; Vinters, Harry V.; Cornwell, Lindsey B.; Saing, Tommy; Cole, Gregory M.

    2012-01-01

    The apolipoprotein E4 allele (APOE4) contributes to Alzheimer’s disease (AD) risk and APOE2 is protective, but the relevant cellular mechanisms are unknown. We have used flow cytometry analysis to measure apolipoprotein E (apoE) and amyloid beta peptide (Aβ) levels in large populations of synaptic terminals from AD and aged cognitively normal controls, and demonstrate that modest but significant increases in soluble apoE levels accompany elevated Aβ in AD cortical synapses and in an APP/PS1 rat model of AD. Dual labeling experiments document co-localization of apoE and Aβ in individual synapses with concentration of Aβ in a small population of apoE-positive synapses in both AD and controls. Consistent with a clearance role, the apoE level was higher in Aβ-positive synapses in control cases. In aged targeted replacement mice expressing human apoE, apoE2/4 synaptic terminals demonstrated the highest level of apoE and the lowest level of Aβ compared to apoE3/3 and apoE4/4 lines. In apoE2/4 terminals, the pattern of immunolabeling for apoE and Aβ closely resembled the pattern in human control cases, and elevated apoE was accompanied by elevated free cholesterol in apoE2/4 synaptic terminals. These results are consistent with a role for APOE in Aβ clearance in AD synapses, and suggest that optimal lipidation of apoE2 compared to E3 and E4 makes an important contribution to Aβ clearance and synaptic function. PMID:22020632

  11. A Controlled Intervention to Promote a Healthy Body Image, Reduce Eating Disorder Risk and Prevent Excessive Exercise among Trainee Health Education and Physical Education Teachers

    ERIC Educational Resources Information Center

    Yager, Zali; O'Dea, Jennifer

    2010-01-01

    This study examined the impact of two interventions on body image, eating disorder risk and excessive exercise among 170 (65% female) trainee health education and physical education (HE & PE) teachers of mean (standard deviation) age 21.6 (2.3) who were considered an "at-risk" population for poor body image and eating disorders. In the first year…

  12. A Controlled Intervention to Promote a Healthy Body Image, Reduce Eating Disorder Risk and Prevent Excessive Exercise among Trainee Health Education and Physical Education Teachers

    ERIC Educational Resources Information Center

    Yager, Zali; O'Dea, Jennifer

    2010-01-01

    This study examined the impact of two interventions on body image, eating disorder risk and excessive exercise among 170 (65% female) trainee health education and physical education (HE & PE) teachers of mean (standard deviation) age 21.6 (2.3) who were considered an "at-risk" population for poor body image and eating disorders. In the first year…

  13. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics.

    PubMed

    Karran, Eric; Mercken, Marc; De Strooper, Bart

    2011-08-19

    The amyloid cascade hypothesis, which posits that the deposition of the amyloid-β peptide in the brain is a central event in Alzheimer's disease pathology, has dominated research for the past twenty years. Several therapeutics that were purported to reduce amyloid-β production or aggregation have failed in Phase III clinical testing, and many others are in various stages of development. Therefore, it is timely to review the science underpinning the amyloid cascade hypothesis, consider what type of clinical trials will constitute a valid test of this hypothesis and explore whether amyloid-β-directed therapeutics will provide the medicines that are urgently needed by society for treating this devastating disease.

  14. [Cerebral amyloid angiopathy].

    PubMed

    Sakai, Kenji; Yamada, Masahito

    2014-07-01

    Cerebral amyloid angiopathy (CAA) is a disorder characterized by the accumulation of amyloid proteins in the small and medium-sized blood vessels of the leptomeninges and central nervous system. Amyloid β protein (Aβ), immunoglobulin light chains, cystatin C, prion protein (PrP), ABri/ADan, transthyretin, and gelsoline, are all associated with CAA. While most CAA patients demonstrated sporadic Aβ-type amyloid deposition, a small number of patients present with familial forms, e.g. Dutch-type hereditary cerebral hemorrhage with amyloidosis (HCHWA-D), Icelandic-type HCHWA (HCHWA-I), familial British dementia (FBD), familial Danish dementia (FDD), and PrP-CAA. Deposited amyloid proteins damage smooth muscle cells in blood vessel walls leading to pathological appearances calling 'double-barreled' changes, fibrinoid necrosis, and microaneurysms. These structural abnormalities result in microinfarcts and hemorrhages in the central nervous system. Recurrent hemorrhage is a common clinical manifestation in patients with CAA; however, small multiple infarctions, progressive dementia, transient neurological symptoms, and CAA-related inflammation can also occur. The pathomechanisms of CAA remain unknown. Although improvements in imaging techniques have allowed us to identify patients with CAA more readily, pathological examination is still essential for a definite diagnosis. There have been no curative treatments for CAA so far.

  15. Coconut (Cocos nucifera) Ethanolic Leaf Extract Reduces Amyloid-β (1-42) Aggregation and Paralysis Prevalence in Transgenic Caenorhabditis elegans Independently of Free Radical Scavenging and Acetylcholinesterase Inhibition

    PubMed Central

    Manalo, Rafael Vincent; Silvestre, Maries Ann; Barbosa, Aza Lea Anne; Medina, Paul Mark

    2017-01-01

    Virgin coconut oil (VCO) has been the subject of several studies which have aimed to alleviate Alzheimer’s disease (AD) pathology, focusing on in vitro antioxidant and acetylcholinesterase (AChE) inhibitory activities. Here, we studied an underutilized and lesser-valued part of the coconut tree, specifically the leaves, using in vitro and in vivo approaches. Coconut leaf extract (CLE) was screened for antioxidant and AChE inhibitory properties in vitro and therapeutic effects in two strains of transgenic Caenorhabditis elegans expressing amyloid-β1–42 (Aβ1-42) in muscle cells. CLE demonstrated free radical scavenging activity with an EC50 that is 79-fold less compared to ascorbic acid, and an AChE inhibitory activity that is 131-fold less compared to Rivastigmine. Surprisingly, in spite of its low antioxidant activity and AChE inhibition, CLE reduced Aβ deposits by 30.31% in CL2006 in a dose-independent manner, and reduced the percentage of paralyzed nematodes at the lowest concentration of CLE (159.38 μg/mL), compared to dH2O/vehicle (control). Phytochemical analysis detected glycosides, anthocyanins, and hydrolyzable tannins in CLE, some of which are known to be anti-amyloidogenic. Taken together, these findings suggest that CLE metabolites alternatively decrease AB1–42 aggregation and paralysis prevalence independently of free radical scavenging and AChE inhibition, and this warrants further investigation on the bioactive compounds of CLE. PMID:28536360

  16. Coconut (Cocos nucifera) Ethanolic Leaf Extract Reduces Amyloid-β (1-42) Aggregation and Paralysis Prevalence in Transgenic Caenorhabditis elegans Independently of Free Radical Scavenging and Acetylcholinesterase Inhibition.

    PubMed

    Manalo, Rafael Vincent; Silvestre, Maries Ann; Barbosa, Aza Lea Anne; Medina, Paul Mark

    2017-04-21

    Virgin coconut oil (VCO) has been the subject of several studies which have aimed to alleviate Alzheimer's disease (AD) pathology, focusing on in vitro antioxidant and acetylcholinesterase (AChE) inhibitory activities. Here, we studied an underutilized and lesser-valued part of the coconut tree, specifically the leaves, using in vitro and in vivo approaches. Coconut leaf extract (CLE) was screened for antioxidant and AChE inhibitory properties in vitro and therapeutic effects in two strains of transgenic Caenorhabditis elegans expressing amyloid-β1-42 (Aβ1-42) in muscle cells. CLE demonstrated free radical scavenging activity with an EC50 that is 79-fold less compared to ascorbic acid, and an AChE inhibitory activity that is 131-fold less compared to Rivastigmine. Surprisingly, in spite of its low antioxidant activity and AChE inhibition, CLE reduced Aβ deposits by 30.31% in CL2006 in a dose-independent manner, and reduced the percentage of paralyzed nematodes at the lowest concentration of CLE (159.38 μg/mL), compared to dH₂O/vehicle (control). Phytochemical analysis detected glycosides, anthocyanins, and hydrolyzable tannins in CLE, some of which are known to be anti-amyloidogenic. Taken together, these findings suggest that CLE metabolites alternatively decrease AB1-42 aggregation and paralysis prevalence independently of free radical scavenging and AChE inhibition, and this warrants further investigation on the bioactive compounds of CLE.

  17. Amyloid Beta Mediates Memory Formation

    ERIC Educational Resources Information Center

    Garcia-Osta, Ana; Alberini, Cristina M.

    2009-01-01

    The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid [beta] (1-42) peptide (A[beta][1-42]), which is believed to play a major role in amyloid plaque formation in Alzheimer's disease (AD). Here we provide evidence that, in contrast with its pathological role when accumulated,…

  18. Amyloid Beta Mediates Memory Formation

    ERIC Educational Resources Information Center

    Garcia-Osta, Ana; Alberini, Cristina M.

    2009-01-01

    The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid [beta] (1-42) peptide (A[beta][1-42]), which is believed to play a major role in amyloid plaque formation in Alzheimer's disease (AD). Here we provide evidence that, in contrast with its pathological role when accumulated,…

  19. Characterization of amyloid in equine recurrent uveitis as AA amyloid.

    PubMed

    Ostevik, L; de Souza, G A; Wien, T N; Gunnes, G; Sørby, R

    2014-01-01

    Two horses with chronic uveitis and histological lesions consistent with equine recurrent uveitis (ERU) were examined. Microscopical findings in the ciliary body included deposits of amyloid lining the non-pigmented epithelium, intracytoplasmic, rod-shaped, eosinophilic inclusions and intraepithelial infiltration of T lymphocytes. Ultrastructural examination of the ciliary body of one horse confirmed the presence of abundant extracellular deposits of non-branching fibrils (9-11 nm in diameter) consistent with amyloid. Immunohistochemistry revealed strong positive labelling for AA amyloid and mass spectrometry showed the amyloid to consist primarily of serum amyloid A1 in both cases. The findings suggest that localized, intraocular AA amyloidosis may occur in horses with ERU.

  20. Amyloid Fibril Solubility.

    PubMed

    Rizzi, L G; Auer, S

    2015-11-19

    It is well established that amyloid fibril solubility is protein specific, but how solubility depends on the interactions between the fibril building blocks is not clear. Here we use a simple protein model and perform Monte Carlo simulations to directly measure the solubility of amyloid fibrils as a function of the interaction between the fibril building blocks. Our simulations confirms that the fibril solubility depends on the fibril thickness and that the relationship between the interactions and the solubility can be described by a simple analytical formula. The results presented in this study reveal general rules how side-chain-side-chain interactions, backbone hydrogen bonding, and temperature affect amyloid fibril solubility, which might prove to be a powerful tool to design protein fibrils with desired solubility and aggregation properties in general.

  1. Insulin amyloid at injection sites of patients with diabetes.

    PubMed

    Nilsson, Melanie R

    2016-09-01

    The formation of insulin amyloid can dramatically impact glycemic control in patients with diabetes, making it an important therapeutic consideration. In addition, the cost associated with the excess insulin required by patients with amyloid is estimated to be $3K per patient per year, which adds to the growing financial burden of this disease. Insulin amyloid has been observed with every mode of therapeutic insulin administration (infusion, injection and inhalation), and the number of reported cases has increased significantly since 2002. The new cases represent a much broader demographic, and include many patients who have used exclusively human insulin and human insulin analogs. The reason for the increase in case reports is unknown, but this review explores the possibility that changes in patient care, improved differential diagnosis and/or changes in insulin type and insulin delivery systems may be important factors. The goal of this review is to raise key questions that will inspire proactive measures to prevent, identify and treat insulin amyloid. Furthermore, this comprehensive examination of insulin amyloid can provide insight into important considerations for other injectable drugs that are prone to form amyloid deposits.

  2. Hydrogen Sulfide Inhibits Amyloid Formation

    PubMed Central

    2015-01-01

    Amyloid fibrils are large aggregates of misfolded proteins, which are often associated with various neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and vascular dementia. The amount of hydrogen sulfide (H2S) is known to be significantly reduced in the brain tissue of people diagnosed with Alzheimer’s disease relative to that of healthy individuals. These findings prompted us to investigate the effects of H2S on the formation of amyloids in vitro using a model fibrillogenic protein hen egg white lysozyme (HEWL). HEWL forms typical β-sheet rich fibrils during the course of 70 min at low pH and high temperatures. The addition of H2S completely inhibits the formation of β-sheet and amyloid fibrils, as revealed by deep UV resonance Raman (DUVRR) spectroscopy and ThT fluorescence. Nonresonance Raman spectroscopy shows that disulfide bonds undergo significant rearrangements in the presence of H2S. Raman bands corresponding to disulfide (RSSR) vibrational modes in the 550–500 cm–1 spectral range decrease in intensity and are accompanied by the appearance of a new 490 cm–1 band assigned to the trisulfide group (RSSSR) based on the comparison with model compounds. The formation of RSSSR was proven further using a reaction with TCEP reduction agent and LC-MS analysis of the products. Intrinsic tryptophan fluorescence study shows a strong denaturation of HEWL containing trisulfide bonds. The presented evidence indicates that H2S causes the formation of trisulfide bridges, which destabilizes HEWL structure, preventing protein fibrillation. As a result, small spherical aggregates of unordered protein form, which exhibit no cytotoxicity by contrast with HEWL fibrils. PMID:25545790

  3. Early metformin therapy (age 8-12 years) in girls with precocious pubarche to reduce hirsutism, androgen excess, and oligomenorrhea in adolescence.

    PubMed

    Ibáñez, Lourdes; López-Bermejo, Abel; Díaz, Marta; Marcos, Maria Victoria; de Zegher, Francis

    2011-08-01

    Girls with a combined history of low(-normal) birth weight (LBW) and precocious pubarche (PP) are at high risk to develop polycystic ovary syndrome (PCOS). The objective of the study was to compare the capacity of early vs. late metformin treatment to prevent adolescent PCOS. This was a randomized, open-label study over 7 yr. The study was conducted at a university hospital. Thirty-eight LBW-PP girls were followed up from the mean age 8 until age 15 yr. Early metformin (study yr 1-4; age 8-12 yr) vs. late metformin (yr 6; age 13-14 yr). Measures included height; weight; hirsutism score; menstrual cycle; endocrine-metabolic screening (fasting; follicular phase); C-reactive protein; body composition (absorptiometry); abdominal fat partitioning (magnetic resonance imaging); ovarian morphology (ultrasound); PCOS (National Institutes of Health and Androgen Excess Society definitions) after yr 7 (all girls thus untreated for at least 1 yr). None of the girls dropped out of the study. At age 15 yr, early-metformin girls were taller (4 cm), were in a less proinflammatory state, and had less central fat due to reductions in visceral and hepatic fat. Hirsutism, androgen excess, oligomenorrhea, and PCOS were between 2- and 8-fold more prevalent in late- than early-treated girls. Abdominal adiposity was the first variable to diverge (at age 8-10 yr) between girls without vs. with PCOS at age 15 yr. In LBW-PP girls, early metformin therapy was found to prevent or delay the development of hirsutism, androgen excess, oligomenorrhea, and PCOS more effectively than late metformin. The time window of late childhood and early puberty may be more critical for the development, and thus for the prevention, of adolescent PCOS than the first years beyond menarche.

  4. An investigation into the effects of maternal supplementation with excess iodine on the mechanisms and impacts of reduced IgG absorption in the lamb postpartum.

    PubMed

    McGovern, F M; Sweeney, T; Ryan, M T; Lott, S; Campion, F P; Boland, T M

    2017-04-01

    An experiment was conducted to determine: (1) the effect of excess maternal I supplementation on the thyroid hormone status of the ewe and her progeny; (2) potential mechanisms underpinning the failure of passive transfer associated with excess I and (3) the growing lambs' response to natural gastrointestinal infection. Twin-bearing ewes received one of two treatments (n 32/treatment group): basal diet (C) or C plus 26·6 mg of iodine/ewe per d (I), supplied as calcium iodate. Ewes were individually fed from day 119 of gestation to parturition. Progeny of I ewes had lower (P<0·01) serum IgG concentrations from 24 h to 28 d postpartum but higher serum IgG concentrations at day 70 postpartum (P<0·05). I supplementation increased the relative expression of Fc receptor, IgA, IgM high affinity and polymeric Ig receptor in the ileum of the lamb at 24 h postpartum; however, thyroid hormone receptor-β (THRB) and β-2-microglobulin (B2M) expression declined (P<0·05). Progeny of I ewes had higher growth rates to weaning (P<0·05) and lower faecal egg count (FEC) for Nematodirus battus (P<0·05) between weeks 6 and 10 postpartum. In conclusion, excess maternal I supplementation negatively affected the thyroid hormone status, serum IgG concentration, ileal morphology and the gene expression of THRB and B2M in the ileum and ras-related protein (RAB) RAB25 and the mucin gene (MUC) MUC1 in the duodenum of the lamb postpartum. These effects were followed by an enhancement of average daily gain and lower N. battus FEC in the pre-weaning period of I-supplemented lambs.

  5. Dietary Selenium Deficiency or Excess Reduces Sperm Quality and Testicular mRNA Abundance of Nuclear Glutathione Peroxidase 4 in Rats.

    PubMed

    Zhou, Ji-Chang; Zheng, Shijie; Mo, Junluan; Liang, Xiongshun; Xu, Yuanfei; Zhang, Huimin; Gong, Chunmei; Liu, Xiao-Li; Lei, Xin Gen

    2017-10-01

    Background: Glutathione peroxidase (GPX) 4 and selenoprotein P (SELENOP) are abundant, and several variants are expressed in the testis.Objective: We determined the effects of dietary selenium deficiency or excess on sperm quality and expressions of GPX4 and SELENOP variants in rat testis and liver.Methods: After weaning, male Sprague-Dawley rats were fed a Se-deficient basal diet (BD) for 5 wk until they were 9 wk old [mean ± SEM body weight (BW) = 256 ± 5 g]. They were then fed the BD diet alone (deficient) or with 0.25 (adequate), 3 (excess), or 5 (excess) mg Se/kg for 4 wk. Testis, liver, blood, and semen were collected to assay for selenoprotein mRNA and protein abundances, selenium concentration, GPX activity, 8-hydroxy-deoxyguanosine concentration, and sperm quality.Results: Dietary selenium supplementations elevated (P < 0.05) tissue selenium concentrations and GPX activities. Compared with those fed BD + 0.25 mg Se/kg, rats fed BD showed lower (P < 0.05) BW gain (86%) and sperm density (57%) but higher (P < 0.05) plasma 8-hydroxy-deoxyguanosine concentrations (189%), and nonprogressive sperm motility (4.4-fold). Likewise, rats fed BD + 5 mg Se/kg had (P = 0.06) lower BW gain and higher (1.9-fold) sperm deformity rates than those in the selenium-adequate group. Compared with the selenium-adequate group, dietary selenium deficiency (BD) or excess (BD + 3 or 5 mg Se/kg) resulted in 45-77% lower (P < 0.05) nuclear Gpx4 (nGpx4) mRNA abundance in the testis. Rats fed BD had lower (P < 0.05) mRNA levels of 2 Selenop variants in both testis and liver than those in the other groups. Testicular SELENOP was 155-170% higher (P < 0.05) in rats fed BD + 5 mg Se/kg and hepatic c/mGPX4 was 13-15% lower (P < 0.05) in rats fed BD than in the other groups.Conclusions: The mRNA abundance of rat testicular nGPX4 responded to dietary selenium concentrations in similar ways to sperm parameters and may be used as a sensitive marker to assess appropriate Se status for male

  6. Accumulation of murine amyloid-β mimics early Alzheimer's disease.

    PubMed

    Krohn, Markus; Bracke, Alexander; Avchalumov, Yosef; Schumacher, Toni; Hofrichter, Jacqueline; Paarmann, Kristin; Fröhlich, Christina; Lange, Cathleen; Brüning, Thomas; von Bohlen Und Halbach, Oliver; Pahnke, Jens

    2015-08-01

    Amyloidosis mouse models of Alzheimer's disease are generally established by transgenic approaches leading to an overexpression of mutated human genes that are known to be involved in the generation of amyloid-β in Alzheimer's families. Although these models made substantial contributions to the current knowledge about the 'amyloid hypothesis' of Alzheimer's disease, the overproduction of amyloid-β peptides mimics only inherited (familiar) Alzheimer's disease, which accounts for <1% of all patients with Alzheimer's disease. The inherited form is even regarded a 'rare' disease according to the regulations for funding of the European Union (www.erare.eu). Here, we show that mice that are double-deficient for neprilysin (encoded by Mme), one major amyloid-β-degrading enzyme, and the ABC transporter ABCC1, a major contributor to amyloid-β clearance from the brain, develop various aspects of sporadic Alzheimer's disease mimicking the clinical stage of mild cognitive impairment. Using behavioural tests, electrophysiology and morphological analyses, we compared different ABC transporter-deficient animals and found that alterations are most prominent in neprilysin × ABCC1 double-deficient mice. We show that these mice have a reduced probability to survive, show increased anxiety in new environments, and have a reduced working memory performance. Furthermore, we detected morphological changes in the hippocampus and amygdala, e.g. astrogliosis and reduced numbers of synapses, leading to defective long-term potentiation in functional measurements. Compared to human, murine amyloid-β is poorly aggregating, due to changes in three amino acids at N-terminal positions 5, 10, and 13. Interestingly, our findings account for the action of early occurring amyloid-β species/aggregates, i.e. monomers and small amyloid-β oligomers. Thus, neprilysin × ABCC1 double-deficient mice present a new model for early effects of amyloid-β-related mild cognitive impairment that allows

  7. Recent advances in the development of amyloid imaging agents.

    PubMed

    Furumoto, Shozo; Okamura, Nobuyuki; Iwata, Ren; Yanai, Kazuhiko; Arai, Hiroyuki; Kudo, Yukitsuka

    2007-01-01

    Excessive amyloid-beta (Abeta) deposition in the brain is one of the most crucial events in the early pathological stage of Alzheimer's disease (AD). Therefore, Abeta deposits have enough potential to become a useful biomarker for not only an early diagnosis of AD, but also for the assessment of the clinical efficacy of anti-Abeta therapies, if they can be measured non-invasively and reliably in living patients. As a potent candidate technique to measure this biomarker, PET amyloid imaging using a radioligand for Abeta deposits has received much attention. A large number of Abeta ligands have been synthesized and evaluated as candidates for amyloid imaging agents. These can be classified into six categories of derivatives: Congo-red, Thioflavine T, stilbene, vinylbenzoxazole, DDNP, and miscellaneous. Many of these derivatives exhibit high binding affinities to Abeta fibrils (below 20 nM) and some of them also show excellent brain pharmacokinetic profiles. The concept of amyloid imaging is currently being tested in human PET studies using optimized amyloid imaging agents. Despite the small number of subjects, these studies have demonstrated sufficiently promising results. This review article provides an overview of recent advances in the development of amyloid imaging agents, and includes: a summary of the fundamental basis and clinical significance of amyloid imaging; lists of binding affinity data for 135 compounds classified into 12 molecular frameworks; a comprehensive discussion of the in vitro and in vivo features of representative Abeta ligands; and a discussion of the current state of clinical evaluation of these amyloid imaging agents (PIB, SB-13, BF-227, and FDDNP).

  8. Cerebral amyloid angiopathy.

    PubMed

    Yamada, Masahito; Naiki, Hironobu

    2012-01-01

    Cerebral amyloid angiopathy (CAA) is cerebrovascular amyloid deposition. It is classified into several types according to the cerebrovascular amyloid proteins involved [amyloid β-protein (Aβ), cystatin C (ACys), prion protein (APrP), transthyretin (ATTR), gelsolin (AGel), ABri/ADan, and AL]. Sporadic Aβ-type CAA is commonly found in elderly individuals and patients with Alzheimer's disease (AD). CAA-related disorders include hemorrhagic and ischemic brain lesions and dementia. It has been proposed that cerebrovascular Aβ originates mainly from the brain and is transported to the vascular wall through a perivascular drainage pathway, where it polymerizes into fibrils on vascular basement membrane through interactions with extracellular components. CAA would be promoted by overproduction of Aβ40 (a major molecular species of cerebrovascular Aβ), a decrease of Aβ degradation, or reduction of Aβ clearance due to impairment of perivascular drainage pathway. Further understanding of the molecular pathogenesis of CAA would lead to development of disease-modifying therapies for CAA and CAA-related disorders. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Specific binding of DNA to aggregated forms of Alzheimer's disease amyloid peptides.

    PubMed

    Camero, Sergio; Ayuso, Jose M; Barrantes, Alejandro; Benítez, María J; Jiménez, Juan S

    2013-04-01

    Anomalous protein aggregation is closely associated to age-related mental illness. Extraneuronal plaques, mainly composed of aggregated amyloid peptides, are considered as hallmarks of Alzheimer's disease. According to the amyloid cascade hypothesis, this disease starts as a consequence of an abnormal processing of the amyloid precursor protein resulting in an excess of amyloid peptides. Nuclear localization of amyloid peptide aggregates together with amyloid-DNA interaction, have been repeatedly reported. In this paper we have used surface plasmon resonance and electron microscopy to study the structure and behavior of different peptides and proteins, including β-lactoglobulin, bovine serum albumin, myoglobin, histone, casein and the amyloid-β peptides related to Alzheimer's disease Aβ25-35 and Aβ1-40. The main purpose of this study is to investigate whether proneness to DNA interaction is a general property displayed by aggregated forms of proteins, or it is an interaction specifically related to the aggregated forms of those particular proteins and peptides related to neurodegenerative diseases. Our results reveal that those aggregates formed by amyloid peptides show a particular proneness to interact with DNA. They are the only aggregated structures capable of binding DNA, and show more affinity for DNA than for other polyanions like heparin and polyglutamic acid, therefore strengthening the hypothesis that amyloid peptides may, by means of interaction with nuclear DNA, contribute to the onset of Alzheimer's disease.

  10. Young microglia restore amyloid plaque clearance of aged microglia.

    PubMed

    Daria, Anna; Colombo, Alessio; Llovera, Gemma; Hampel, Heike; Willem, Michael; Liesz, Arthur; Haass, Christian; Tahirovic, Sabina

    2017-03-01

    Alzheimer's disease (AD) is characterized by deposition of amyloid plaques, neurofibrillary tangles, and neuroinflammation. In order to study microglial contribution to amyloid plaque phagocytosis, we developed a novel ex vivo model by co-culturing organotypic brain slices from up to 20-month-old, amyloid-bearing AD mouse model (APPPS1) and young, neonatal wild-type (WT) mice. Surprisingly, co-culturing resulted in proliferation, recruitment, and clustering of old microglial cells around amyloid plaques and clearance of the plaque halo. Depletion of either old or young microglial cells prevented amyloid plaque clearance, indicating a synergistic effect of both populations. Exposing old microglial cells to conditioned media of young microglia or addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was sufficient to induce microglial proliferation and reduce amyloid plaque size. Our data suggest that microglial dysfunction in AD may be reversible and their phagocytic ability can be modulated to limit amyloid accumulation. This novel ex vivo model provides a valuable system for identification, screening, and testing of compounds aimed to therapeutically reinforce microglial phagocytosis. © 2016 The Authors.

  11. Amyloid-β and Astrocytes Interplay in Amyloid-β Related Disorders

    PubMed Central

    Batarseh, Yazan S.; Duong, Quoc-Viet; Mousa, Youssef M.; Al Rihani, Sweilem B.; Elfakhri, Khaled; Kaddoumi, Amal

    2016-01-01

    Amyloid-β (Aβ) pathology is known to promote chronic inflammatory responses in the brain. It was thought previously that Aβ is only associated with Alzheimer’s disease and Down syndrome. However, studies have shown its involvement in many other neurological disorders. The role of astrocytes in handling the excess levels of Aβ has been highlighted in the literature. Astrocytes have a distinctive function in both neuronal support and protection, thus its involvement in Aβ pathological process may tip the balance toward chronic inflammation and neuronal death. In this review we describe the involvement of astrocytes in Aβ related disorders including Alzheimer’s disease, Down syndrome, cerebral amyloid angiopathy, and frontotemporal dementia. PMID:26959008

  12. Origins of amyloid

    PubMed Central

    2013-01-01

    Background Amyloid-β plaques are a defining characteristic of Alzheimer Disease. However, Amyloid-β deposition is also found in other forms of dementia and in non-pathological contexts. Amyloid-β deposition is variable among vertebrate species and the evolutionary emergence of the amyloidogenic property is currently unknown. Evolutionary persistence of a pathological peptide sequence may depend on the functions of the precursor gene, conservation or mutation of nucleotides or peptide domains within the precursor gene, or a species-specific physiological environment. Results In this study, we asked when amyloidogenic Amyloid-β first arose using phylogenetic trees constructed for the Amyloid-β Precursor Protein gene family and by modeling the potential for Amyloid-β aggregation across species in silico. We collected the most comprehensive set of sequences for the Amyloid-β Precursor Protein family using an automated, iterative meta-database search and constructed a highly resolved phylogeny. The analysis revealed that the ancestral gene for invertebrate and vertebrate Amyloid-β Precursor Protein gene families arose around metazoic speciation during the Ediacaran period. Synapomorphic frequencies found domain-specific conservation of sequence. Analyses of aggregation potential showed that potentially amyloidogenic sequences are a ubiquitous feature of vertebrate Amyloid-β Precursor Protein but are also found in echinoderm, nematode, and cephalochordate, and hymenoptera species homologues. Conclusions The Amyloid-β Precursor Protein gene is ancient and highly conserved. The amyloid forming Amyloid-β domains may have been present in early deuterostomes, but more recent mutations appear to have resulted in potentially unrelated amyoid forming sequences. Our results further highlight that the species-specific physiological environment is as critical to Amyloid-β formation as the peptide sequence. PMID:23627794

  13. Amyloid Aggregation and Membrane Disruption by Amyloid Proteins

    NASA Astrophysics Data System (ADS)

    Ramamoorthy, Ayyalusamy

    2013-03-01

    Amyloidogenesis has been the focus of intense basic and clinical research, as an increasing number of amyloidogenic proteins have been linked to common and incurable degenerative diseases including Alzheimer's, type II diabetes, and Parkinson's. Recent studies suggest that the cell toxicity is mainly due to intermediates generated during the assembly process of amyloid fibers, which have been proposed to attack cells in a variety of ways. Disruption of cell membranes is believed to be one of the key components of amyloid toxicity. However, the mechanism by which this occurs is not fully understood. Our research in this area is focused on the investigation of the early events in the aggregation and membrane disruption of amyloid proteins, Islet amyloid polypeptide protein (IAPP, also known as amylin) and amyloid-beta peptide, on the molecular level. Structural insights into the mechanisms of membrane disruption by these amyloid proteins and the role of membrane components on the membrane disruption will be presented.

  14. Targeting the γ-/β-secretase interaction reduces β-amyloid generation and ameliorates Alzheimer’s disease-related pathogenesis

    PubMed Central

    Cui, Jin; Wang, Xiaoyin; Li, Xiaohang; Wang, Xin; Zhang, Chenlu; Li, Wei; Zhang, Yangming; Gu, Haifeng; Xie, Xin; Nan, Fajun; Zhao, Jian; Pei, Gang

    2015-01-01

    Despite decades of intense global effort, no disease-modifying drugs for Alzheimer’s disease have emerged. Molecules targeting catalytic activities of γ-secretase or β-site APP-cleaving enzyme 1 (BACE1) have been beset by undesired side effects. We hypothesized that blocking the interaction between BACE1 and γ-secretase subunit presenilin-1 (PS1) might offer an alternative strategy to selectively suppress Aβ generation. Through high-throughput screening, we discovered that 3-α-akebonoic acid (3AA) interferes with PS1/BACE1 interaction and reduces Aβ production. Structural analogs of 3AA were systematically synthesized and the functional analog XYT472B was identified. Photo-activated crosslinking and biochemical competition assays showed that 3AA and XYT472B bind to PS1, interfere with PS1/BACE1 interaction, and reduce Aβ production, whereas sparing secretase activities. Furthermore, treatment of APP/PS1 mice with XYT472B alleviated cognitive dysfunction and Aβ-related pathology. Together, our results indicate that chemical interference of PS1/BACE1 interaction is a promising strategy for Alzheimer’s disease therapeutics. PMID:27462420

  15. EPA and California Air Resources Board Approve Remedy to Reduce Excess NOx Emissions from Automatic Transmission “Generation 2” 2.0-Liter Diesel Vehicles

    EPA Pesticide Factsheets

    On May 17, 2017, EPA and the California Air Resources Board (CARB) approved an emissions modification proposed by Volkswagen that will reduce NOx emissions from automatic transmission diesel Passats for model years 2012-2014.

  16. EPA and California Air Resources Board Approve Remedy to Reduce Excess NOx Emissions from “Generation 1” 2.0-Liter Diesel Vehicles

    EPA Pesticide Factsheets

    EPA and CARB approve an emissions modification proposed by Volkswagen (VW) to reduce nitrogen oxides emissions from model year 2009-2014, generation 1, 2.0 liter diesel Jetta, Golf, Beetle, and Audi A3 vehicles.

  17. White matter hyperintensities predict amyloid increase in Alzheimer's disease.

    PubMed

    Grimmer, Timo; Faust, Maximilian; Auer, Florian; Alexopoulos, Panagiotis; Förstl, Hans; Henriksen, Gjermund; Perneczky, Robert; Sorg, Christian; Yousefi, Behrooz H; Drzezga, Alexander; Kurz, Alexander

    2012-12-01

    Impaired amyloid clearance probably contributes to increased amyloid deposition in sporadic Alzheimer's disease (AD). Diminished perivascular drainage due to cerebral small-vessel disease (CSVD) has been proposed as a cause of reduced amyloid clearance. White matter hyperintensities (WMHs) are considered to reflect CSVD and can be measured using fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). Amyloid deposition can be determined in vivo using Pittsburgh compound B ([11C]PiB) positron emission tomography (PET). We aimed to elucidate the association between WMH and the progression of amyloid deposition in patients with AD. Twenty-two patients with probable AD underwent FLAIR-MRI and [11C]PiB-PET examinations at baseline (BL) and after a mean follow-up (FU) interval of 28 months. The relationship between BL-WMH and the progression of cerebral amyloid between BL and FU was examined using a regions-of-interest (ROI) approach. The region-specific variability of this relationship was analyzed using a voxel-based method. The longitudinal analysis revealed a statistically significant association between the amount of BL-WMH and the progression of amyloid load between BL and FU (p = 0.006, adjusted R2 = 0.375, standardized coefficient β = 0.384). The association was particularly observed in parieto-occipital regions and tended to be closer in regions adjacent to the brain surface. According to our knowledge, this is the first in vivo study in human being supporting the hypothesis that impaired amyloid clearance along perivascular drainage pathways may contribute to β-amyloid deposition in sporadic AD. The extent of WMH might be a relevant factor to be assessed in antiamyloid drug trials.

  18. Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer's Disease

    PubMed Central

    Spilman, Patricia; Podlutskaya, Natalia; Hart, Matthew J.; Debnath, Jayanta; Gorostiza, Olivia; Bredesen, Dale; Richardson, Arlan; Strong, Randy; Galvan, Veronica

    2010-01-01

    Background Reduced TOR signaling has been shown to significantly increase lifespan in a variety of organisms [1], [2], [3], [4]. It was recently demonstrated that long-term treatment with rapamycin, an inhibitor of the mTOR pathway[5], or ablation of the mTOR target p70S6K[6] extends lifespan in mice, possibly by delaying aging. Whether inhibition of the mTOR pathway would delay or prevent age-associated disease such as AD remained to be determined. Methodology/Principal Findings We used rapamycin administration and behavioral tools in a mouse model of AD as well as standard biochemical and immunohistochemical measures in brain tissue to provide answers for this question. Here we show that long-term inhibition of mTOR by rapamycin prevented AD-like cognitive deficits and lowered levels of Aβ42, a major toxic species in AD[7], in the PDAPP transgenic mouse model. These data indicate that inhibition of the mTOR pathway can reduce Aβ42 levels in vivo and block or delay AD in mice. As expected from the inhibition of mTOR, autophagy was increased in neurons of rapamycin-treated transgenic, but not in non-transgenic, PDAPP mice, suggesting that the reduction in Aβ and the improvement in cognitive function are due in part to increased autophagy, possibly as a response to high levels of Aβ. Conclusions/Significance Our data suggest that inhibition of mTOR by rapamycin, an intervention that extends lifespan in mice, can slow or block AD progression in a transgenic mouse model of the disease. Rapamycin, already used in clinical settings, may be a potentially effective therapeutic agent for the treatment of AD. PMID:20376313

  19. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease.

    PubMed

    Spilman, Patricia; Podlutskaya, Natalia; Hart, Matthew J; Debnath, Jayanta; Gorostiza, Olivia; Bredesen, Dale; Richardson, Arlan; Strong, Randy; Galvan, Veronica

    2010-04-01

    Reduced TOR signaling has been shown to significantly increase lifespan in a variety of organisms [1], [2], [3], [4]. It was recently demonstrated that long-term treatment with rapamycin, an inhibitor of the mTOR pathway[5], or ablation of the mTOR target p70S6K[6] extends lifespan in mice, possibly by delaying aging. Whether inhibition of the mTOR pathway would delay or prevent age-associated disease such as AD remained to be determined. We used rapamycin administration and behavioral tools in a mouse model of AD as well as standard biochemical and immunohistochemical measures in brain tissue to provide answers for this question. Here we show that long-term inhibition of mTOR by rapamycin prevented AD-like cognitive deficits and lowered levels of Abeta(42), a major toxic species in AD[7], in the PDAPP transgenic mouse model. These data indicate that inhibition of the mTOR pathway can reduce Abeta(42) levels in vivo and block or delay AD in mice. As expected from the inhibition of mTOR, autophagy was increased in neurons of rapamycin-treated transgenic, but not in non-transgenic, PDAPP mice, suggesting that the reduction in Abeta and the improvement in cognitive function are due in part to increased autophagy, possibly as a response to high levels of Abeta. Our data suggest that inhibition of mTOR by rapamycin, an intervention that extends lifespan in mice, can slow or block AD progression in a transgenic mouse model of the disease. Rapamycin, already used in clinical settings, may be a potentially effective therapeutic agent for the treatment of AD.

  20. Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy.

    PubMed

    Saito, Satoshi; Yamamoto, Yumi; Maki, Takakuni; Hattori, Yorito; Ito, Hideki; Mizuno, Katsuhiko; Harada-Shiba, Mariko; Kalaria, Raj N; Fukushima, Masanori; Takahashi, Ryosuke; Ihara, Masafumi

    2017-04-04

    Cerebral amyloid angiopathy (CAA) induces various forms of cerebral infarcts and hemorrhages from vascular amyloid-β accumulation, resulting in acceleration of cognitive impairment, which is currently untreatable. Soluble amyloid-β protein likely impairs cerebrovascular integrity as well as cognitive function in early stage Alzheimer's disease. Taxifolin, a flavonol with strong anti-oxidative and anti-glycation activities, has been reported to disassemble amyloid-β in vitro but the in vivo relevance remains unknown. Here, we investigated whether taxifolin has therapeutic potential in attenuating CAA, hypothesizing that inhibiting amyloid-β assembly may facilitate its clearance through several elimination pathways. Vehicle- or taxifolin-treated Tg-SwDI mice (commonly used to model CAA) were used in this investigation. Cognitive and cerebrovascular function, as well as the solubility and oligomerization of brain amyloid-β proteins, were investigated. Spatial reference memory was assessed by water maze test. Cerebral blood flow was measured with laser speckle flowmetry and cerebrovascular reactivity evaluated by monitoring cerebral blood flow changes in response to hypercapnia. Significantly reduced cerebrovascular pan-amyloid-β and amyloid-β1-40 accumulation was found in taxifolin-treated Tg-SwDI mice compared to vehicle-treated counterparts (n = 5). Spatial reference memory was severely impaired in vehicle-treated Tg-SwDI mice but normalized after taxifolin treatment, with scoring similar to wild type mice (n = 10-17). Furthermore, taxifolin completely restored decreased cerebral blood flow and cerebrovascular reactivity in Tg-SwDI mice (n = 4-6). An in vitro thioflavin-T assay showed taxifolin treatment resulted in efficient inhibition of amyloid-β1-40 assembly. In addition, a filter trap assay and ELISA showed Tg-SwDI mouse brain homogenates exhibited significantly reduced levels of amyloid-β oligomers in vivo after taxifolin treatment (n

  1. Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta.

    PubMed

    Atwood, Craig S; Obrenovich, Mark E; Liu, Tianbing; Chan, Hsien; Perry, George; Smith, Mark A; Martins, Ralph N

    2003-09-01

    Although much maligned, the amyloid-beta (Abeta) protein has been shown to possess a number of trophic properties that emanate from the protein's ability to bind Cu, Fe and Zn. Abeta belongs to a group of proteins that capture redox metal ions (even under mildly acidotic conditions), thereby preventing them from participating in redox cycling with other ligands. The coordination of Cu appears to be crucial for Abeta's own antioxidant activity that has been demonstrated both in vitro as well as in the brain, cerebrospinal fluid and plasma. The chelation of Cu by Abeta would therefore be predicted to dampen oxidative stress in the mildly acidotic and oxidative environment that accompanies acute brain trauma and Alzheimer's disease (AD). Given that oxidative stress promotes Abeta generation, the formation of diffuse amyloid plaques is likely to be a compensatory response to remove reactive oxygen species. This review weighs up the evidence supporting both the trophic and toxic properties of Abeta, and while evidence for direct Abeta neurotoxicity in vivo is scarce, we postulate that the product of Abeta's antioxidant activity, hydrogen peroxide (H(2)O(2)), is likely to mediate toxicity as the levels of this oxidant rise with the accumulation of Abeta in the AD brain. We propose that metal ion chelators, antioxidants, antiinflammatories and amyloid-lowering drugs that target the reduction of H(2)O(2) and/or Abeta generation may be efficacious in decreasing neurotoxicity. However, given the antioxidant activity of Abeta, we suggest that the excessive removal of Abeta may prevent adequate chelation of metal ions and removal of O(2)(-z.ccirf;), leading to enhanced, rather than reduced, neuronal oxidative stress.

  2. Targeting CCR3 to Reduce Amyloid-β Production, Tau Hyperphosphorylation, and Synaptic Loss in a Mouse Model of Alzheimer's Disease.

    PubMed

    Zhu, Chunyan; Xu, Bing; Sun, Xiaohong; Zhu, Qiwen; Sui, Yi

    2016-11-23

    The majority of Alzheimer's disease (AD) patients have a late onset, and chronic neuroinflammation, characterized by glial activation and secretion of pro-inflammatory cytokines and chemokines, plays a role in the pathogenesis of AD. The chemokine CCL11 has been shown to be a causative factor of cognitive decline in the process of aging, but little is known whether it is involved in the pathogenesis of AD. In the present study, we showed that CCR3, the receptor for CCL11, was expressed by hippocampal neurons and treatment of primary hippocampal neuronal cultures (14 days in vitro) with CCL11 resulted in activation of cyclin-dependent kinase 5 and glycogen synthase kinase-3β, associated with elevated tau phosphorylation at multiple sites. CCL11 treatment also induced the production of Aβ and dendritic spine loss in the hippocampal neuronal cultures. All these effects were blocked by the CCR3 specific antagonist, GW766994. An age-dependent increase in CCL11, predominantly expressed by the activated microglia, was observed in the cerebrospinal fluid of both APP/PS1 double transgenic mice and wild-type (WT) littermates, with a markedly higher level in APP/PS1 double transgenic mice than that in WT littermates. Deletion of CCR3 in APP/PS1 double transgenic mice significantly reduced the phosphorylation of CDK5 and GSK3β, tau hyperphosphorylation, Aβ deposition, microgliosis, astrogliosis, synaptic loss, and spatial learning and memory deficits. Thus, the age-related increase in CCL11 may be a risk factor of AD, and antagonizing CCR3 may bring therapeutic benefits to AD.

  3. Amyloids: from Pathogenesis to Function.

    PubMed

    Nizhnikov, A A; Antonets, K S; Inge-Vechtomov, S G

    2015-09-01

    The term "amyloids" refers to fibrillar protein aggregates with cross-β structure. They have been a subject of intense scrutiny since the middle of the previous century. First, this interest is due to association of amyloids with dozens of incurable human diseases called amyloidoses, which affect hundreds of millions of people. However, during the last decade the paradigm of amyloids as pathogens has changed due to an increase in understanding of their role as a specific variant of quaternary protein structure essential for the living cell. Thus, functional amyloids are found in all domains of the living world, and they fulfill a variety of roles ranging from biofilm formation in bacteria to long-term memory regulation in higher eukaryotes. Prions, which are proteins capable of existing under the same conditions in two or more conformations at least one of which having infective properties, also typically have amyloid features. There are weighty reasons to believe that the currently known amyloids are only a minority of their real number. This review provides a retrospective analysis of stages in the development of amyloid biology that during the last decade resulted, on one hand, in reinterpretation of the biological role of amyloids, and on the other hand, in the development of systems biology of amyloids, or amyloidomics.

  4. Antimicrobial Properties of Amyloid Peptides

    PubMed Central

    Kagan, Bruce L.; Jang, Hyunbum; Capone, Ricardo; Arce, Fernando Teran; Ramachandran, Srinivasan; Lal, Ratnesh; Nussinov, Ruth

    2011-01-01

    More than two dozen clinical syndromes known as amyloid diseases are characterized by the buildup of extended insoluble fibrillar deposits in tissues. These amorphous Congo red staining deposits known as amyloids exhibit a characteristic green birefringence and cross-β structure. Substantial evidence implicates oligomeric intermediates of amyloids as toxic species in the pathogenesis of these chronic disease states. A growing body of data has suggested that these toxic species form ion channels in cellular membranes causing disruption of calcium homeostasis, membrane depolarization, energy drainage, and in some cases apoptosis. Amyloid peptide channels exhibit a number of common biological properties including the universal U-shape β-strand-turn-β-strand structure, irreversible and spontaneous insertion into membranes, production of large heterogeneous single-channel conductances, relatively poor ion selectivity, inhibition by Congo red, and channel blockade by zinc. Recent evidence has suggested that increased amounts of amyloids are not only toxic to its host target cells but also possess antimicrobial activity. Furthermore, at least one human antimicrobial peptide, protegrin-1, which kills microbes by a channel-forming mechanism, has been shown to possess the ability to form extended amyloid fibrils very similar to those of classic disease-forming amyloids. In this paper, we will review the reported antimicrobial properties of amyloids and the implications of these discoveries for our understanding of amyloid structure and function. PMID:22081976

  5. Levels of Soluble Apolipoprotein E/Amyloid-β (Aβ) Complex Are Reduced and Oligomeric Aβ Increased with APOE4 and Alzheimer Disease in a Transgenic Mouse Model and Human Samples*♦

    PubMed Central

    Tai, Leon M.; Bilousova, Tina; Jungbauer, Lisa; Roeske, Stephen K.; Youmans, Katherine L.; Yu, Chunjiang; Poon, Wayne W.; Cornwell, Lindsey B.; Miller, Carol A.; Vinters, Harry V.; Van Eldik, Linda J.; Fardo, David W.; Estus, Steve; Bu, Guojun; Gylys, Karen Hoppens; LaDu, Mary Jo

    2013-01-01

    Human apolipoprotein E (apoE) isoforms may differentially modulate amyloid-β (Aβ) levels. Evidence suggests physical interactions between apoE and Aβ are partially responsible for these functional effects. However, the apoE/Aβ complex is not a single static structure; rather, it is defined by detection methods. Thus, literature results are inconsistent and difficult to interpret. An ELISA was developed to measure soluble apoE/Aβ in a single, quantitative method and was used to address the hypothesis that reduced levels of soluble apoE/Aβ and an increase in soluble Aβ, specifically oligomeric Aβ (oAβ), are associated with APOE4 and AD. Previously, soluble Aβ42 and oAβ levels were greater with APOE4 compared with APOE2/APOE3 in hippocampal homogenates from EFAD transgenic mice (expressing five familial AD mutations and human apoE isoforms). In this study, soluble apoE/Aβ levels were lower in E4FAD mice compared with E2FAD and E3FAD mice, thus providing evidence that apoE/Aβ levels isoform-specifically modulate soluble oAβ clearance. Similar results were observed in soluble preparations of human cortical synaptosomes; apoE/Aβ levels were lower in AD patients compared with controls and lower with APOE4 in the AD cohort. In human CSF, apoE/Aβ levels were also lower in AD patients and with APOE4 in the AD cohort. Importantly, although total Aβ42 levels decreased in AD patients compared with controls, oAβ levels increased and were greater with APOE4 in the AD cohort. Overall, apoE isoform-specific formation of soluble apoE/Aβ modulates oAβ levels, suggesting a basis for APOE4-induced AD risk and a mechanistic approach to AD biomarkers. PMID:23293020

  6. Neuronal activity and amyloid plaque pathology: an update.

    PubMed

    Ovsepian, Saak V; O'Leary, Valerie B

    2016-01-01

    A breakthrough in Alzheimer's disease (AD) research came with the discovery of the link between activity-dependent release of amyloid-β (Aβ) from neurons and formation of amyloid plaques. Along with elucidating the cellular basis of behavioral-dependent fluctuations in Aβ levels in the brain, insights have been gained toward understanding the mechanisms that warrant selective vulnerability of various forebrain circuits to amyloid pathology. The notion of elevated activity as a source of excessive Aβ production and plaque formation is, however, in conflict with ample electrophysiological data, which demonstrate exceedingly intense activity (both intrinsic and synaptic) of neurons in several brain regions that are spared or marginally affected by amyloid plaques of AD. Thus, the link between the functional load of brain circuits and their vulnerability to amyloidosis, while evident, is also complex and remains poorly understood. Here, we discuss emerging data suggestive of a major role for super-intense synchronous activity of cortical and limbic networks in excessive Aβ production and plaque formation. It is proposed that dense recurrent wiring of associative areas prone to epileptic seizures might be of critical relevance to their higher susceptibility to plaque pathology and related functional impairments.

  7. Specific combinations of ion channel inhibitors reduce excessive Ca(2+) influx as a consequence of oxidative stress and increase neuronal and glial cell viability in vitro.

    PubMed

    O'Hare Doig, Ryan L; Bartlett, Carole A; Smith, Nicole M; Hodgetts, Stuart I; Dunlop, Sarah A; Hool, Livia; Fitzgerald, Melinda

    2016-12-17

    Combinations of Ca(2+) channel inhibitors have been proposed as an effective means to prevent excess Ca(2+) flux and death of neurons and glia following neurotrauma in vivo. However, it is not yet known if beneficial outcomes such as improved viability have been due to direct effects on intracellular Ca(2+) concentrations. Here, the effects of combinations of Lomerizine (Lom), 2,3-dioxo-7-(1H-imidazol-1-yl)6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl]acetic acid monohydrate (YM872), 3,5-dimethyl-1-adamantanamine (memantine (Mem)) and/or adenosine 5'-triphosphate periodate oxidized sodium salt (oxATP) to block voltage-gated Ca(2+) channels, Ca(2+) permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, NMDA receptors and purinergic P2X7 receptors (P2X7R) respectively, on Ca(2+) concentration and viability of rat primary mixed cortical (MC) cultures exposed to hydrogen peroxide (H2O2) insult, were assessed. The contribution of ryanodine-sensitive intracellular stores to intracellular Ca(2+) concentration was also assessed. Live cell calcium imaging revealed that a 30min H2O2 insult induced a slow increase in intracellular Ca(2+), in part from intracellular sources, associated with loss of cell viability by 6h. Most combinations of inhibitors that included oxATP significantly decreased Ca(2+) influx and increased cell viability when administered simultaneously with H2O2. However, reductions in intracellular Ca(2+) concentration were not always linked to improved cell viability. Examination of the density of specific cell subpopulations demonstrated that most combinations of inhibitors that included oxATP preserved NG2+ non-oligodendroglial cells, but preservation of astrocytes and neurons required additional inhibitors. Olig2(+) oligodendroglia and ED-1(+) activated microglia/macrophages were not preserved by any of the inhibitor combinations. These data indicate that following H2O2 insult, limiting intracellular Ca(2+) entry via P2X7R is

  8. Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease.

    PubMed

    Helmfors, Linda; Boman, Andrea; Civitelli, Livia; Nath, Sangeeta; Sandin, Linnea; Janefjord, Camilla; McCann, Heather; Zetterberg, Henrik; Blennow, Kaj; Halliday, Glenda; Brorsson, Ann-Christin; Kågedal, Katarina

    2015-11-01

    The hallmarks of Alzheimer disease are amyloid-β plaques and neurofibrillary tangles accompanied by signs of neuroinflammation. Lysozyme is a major player in the innate immune system and has recently been shown to prevent the aggregation of amyloid-β1-40 in vitro. In this study we found that patients with Alzheimer disease have increased lysozyme levels in the cerebrospinal fluid and lysozyme co-localized with amyloid-β in plaques. In Drosophila neuronal co-expression of lysozyme and amyloid-β1-42 reduced the formation of soluble and insoluble amyloid-β species, prolonged survival and improved the activity of amyloid-β1-42 transgenic flies. This suggests that lysozyme levels rise in Alzheimer disease as a compensatory response to amyloid-β increases and aggregation. In support of this, in vitro aggregation assays revealed that lysozyme associates with amyloid-β1-42 and alters its aggregation pathway to counteract the formation of toxic amyloid-β species. Overall, these studies establish a protective role for lysozyme against amyloid-β associated toxicities and identify increased lysozyme in patients with Alzheimer disease. Therefore, lysozyme has potential as a new biomarker as well as a therapeutic target for Alzheimer disease.

  9. Human islet amyloid polypeptide expression in COS-1 cells. A model of intracellular amyloidogenesis.

    PubMed Central

    O'Brien, T. D.; Butler, P. C.; Kreutter, D. K.; Kane, L. A.; Eberhardt, N. L.

    1995-01-01

    Non-insulin-dependent diabetes mellitus is characterized by concurrent loss of beta-cells and deposition of islet amyloid derived from islet amyloid polypeptide (IAPP). We have previously demonstrated that IAPP-derived amyloid forms intracellularly in humans with chronic excess insulin expression (eg, insulinoma and insulin receptor antibody-induced insulin resistance). To determine whether overexpression of IAPP results in intracellular amyloid in mammalian cells, we transfected COS cells with vectors expressing amyloidogenic human IAPP or non-amyloidogenic rat IAPP. Transfected COS-1 cells secreted comparable amounts of human IAPP and rat IAPP (2.1 to 2.8 nmol/L/48 hours). After 96 hours, 90% of cells expressing human IAPP contained amyloid fibrils and were degenerating or dead, whereas cells transfected with rat IAPP lacked amyloid and were viable. Thus, overexpression of human IAPP can result in intracellular amyloid formation that is associated with cell death, suggesting that intracellular amyloid may play a role in beta-cell loss in non-insulin-dependent diabetes mellitus. Images Figure 1 Figure 2 PMID:7677175

  10. Morin hydrate inhibits amyloid formation by islet amyloid polypeptide and disaggregates amyloid fibers

    PubMed Central

    Noor, Harris; Cao, Ping; Raleigh, Daniel P

    2012-01-01

    The polypeptide hormone Islet Amyloid Polypeptide (IAPP, amylin) is responsible for islet amyloid formation in type-2 diabetes and in islet cell transplants, where it may contribute to graft failure. Human IAPP is extremely amyloidogenic and fewer inhibitors of IAPP amyloid formation have been reported than for the Alzheimer's Aβ peptide or for α-synuclein. The ability of a set of hydroxyflavones to inhibit IAPP amyloid formation was tested. Fluorescence detected thioflavin-T-binding assays are the most popular methods for measuring the kinetics of amyloid formation and for screening potential inhibitors; however, we show that they can lead to false positives with hydroxyflavones. Several of the compounds inhibit thioflavin-T fluorescence, but not amyloid formation; a result which highlights the hazards of relying solely on thioflavin-T assays to screen potential inhibitors. Transmission electron microscopy (TEM) and right-angle light scattering show that Morin hydrate (2′,3,4′,5,7-Pentahydroxyflavone) inhibits amyloid formation by human IAPP and disaggregates preformed IAPP amyloid fibers. In contrast, Myricetin, Kaempferol, and Quercetin, which differ only in hydroxyl groups on the B-ring, are not effective inhibitors. Morin hydrate represents a new type of IAPP amyloid inhibitor and the results with the other compounds highlight the importance of the substitution pattern on the B-ring. PMID:22238175

  11. Double-dose β-glucan treatment in WSSV-challenged shrimp reduces viral replication but causes mortality possibly due to excessive ROS production.

    PubMed

    Thitamadee, Siripong; Srisala, Jiraporn; Taengchaiyaphum, Suparat; Sritunyalucksana, Kallaya

    2014-10-01

    In our research efforts to reduce the impact of white spot syndrome virus (WSSV) disease outbreaks in shrimp aquaculture, we studied the effect of β-glucan administration to activate the prophenoloxidase (proPO) enzymatic cascade prior to WSSV challenge. Injection of a single dose of β-glucan (5 μg/g) prior to WSSV challenge resulted in activation of the proPO system and reduced shrimp mortality (25-50%) when compared to controls (100%). By contrast, no significant reduction was observed using yellow head virus (YHV) in a similar protocol. We subsequently hypothesized that administration of a second dose of β-glucan after WSSV challenge might reduce shrimp mortality further. Surprisingly, the opposite occurred, and mortality of the WSSV-infected shrimp increased to 100% after the second β-glucan dose. Both immunofluorescence and RT-PCR assays revealed low WSSV levels in hemocytes of shrimp collected after the second dose of β-glucan administration, suggesting that the cause of increased mortality was unlikely to be increased WSSV replication. We found from measured phenoloxidase acitivity (PO) and H2O2 production that the higher mortality may have resulted from a combination of WSSV infection plus over-production of reactive oxygen species (ROS) stimulated by two doses of β-glucan. Thus, caution may be prudent in continuous or prolonged activation of the shrimp immune system by β-glucan administration lest it exacerbate shrimp mortality in the event of WSSV infection. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Excess electron states in reduced bulk anatase TiO2: comparison of standard GGA, GGA+U, and hybrid DFT calculations.

    PubMed

    Finazzi, Emanuele; Di Valentin, Cristiana; Pacchioni, Gianfranco; Selloni, Annabella

    2008-10-21

    The removal of lattice O atoms, as well as the addition of interstitial H atoms, in TiO(2) is known to cause the reduction in the material and the formation of "Ti(3+)" ions. By means of electronic structure calculations we have studied the nature of such oxygen vacancy and hydrogen impurity states in the bulk of the anatase polymorph of TiO(2). The spin polarized nature of these centers, the localized or delocalized character of the extra electrons, the presence of defect-induced states in the gap, and the polaronic distortion around the defect have been investigated with different theoretical methods: standard density functional theory (DFT) in the generalized-gradient approximation (GGA), GGA+U methods as a function of the U parameter, and two hybrid functionals with different admixtures of Hartree-Fock exchange. The results are found to be strongly dependent on the method used. Only GGA+U or hybrid functionals are able to reproduce the presence of states at about 1 eV below the conduction band, which are experimentally observed in reduced titania. The corresponding electronic states are localized on Ti 3d levels, but partly delocalized solutions are very close in energy. These findings show the limited predictive power of these theoretical methods to describe the electronic structure of reduced titania in the absence of accurate experimental data.

  13. Effect of trehalose on amyloid β (29-40)-membrane interaction

    NASA Astrophysics Data System (ADS)

    Reddy, Allam S.; Izmitli, Aslin; de Pablo, J. J.

    2009-08-01

    A growing body of experimental evidence indicates that the interaction between amyloid β peptide and lipid bilayer membranes plays an important role in the development of Alzheimer disease. Recent experimental evidence also suggests that trehalose, a simple disaccharide, reduces the toxicity of amyloid β peptide. Molecular simulations are used to examine the effect of trehalose on the conformational stability of amyloid β peptide in aqueous solution and its effect on the interaction between amyloid β peptide and a model phospholipid bilayer membrane. It is found that, in aqueous solution, the peptide exhibits a random coil conformation but, in the presence of trehalose, it adopts an alpha helical conformation. It is then shown that the insertion of amyloid β peptide into a membrane is more favorable when the peptide is folded into an α-helix than in a random coil conformation, thereby suggesting that trehalose promotes the insertion of α-helical amyloid β into biological membranes.

  14. Effect of trehalose on amyloid beta (29-40)-membrane interaction.

    PubMed

    Reddy, Allam S; Izmitli, Aslin; de Pablo, J J

    2009-08-28

    A growing body of experimental evidence indicates that the interaction between amyloid beta peptide and lipid bilayer membranes plays an important role in the development of Alzheimer disease. Recent experimental evidence also suggests that trehalose, a simple disaccharide, reduces the toxicity of amyloid beta peptide. Molecular simulations are used to examine the effect of trehalose on the conformational stability of amyloid beta peptide in aqueous solution and its effect on the interaction between amyloid beta peptide and a model phospholipid bilayer membrane. It is found that, in aqueous solution, the peptide exhibits a random coil conformation but, in the presence of trehalose, it adopts an alpha helical conformation. It is then shown that the insertion of amyloid beta peptide into a membrane is more favorable when the peptide is folded into an alpha-helix than in a random coil conformation, thereby suggesting that trehalose promotes the insertion of alpha-helical amyloid beta into biological membranes.

  15. β-asarone improves learning and memory and reduces Acetyl Cholinesterase and Beta-amyloid 42 levels in APP/PS1 transgenic mice by regulating Beclin-1-dependent autophagy.

    PubMed

    Deng, Minzhen; Huang, Liping; Ning, Baile; Wang, Nanbu; Zhang, Qinxin; Zhu, Caixia; Fang, Yongqi

    2016-12-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly, and studies have suggested that β-asarone has pharmacological effects on beta-amyloid (Aβ) injected in the rat hippocampus. However, the effect of β-asarone on autophagy in the APP/PS1 transgenic mouse is unreported. APP/PS1 transgenic mice were randomly divided into six groups (n=10/group): an untreated group, an Aricept-treated group, a 3-MA-treated group, a rapamycin-treated group, an LY294002-treated group, a β-asarone-treated group. The control group consisted of wild-type C57BL/6 mice. All treatments were administered to the mice for 30 days. Spatial learning and memory were assessed by water maze, passive avoidance, and step-down tests. AChE and Aβ42 levels in the hippocampus were determined by ELISA. p-Akt, p-mTOR, and LC3B expression were detected by flow cytometry. The expression of p-Akt, p-mTOR, Beclin-1, and p62 proteins was assessed by western blot. Changes in autophagy were viewed using a transmission electron microscope. APP and Beclin-1 mRNA levels were measured by Real-Time PCR. The learning and memory of APP/PS1 transgenic mice were improved significantly after β-asarone treatment compared with the untreated group. In addition, β-asarone treatment reduced AChE and Aβ42 levels, increased p-mTOR and p62 expression, decreased p-Akt, Beclin-1, and LC3B expression, decreased the number of autophagosomes and reduced APP mRNA and Beclin-1 mRNA levels compared with the untreated group. That is, β-asarone treatment can improve the learning and memory abilities of APP/PS1 transgenic mouse by inhibiting Beclin-1-dependent autophagy via the PI3K/Akt/mTOR pathway. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Ovine colostrum nanopeptide affects amyloid beta aggregation.

    PubMed

    Janusz, Maria; Woszczyna, Mirosław; Lisowski, Marek; Kubis, Adriana; Macała, Józefa; Gotszalk, Teodor; Lisowski, Józef

    2009-01-05

    A colostral proline-rich polypeptide complex (PRP) consisting of over 30 peptides shows beneficial effects in Alzheimer's disease (AD) patients when administered in the form of sublinqual tablets called Colostrinin. The aim of the present studies was to investigate whether nanopeptide fragment of PRP (NP) - one of the PRP complex components can affect aggregation of amyloid beta (Abeta1-42). The effect of NP on Abeta aggregation was studied using Thioflavin T (ThT) binding, atomic force microscopy, and analyzing circular dichroism spectra. Results presented suggest that NP can directly interact with amyloid beta, inhibit its aggregation and disrupt existing aggregates acting as a beta sheet breaker and reduce toxicity induced by aggregated forms of Abeta.

  17. Amyloid fibrils composed of hexameric peptides attenuate neuroinflammation.

    PubMed

    Kurnellas, Michael P; Adams, Chris M; Sobel, Raymond A; Steinman, Lawrence; Rothbard, Jonathan B

    2013-04-03

    The amyloid-forming proteins tau, αB crystallin, and amyloid P protein are all found in lesions of multiple sclerosis (MS). Our previous work established that amyloidogenic peptides from the small heat shock protein αB crystallin (HspB5) and from amyloid β fibrils, characteristic of Alzheimer's disease, were therapeutic in experimental autoimmune encephalomyelitis (EAE), reflecting aspects of the pathology of MS. To understand the molecular basis for the therapeutic effect, we showed a set of amyloidogenic peptides composed of six amino acids, including those from tau, amyloid β A4, major prion protein (PrP), HspB5, amylin, serum amyloid P, and insulin B chain, to be anti-inflammatory and capable of reducing serological levels of interleukin-6 and attenuating paralysis in EAE. The chaperone function of the fibrils correlates with the therapeutic outcome. Fibrils composed of tau 623-628 precipitated 49 plasma proteins, including apolipoprotein B-100, clusterin, transthyretin, and complement C3, supporting the hypothesis that the fibrils are active biological agents. Amyloid fibrils thus may provide benefit in MS and other neuroinflammatory disorders.

  18. Amyloid enhancing factor activity is associated with ubiquitin.

    PubMed

    Alizadeh-Khiavi, K; Normand, J; Chronopoulos, S; Ali, A; Ali-Khan, Z

    1992-01-01

    Crude amyloid enhancing factor (AEF) drastically reduces the pre-amyloid phase on passive transfer and induces amyloid deposition in the recipient mice in 48-120 h. We attempted to purify AEF from murine amyloidotic liver and spleen extracts by using gel filtration, preparative sodium dodecyl sulphate-polyacrylamide gel electrophoresis and ion exchange chromatography and isolated a 5.5 kDa peptide. In the mouse bioassay, this peptide induced accelerated splenic AA deposition in a dose-dependent manner. Based on structural, electrophoretic and immunochemical criteria the peptide was identified as ubiquitin. A polyclonal rabbit anti-bovine ubiquitin IgG antibody (RABU) abolished the in vivo AEF activity of crude murine AEF in a dose-dependent manner. Monomeric ubiquitin and its large molecular weight adducts were isolated from crude AEF using cyanogen bromide-activated sepharose conjugated to RABU and size exclusion chromatography methods. These were assayed and were found to possess AEF activity. Furthermore, increased levels of ubiquitin, a phenomenon similar to that of AEF, were detected by immunocytochemistry in mouse peritoneal leucocytes prior to and during amyloid deposition. Since AEF shares a number of biological and functional properties with ubiquitin, we suggest a possible role of ubiquitin as an AEF, and that serum amyloid protein A and ubiquitin, the two reactants generated during inflammatory stress conditions, may converge to induce AA amyloid deposition.

  19. Towards a Pharmacophore for Amyloid

    SciTech Connect

    Landau, Meytal; Sawaya, Michael R.; Faull, Kym F.; Laganowsky, Arthur; Jiang, Lin; Sievers, Stuart A.; Liu, Jie; Barrio, Jorge R.; Eisenberg, David

    2011-09-16

    Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of {beta}-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. The devastating and incurable dementia known as Alzheimer's disease affects the thinking, memory, and behavior of dozens of millions of people worldwide. Although amyloid fibers and oligomers of two proteins, tau and amyloid-{beta}, have been identified in association with this disease, the development of diagnostics and therapeutics has proceeded to date in a near vacuum of information about their structures. Here we report the first atomic structures of small molecules bound to amyloid. These are of the dye orange-G, the natural compound curcumin, and the Alzheimer's diagnostic compound DDNP bound to amyloid-like segments of tau and amyloid-{beta}. The structures reveal the molecular framework of small-molecule binding, within cylindrical cavities running along the {beta}-spines of the fibers. Negatively charged orange-G wedges into a specific binding site between two sheets of the fiber, combining apolar binding with electrostatic interactions, whereas uncharged compounds slide along the cavity. We observed that different amyloid polymorphs bind different small molecules, revealing that a cocktail of compounds

  20. Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents.

    PubMed

    Turner, Nigel; Bruce, Clinton R; Beale, Susan M; Hoehn, Kyle L; So, Trina; Rolph, Michael S; Cooney, Gregory J

    2007-08-01

    A reduced capacity for mitochondrial fatty acid oxidation in skeletal muscle has been proposed as a major factor leading to the accumulation of intramuscular lipids and their subsequent deleterious effects on insulin action. Here, we examine markers of mitochondrial fatty acid oxidative capacity in rodent models of insulin resistance associated with an oversupply of lipids. C57BL/6J mice were fed a high-fat diet for either 5 or 20 weeks. Several markers of muscle mitochondrial fatty acid oxidative capacity were measured, including (14)C-palmitate oxidation, palmitoyl-CoA oxidation in isolated mitochondria, oxidative enzyme activity (citrate synthase, beta-hydroxyacyl CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, and carnitine palmitoyl-transferase 1), and expression of proteins involved in mitochondrial metabolism. Enzyme activity and mitochondrial protein expression were also examined in muscle from other rodent models of insulin resistance. Compared with standard diet-fed controls, muscle from fat-fed mice displayed elevated palmitate oxidation rate (5 weeks +23%, P < 0.05, and 20 weeks +29%, P < 0.05) and increased palmitoyl-CoA oxidation in isolated mitochondria (20 weeks +49%, P < 0.01). Furthermore, oxidative enzyme activity and protein expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, uncoupling protein (UCP) 3, and mitochondrial respiratory chain subunits were significantly elevated in fat-fed animals. A similar pattern was present in muscle of fat-fed rats, obese Zucker rats, and db/db mice, with increases observed for oxidative enzyme activity and expression of PGC-1alpha, UCP3, and subunits of the mitochondrial respiratory chain. These findings suggest that high lipid availability does not lead to intramuscular lipid accumulation and insulin resistance in rodents by decreasing muscle mitochondrial fatty acid oxidative capacity.

  1. Obesogenic environment by excess of dietary fats in different phases of development reduces spermatic efficiency of wistar rats at adulthood: correlations with metabolic status.

    PubMed

    Reame, Vanessa; Pytlowanciv, Eloísa Zanin; Ribeiro, Daniele Lisboa; Pissolato, Thiago Feres; Taboga, Sebastião Roberto; Góes, Rejane Maira; Pinto-Fochi, Maria Etelvina

    2014-12-01

    This study compares the impact of obesogenic environment (OE) in six different periods of development on sperm parameters and the testicular structure of adult rats and their correlations with sex steroid and metabolic scenario. Wistar rats were exposed to OE during gestation (O1), during gestation/lactation (O2), from weaning to adulthood (O3), from lactation to adulthood (O4), from gestation to sexual maturity (O5), and after sexual maturation (O6). OE was induced by a 20% fat diet, and control groups were fed a balanced diet (4% fat). Serum leptin levels and adiposity index indicate that all groups were obese, except for O1. Three progressive levels of impaired metabolic status were observed: O1 presented insulin resistance, O2 were insulin resistant and obese, and groups O3, O4, and O5 were insulin resistant, obese, and diabetic. These three levels of metabolic damage were proportional to the increase of leptin and decreased circulating testosterone. The impairment in the daily sperm production (DSP) paralleled these three levels of metabolic and hormonal damage being marginal in O1, increasing in O2, and being higher in groups O3, O4, O5, and O6. None of the OE periods affected the sperm transit time in the epididymis, and the lower sperm reserves were caused mainly by impaired DSP. In conclusion, OE during sexual maturation markedly reduces the DSP at adulthood in the rat. A severe reduction in the DSP also occurs in OE exposure during gestation/lactation but not in gestation, indicating that breast-feeding is a critical period for spermatogenic impairment under obesogenic conditions. © 2014 by the Society for the Study of Reproduction, Inc.

  2. Hacking the code of amyloid formation: the amyloid stretch hypothesis.

    PubMed

    Pastor, M Teresa; Esteras-Chopo, Alexandra; Serrano, Luis

    2007-01-01

    Many research efforts in the last years have been directed towards understanding the factors determining protein misfolding and amyloid formation. Protein stability and amino acid composition have been identified as the two major factors in vitro. The research of our group has been focused on understanding the relationship between amino acid sequence and amyloid formation. Our approach has been the design of simple model systems that reproduce the biophysical properties of natural amyloids. An amyloid sequence pattern was extracted that can be used to detect amyloidogenic hexapeptide stretches in proteins. We have added evidence supporting that these amyloidogenic stretches can trigger amyloid formation by nonamyloidogenic proteins. Some experimental results in other amyloid proteins will be analyzed under the conclusions obtained in these studies. Our conclusions together with evidences from other groups suggest that amyloid formation is the result of the interplay between a decrease of protein stability, and the presence of highly amyloidogenic regions in proteins. As many of these results have been obtained in vitro, the challenge for the next years will be to demonstrate their validity in in vivo systems.

  3. Matrix Metalloproteinase-9 Protects Islets from Amyloid-induced Toxicity*

    PubMed Central

    Meier, Daniel T.; Tu, Ling-Hsien; Zraika, Sakeneh; Hogan, Meghan F.; Templin, Andrew T.; Hull, Rebecca L.; Raleigh, Daniel P.; Kahn, Steven E.

    2015-01-01

    Deposition of human islet amyloid polypeptide (hIAPP, also known as amylin) as islet amyloid is a characteristic feature of the pancreas in type 2 diabetes, contributing to increased β-cell apoptosis and reduced β-cell mass. Matrix metalloproteinase-9 (MMP-9) is active in islets and cleaves hIAPP. We investigated whether hIAPP fragments arising from MMP-9 cleavage retain the potential to aggregate and cause toxicity, and whether overexpressing MMP-9 in amyloid-prone islets reduces amyloid burden and the resulting β-cell toxicity. Synthetic hIAPP was incubated with MMP-9 and the major hIAPP fragments observed by MS comprised residues 1–15, 1–25, 16–37, 16–25, and 26–37. The fragments 1–15, 1–25, and 26–37 did not form amyloid fibrils in vitro and they were not cytotoxic when incubated with β cells. Mixtures of these fragments with full-length hIAPP did not modulate the kinetics of fibril formation by full-length hIAPP. In contrast, the 16–37 fragment formed fibrils more rapidly than full-length hIAPP but was less cytotoxic. Co-incubation of MMP-9 and fragment 16–37 ablated amyloidogenicity, suggesting that MMP-9 cleaves hIAPP 16–37 into non-amyloidogenic fragments. Consistent with MMP-9 cleavage resulting in largely non-amyloidogenic degradation products, adenoviral overexpression of MMP-9 in amyloid-prone islets reduced amyloid deposition and β-cell apoptosis. These findings suggest that increasing islet MMP-9 activity might be a strategy to limit β-cell loss in type 2 diabetes. PMID:26483547

  4. Calnuc binds to Alzheimer's beta-amyloid precursor protein and affects its biogenesis.

    PubMed

    Lin, Ping; Li, Feng; Zhang, Yun-Wu; Huang, Haining; Tong, Gary; Farquhar, Marilyn Gist; Xu, Huaxi

    2007-03-01

    Calnuc, a Golgi calcium binding protein, plays a key role in the constitution of calcium storage. Abnormal calcium homeostasis has been linked to Alzheimer's disease (AD). Excessive production and/or accumulation of beta-amyloid (Abeta) peptides that are proteolytically derived from the beta-amyloid precursor protein (APP) have been linked to the pathogenesis of AD. APP has also been indicated to play multiple physiological functions. In this study, we demonstrate that calnuc interacts with APP through direct binding to the carboxyl-terminal region of APP, possibly in a calcium-sensitive manner. Immunofluorescence study revealed that the two proteins co-localize in the Golgi in both cultured cells and mouse brains. Over-expression of calnuc in neuroblastoma cells significantly reduces the level of endogenous APP. Conversely, down-regulation of calnuc by siRNA increases cellular levels of APP. Additionally, we show that over-expression of calnuc down-regulates the APP mRNA level and inhibits APP biosynthesis, which in turn results in a parallel reduction of APP proteolytic metabolites, sAPP, CTFs and Abeta. Furthermore, we found that the level of calnuc was significantly decreased in the brain of AD patients as compared with that of age-matched non-AD controls. Our results suggest a novel function of calnuc in modulating the levels of APP and its proteolytic metabolites, which may further affect the patho/physiological functions of APP including AD pathogenesis.

  5. Familial amyloid polyneuropathy.

    PubMed

    Planté-Bordeneuve, Violaine; Said, Gerard

    2011-12-01

    Familial amyloid polyneuropathies (FAPs) are a group of life-threatening multisystem disorders transmitted as an autosomal dominant trait. Nerve lesions are induced by deposits of amyloid fibrils, most commonly due to mutated transthyretin (TTR). Less often the precursor of amyloidosis is mutant apolipoprotein A-1 or gelsolin. The first identified cause of FAP-the TTR Val30Met mutation-is still the most common of more than 100 amyloidogenic point mutations identified worldwide. The penetrance and age at onset of FAP among people carrying the same mutation vary between countries. The symptomatology and clinical course of FAP can be highly variable. TTR FAP typically causes a nerve length-dependent polyneuropathy that starts in the feet with loss of temperature and pain sensations, along with life-threatening autonomic dysfunction leading to cachexia and death within 10 years on average. TTR is synthesised mainly in the liver, and liver transplantation seems to have a favourable effect on the course of neuropathy, but not on cardiac or eye lesions. Oral administration of tafamidis meglumine, which prevents misfolding and deposition of mutated TTR, is under evaluation in patients with TTR FAP. In future, patients with FAP might benefit from gene therapy; however, genetic counselling is recommended for the prevention of all types of FAP.

  6. Failure of Aβ(1-40) amyloid fibrils under tensile loading.

    PubMed

    Paparcone, Raffaella; Buehler, Markus J

    2011-05-01

    Amyloid fibrils and plaques are detected in the brain tissue of patients affected by Alzheimer's disease, but have also been found as part of normal physiological processes such as bacterial adhesion. Due to their highly organized structures, amyloid proteins have also been used for the development of nanomaterials, for a variety of applications including biomaterials for tissue engineering, nanolectronics, or optical devices. Past research on amyloid fibrils resulted in advances in identifying their mechanical properties, revealing a remarkable stiffness. However, the failure mechanism under tensile loading has not been elucidated yet, despite its importance for the understanding of key mechanical properties of amyloid fibrils and plaques as well as the growth and aggregation of amyloids into long fibers and plaques. Here we report a molecular level analysis of failure of amyloids under uniaxial tensile loading. Our molecular modeling results demonstrate that amyloid fibrils are extremely stiff with a Young's modulus in the range of 18-30 GPa, in good agreement with previous experimental and computational findings. The most important contribution of our study is our finding that amyloid fibrils fail at relatively small strains of 2.5%-4%, and at stress levels in the range of 1.02 to 0.64 GPa, in good agreement with experimental findings. Notably, we find that the strength properties of amyloid fibrils are extremely length dependent, and that longer amyloid fibrils show drastically smaller failure strains and failure stresses. As a result, longer fibrils in excess of hundreds of nanometers to micrometers have a greatly enhanced propensity towards spontaneous fragmentation and failure. We use a combination of simulation results and simple theoretical models to define critical fibril lengths where distinct failure mechanisms dominate.

  7. Engineering theranostic nanovehicles capable of targeting cerebrovascular amyloid deposits.

    PubMed

    Agyare, Edward K; Jaruszewski, Kristen M; Curran, Geoffry L; Rosenberg, Jens T; Grant, Samuel C; Lowe, Val J; Ramakrishnan, Subramanian; Paravastu, Anant K; Poduslo, Joseph F; Kandimalla, Karunya K

    2014-07-10

    Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid beta (Aβ) proteins within the walls of the cerebral vasculature with subsequent aggressive vascular inflammation leading to recurrent hemorrhagic strokes. The objective of the study was to develop theranostic nanovehicles (TNVs) capable of a) targeting cerebrovascular amyloid; b) providing magnetic resonance imaging (MRI) contrast for the early detection of CAA; and c) treating cerebrovascular inflammation resulting from CAA. The TNVs comprised of a polymeric nanocore made from Magnevist (MRI contrast agent) conjugated chitosan. The nanocore was also loaded with cyclophosphamide (CYC), an immunosuppressant shown to reduce the cerebrovascular inflammation in CAA. Putrescine modified F(ab')2 fragment of anti-amyloid antibody, IgG4.1 (pF(ab')24.1) was conjugated to the surface of the nanocore to target cerebrovascular amyloid. The average size of the control chitosan nanoparticles (conjugated with albumin and are devoid of Magnevist, CYC, and pF(ab')24.1) was 164±1.2 nm and that of the TNVs was 239±4.1 nm. The zeta potential values of the CCNs and TNVs were 21.6±1.7 mV and 11.9±0.5 mV, respectively. The leakage of Magnevist from the TNVs was a modest 0.2% over 4 days, and the CYC release from the TNVs followed Higuchi's model that describes sustained drug release from polymeric matrices. The studies conducted in polarized human microvascular endothelial cell monolayers (hCMEC/D3) in vitro as well as in mice in vivo have demonstrated the ability of TNVs to target cerebrovascular amyloid. In addition, the TNVs provided contrast for imaging cerebrovascular amyloid using MRI and single photon emission computed tomography. Moreover, the TNVs were shown to reduce pro-inflammatory cytokine production by the Aβ challenged blood brain barrier (BBB) endothelium more effectively than the cyclophosphamide alone.

  8. Peptide p5 binds both heparinase-sensitive glycosaminoglycans and fibrils in patient-derived AL amyloid extracts.

    PubMed

    Martin, Emily B; Williams, Angela; Heidel, Eric; Macy, Sallie; Kennel, Stephen J; Wall, Jonathan S

    2013-06-21

    In previously published work, we have described heparin-binding synthetic peptides that preferentially recognize amyloid deposits in a mouse model of reactive systemic (AA) amyloidosis and can be imaged by using positron and single photon emission tomographic imaging. We wanted to extend these findings to the most common form of visceral amyloidosis, namely light chain (AL); however, there are no robust experimental animal models of AL amyloidosis. To further define the binding of the lead peptide, p5, to AL amyloid, we characterized the reactivity in vitro of p5 with in situ and patient-derived AL amyloid extracts which contain both hypersulfated heparan sulfate proteoglycans as well as amyloid fibrils. Histochemical staining demonstrated that the peptide specifically localized with tissue-associated AL amyloid deposits. Although we anticipated that p5 would undergo electrostatic interactions with the amyloid-associated glycosaminoglycans expressing heparin-like side chains, no significant correlation between peptide binding and glycosaminoglycan content within amyloid extracts was observed. In contrast, following heparinase I treatment, although overall binding was reduced, a positive correlation between peptide binding and amyloid fibril content became evident. This interaction was further confirmed using synthetic light chain fibrils that contain no carbohydrates. These data suggest that p5 can bind to both the sulfated glycosaminoglycans and protein fibril components of AL amyloid. Understanding these complex electrostatic interactions will aid in the optimization of synthetic peptides for use as amyloid imaging agents and potentially as therapeutics for the treatment of amyloid diseases.

  9. Reducing Excessive Deadline Obligations Act of 2013

    THOMAS, 113th Congress

    Rep. Gardner, Cory [R-CO-4

    2013-06-06

    Senate - 01/13/2014 Received in the Senate and Read twice and referred to the Committee on Environment and Public Works. (All Actions) Tracker: This bill has the status Passed HouseHere are the steps for Status of Legislation:

  10. How can we reduce excessive prescribing?

    PubMed

    Griffiths, Matt

    2017-08-09

    Modern prescribing can be very easy. In many cases, we don't even have to write a prescription - just a few clicks can start a chain of events, affecting patients' lives more than we can imagine. Although it is easy to look for a quick pharmacological fix, consider carefully whether the patient really needs the medication you are prescribing.

  11. Reducing Excessive Deadline Obligations Act of 2013

    THOMAS, 113th Congress

    Rep. Gardner, Cory [R-CO-4

    2013-06-06

    01/13/2014 Received in the Senate and Read twice and referred to the Committee on Environment and Public Works. (All Actions) Tracker: This bill has the status Passed HouseHere are the steps for Status of Legislation:

  12. The effect of tachykinin neuropeptides on amyloid {beta} aggregation

    SciTech Connect

    Flashner, Efrat; Raviv, Uri; Friedler, Assaf

    2011-04-01

    Research highlights: {yields} Mechanistic explanation of how tachykinin neuropeptides reduce A{beta}-induced neurotoxicity. {yields} Biophysical studies suggest that tachykinins do not modulate the distribution of A{beta} oligomeric states, but rather may incorporate into the fibrils. {yields} A possible strategy to inhibit toxicity of amyloid fibrils. -- Abstract: A hallmark of Alzheimer's disease is production of amyloid {beta} peptides resulting from aberrant cleavage of the amyloid precursor protein. Amyloid {beta} assembles into fibrils under physiological conditions, through formation of neurotoxic intermediate oligomers. Tachykinin peptides are known to affect amyloid {beta} neurotoxicity in cells. To understand the mechanism of this effect, we studied how tachykinins affect A{beta}(1-40) aggregation in vitro. Fibrils grown in the presence of tachykinins exhibited reduced thioflavin T (ThT) fluorescence, while their morphology, observed in transmission electron microscopy (TEM), did not alter. Cross linking studies revealed that the distribution of low molecular weight species was not affected by tachykinins. Our results suggest that there may be a specific interaction between tachykinins and A{beta}(1-40) that allows them to co-assemble. This effect may explain the reduction of A{beta}(1-40) neurotoxicity in cells treated with tachykinins.

  13. Apoptosis Repressor With Caspase Recruitment Domain Ameliorates Amyloid-Induced β-Cell Apoptosis and JNK Pathway Activation.

    PubMed

    Templin, Andrew T; Samarasekera, Tanya; Meier, Daniel T; Hogan, Meghan F; Mellati, Mahnaz; Crow, Michael T; Kitsis, Richard N; Zraika, Sakeneh; Hull, Rebecca L; Kahn, Steven E

    2017-10-01

    Islet amyloid is present in more than 90% of individuals with type 2 diabetes, where it contributes to β-cell apoptosis and insufficient insulin secretion. Apoptosis repressor with caspase recruitment domain (ARC) binds and inactivates components of the intrinsic and extrinsic apoptosis pathways and was recently found to be expressed in islet β-cells. Using a human islet amyloid polypeptide transgenic mouse model of islet amyloidosis, we show ARC knockdown increases amyloid-induced β-cell apoptosis and loss, while ARC overexpression decreases amyloid-induced apoptosis, thus preserving β-cells. These effects occurred in the absence of changes in islet amyloid deposition, indicating ARC acts downstream of amyloid formation. Because islet amyloid increases c-Jun N-terminal kinase (JNK) pathway activation, we investigated whether ARC affects JNK signaling in amyloid-forming islets. We found ARC knockdown enhances JNK pathway activation, whereas ARC overexpression reduces JNK, c-Jun phosphorylation, and c-Jun target gene expression (Jun and Tnf). Immunoprecipitation of ARC from mouse islet lysates showed ARC binds JNK, suggesting interaction between JNK and ARC decreases amyloid-induced JNK phosphorylation and downstream signaling. These data indicate that ARC overexpression diminishes amyloid-induced JNK pathway activation and apoptosis in the β-cell, a strategy that may reduce β-cell loss in type 2 diabetes. © 2017 by the American Diabetes Association.

  14. Cerebral Amyloid Angiopathy: Emerging Concepts

    PubMed Central

    2015-01-01

    Cerebral amyloid angiopathy (CAA) involves cerebrovascular amyloid deposition and is classified into several types according to the amyloid protein involved. Of these, sporadic amyloid β-protein (Aβ)-type CAA is most commonly found in older individuals and in patients with Alzheimer's disease (AD). Cerebrovascular Aβ deposits accompany functional and pathological changes in cerebral blood vessels (CAA-associated vasculopathies). CAA-associated vasculopathies lead to development of hemorrhagic lesions [lobar intracerebral macrohemorrhage, cortical microhemorrhage, and cortical superficial siderosis (cSS)/focal convexity subarachnoid hemorrhage (SAH)], ischemic lesions (cortical infarction and ischemic changes of the white matter), and encephalopathies that include subacute leukoencephalopathy caused by CAA-associated inflammation/angiitis. Thus, CAA is related to dementia, stroke, and encephalopathies. Recent advances in diagnostic procedures, particularly neuroimaging, have enabled us to establish a clinical diagnosis of CAA without brain biopsies. Sensitive magnetic resonance imaging (MRI) methods, such as gradient-echo T2* imaging and susceptibility-weighted imaging, are useful for detecting cortical microhemorrhages and cSS. Amyloid imaging with amyloid-binding positron emission tomography (PET) ligands, such as Pittsburgh Compound B, can detect CAA, although they cannot discriminate vascular from parenchymal amyloid deposits. In addition, cerebrospinal fluid markers may be useful, including levels of Aβ40 for CAA and anti-Aβ antibody for CAA-related inflammation. Moreover, cSS is closely associated with transient focal neurological episodes (TFNE). CAA-related inflammation/angiitis shares pathophysiology with amyloid-related imaging abnormalities (ARIA) induced by Aβ immunotherapies in AD patients. This article reviews CAA and CAA-related disorders with respect to their epidemiology, pathology, pathophysiology, clinical features, biomarkers, diagnosis

  15. Peptide p5 binds both heparinase-sensitive glycosaminoglycans and fibrils in patient-derived AL amyloid extracts

    SciTech Connect

    Martin, Emily B.; Williams, Angela; Heidel, Eric; Macy, Sallie; Kennel, Stephen J.; Wall, Jonathan S.

    2013-06-21

    Highlights: •Polybasic peptide p5 binds human light chain amyloid extracts. •The binding of p5 with amyloid involves both glycosaminoglycans and fibrils. •Heparinase treatment led to a correlation between p5 binding and fibril content. •p5 binding to AL amyloid requires electrostatic interactions. -- Abstract: In previously published work, we have described heparin-binding synthetic peptides that preferentially recognize amyloid deposits in a mouse model of reactive systemic (AA) amyloidosis and can be imaged by using positron and single photon emission tomographic imaging. We wanted to extend these findings to the most common form of visceral amyloidosis, namely light chain (AL); however, there are no robust experimental animal models of AL amyloidosis. To further define the binding of the lead peptide, p5, to AL amyloid, we characterized the reactivity in vitro of p5 with in situ and patient-derived AL amyloid extracts which contain both hypersulfated heparan sulfate proteoglycans as well as amyloid fibrils. Histochemical staining demonstrated that the peptide specifically localized with tissue-associated AL amyloid deposits. Although we anticipated that p5 would undergo electrostatic interactions with the amyloid-associated glycosaminoglycans expressing heparin-like side chains, no significant correlation between peptide binding and glycosaminoglycan content within amyloid extracts was observed. In contrast, following heparinase I treatment, although overall binding was reduced, a positive correlation between peptide binding and amyloid fibril content became evident. This interaction was further confirmed using synthetic light chain fibrils that contain no carbohydrates. These data suggest that p5 can bind to both the sulfated glycosaminoglycans and protein fibril components of AL amyloid. Understanding these complex electrostatic interactions will aid in the optimization of synthetic peptides for use as amyloid imaging agents and potentially as

  16. Problems of Excess Capacity

    NASA Technical Reports Server (NTRS)

    Douglas, G.

    1972-01-01

    The problems of excess capacity in the airline industry are discussed with focus on the following topics: load factors; fair rate of return on investment; service-quality rivalry among airlines; pricing (fare) policies; aircraft production; and the impacts of excess capacity on operating costs. Also included is a discussion of the interrelationships among these topics.

  17. Invariant NKT cells modulate the suppressive activity of Serum Amyloid A-differentiated IL-10-secreting neutrophils

    PubMed Central

    De Santo, Carmela; Arscott, Ramon; Booth, Sarah; Karydis, Ioannis; Jones, Margaret; Asher, Ruth; Salio, Mariolina; Middleton, Mark; Cerundolo, Vincenzo

    2010-01-01

    Neutrophils are the primary effector cells during inflammation, but can also control excessive inflammatory responses by secreting anti-inflammatory cytokines. However, the mechanisms modulating their plasticity remain unclear. We now show that systemic serum amyloid A-1 (SAA-1) controls the plasticity of neutrophil differentiation. SAA-1 not only induced anti-inflammatory IL-10-secreting neutrophils but also promoted invariant NKT (iNKT) cell interaction with these neutrophils, a process that limits their suppressive activity by reducing IL-10 and enhancing IL-12 production. Because SAA-1-producing melanomas promote differentiation of IL-10-secreting neutrophils, harnessing iNKT cells could be useful therapeutically by reducing the frequency of immunosuppressive neutrophils and restoring tumor specific immune responses. PMID:20890286

  18. ABCA7 Mediates Phagocytic Clearance of Amyloid-β in the Brain.

    PubMed

    Fu, YuHong; Hsiao, Jen-Hsiang T; Paxinos, George; Halliday, Glenda M; Kim, Woojin Scott

    2016-09-06

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia and abnormal deposits of aggregated amyloid-β in the brain. Recent genome-wide association studies have revealed that ABCA7 is strongly associated with AD. In vitro evidence suggests that the role of ABCA7 is related to phagocytic activity. Deletion of ABCA7 in a mouse model of AD exacerbates cerebral amyloid-β plaque load. However, the biological role of ABCA7 in AD brain pathogenesis is unknown. We show that ABCA7 is highly expressed in microglia and when monocytes are differentiated into macrophages. We hypothesized that ABCA7 plays a protective role in the brain that is related to phagocytic clearance of amyloid-β. We isolated microglia and macrophages from Abca7-/- and wild type mice and tested them for their capacity to phagocytose amyloid-β oligomers. We found that the phagocytic clearance of amyloid-β was substantially reduced in both microglia and macrophages from Abca7-/- mice compared to wild type mice. Consistent with these results, in vivo phagocytic clearance of amyloid-β oligomers in the hippocampus was reduced in Abca7-/- mice. Furthermore, ABCA7 transcription was upregulated in AD brains and in amyloidogenic mouse brains specifically in the hippocampus as a response to the amyloid-β pathogenic state. Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD.

  19. Excessive Acquisition in Hoarding

    PubMed Central

    Frost, Randy O.; Tolin, David F.; Steketee, Gail; Fitch, Kristin E.; Selbo-Bruns, Alexandra

    2009-01-01

    Compulsive hoarding (the acquisition of and failure to discard large numbers of possessions) is associated with substantial health risk, impairment, and economic burden. However, little research has examined separate components of this definition, particularly excessive acquisition. The present study examined acquisition in hoarding. Participants, 878 self-identified with hoarding and 665 family informants (not matched to hoarding participants), completed an internet survey. Among hoarding participants who met criteria for clinically significant hoarding, 61% met criteria for a diagnosis of compulsive buying and approximately 85% reported excessive acquisition. Family informants indicated that nearly 95% exhibited excessive acquisition. Those who acquired excessively had more severe hoarding; their hoarding had an earlier onset and resulted in more psychiatric work impairment days; and they experienced more symptoms of obsessive-compulsive disorder, depression, and anxiety. Two forms of excessive acquisition (buying and free things) each contributed independent variance in the prediction of hoarding severity and related symptoms. PMID:19261435

  20. Excessive acquisition in hoarding.

    PubMed

    Frost, Randy O; Tolin, David F; Steketee, Gail; Fitch, Kristin E; Selbo-Bruns, Alexandra

    2009-06-01

    Compulsive hoarding (the acquisition of and failure to discard large numbers of possessions) is associated with substantial health risk, impairment, and economic burden. However, little research has examined separate components of this definition, particularly excessive acquisition. The present study examined acquisition in hoarding. Participants, 878 self-identified with hoarding and 665 family informants (not matched to hoarding participants), completed an Internet survey. Among hoarding participants who met criteria for clinically significant hoarding, 61% met criteria for a diagnosis of compulsive buying and approximately 85% reported excessive acquisition. Family informants indicated that nearly 95% exhibited excessive acquisition. Those who acquired excessively had more severe hoarding; their hoarding had an earlier onset and resulted in more psychiatric work impairment days; and they experienced more symptoms of obsessive-compulsive disorder, depression, and anxiety. Two forms of excessive acquisition (buying and free things) each contributed independent variance in the prediction of hoarding severity and related symptoms.

  1. Overexpression of heparanase lowers the amyloid burden in amyloid-β precursor protein transgenic mice.

    PubMed

    Jendresen, Charlotte B; Cui, Hao; Zhang, Xiao; Vlodavsky, Israel; Nilsson, Lars N G; Li, Jin-Ping

    2015-02-20

    Heparan sulfate (HS) and HS proteoglycans (HSPGs) colocalize with amyloid-β (Aβ) deposits in Alzheimer disease brain and in Aβ precursor protein (AβPP) transgenic mouse models. Heparanase is an endoglycosidase that specifically degrades the unbranched glycosaminoglycan side chains of HSPGs. The aim of this study was to test the hypothesis that HS and HSPGs are active participators of Aβ pathogenesis in vivo. We therefore generated a double-transgenic mouse model overexpressing both human heparanase and human AβPP harboring the Swedish mutation (tgHpa*Swe). Overexpression of heparanase did not affect AβPP processing because the steady-state levels of Aβ1-40, Aβ1-42, and soluble AβPP β were the same in 2- to 3-month-old double-transgenic tgHpa*Swe and single-transgenic tgSwe mice. In contrast, the Congo red-positive amyloid burden was significantly lower in 15-month-old tgHpa*Swe brain than in tgSwe brain. Likewise, the Aβ burden, measured by Aβx-40 and Aβx-42 immunohistochemistry, was reduced significantly in tgHpa*Swe brain. The intensity of HS-stained plaques correlated with the Aβx-42 burden and was reduced in tgHpa*Swe mice. Moreover, the HS-like molecule heparin facilitated Aβ1-42-aggregation in an in vitro Thioflavin T assay. The findings suggest that HSPGs contribute to amyloid deposition in tgSwe mice by increasing Aβ fibril formation because heparanase-induced fragmentation of HS led to a reduced amyloid burden. Therefore, drugs interfering with Aβ-HSPG interactions might be a potential strategy for Alzheimer disease treatment.

  2. Do proteomics analyses provide insights into reduced oxidative stress in the brain of an Alzheimer disease transgenic mouse model with an M631L amyloid precursor protein substitution and thereby the importance of amyloid-beta-resident methionine 35 in Alzheimer disease pathogenesis?

    PubMed

    Sultana, Rukhsana; Robinson, Renã A S; Lange, Miranda Bader; Fiorini, Ada; Galvan, Veronica; Fombonne, Joanna; Baker, Austin; Gorostiza, Olivia; Zhang, Junli; Cai, Jian; Pierce, William M; Bredesen, Dale E; Butterfield, D Allan

    2012-12-01

    The single methionine (Met/M) residue of amyloid-beta (Aβ) peptide, at position 35 of the 42-mer, has important relevance for Aβ-induced oxidative stress and neurotoxicity. Recent in vivo brain studies in a transgenic (Tg) Alzheimer disease (AD) mouse model with Swedish and Indiana familial AD mutations in human amyloid precursor protein (APP) (referred to as the J20 Tg mouse) demonstrated increased levels of oxidative stress. However, the substitution of the Met631 residue of APP to leucine (Leu/L) (M631L in human APP numbering, referred to as M631L Tg and corresponding to residue 35 of Aβ1-42) resulted in no significant in vivo oxidative stress levels, thereby supporting the hypothesis that Met-35 of Aβ contributes to oxidative insult in the AD brain. It is conceivable that oxidative stress mediated by Met-35 of Aβ is important in regulating numerous downstream effects, leading to differential levels of relevant biochemical pathways in AD. Therefore, in the current study using proteomics, we tested the hypothesis that several brain proteins involved in pathways such as energy and metabolism, antioxidant activity, proteasome degradation, and pH regulation are altered in J20Tg versus M631L Tg AD mice.

  3. Do Proteomics Analyses Provide Insights into Reduced Oxidative Stress in the Brain of an Alzheimer Disease Transgenic Mouse Model with an M631L Amyloid Precursor Protein Substitution and Thereby the Importance of Amyloid-Beta-Resident Methionine 35 in Alzheimer Disease Pathogenesis?

    PubMed Central

    Sultana, Rukhsana; Robinson, Renã A. S.; Bader Lange, Miranda; Fiorini, Ada; Galvan, Veronica; Fombonne, Joanna; Baker, Austin; Gorostiza, Olivia; Zhang, Junli; Cai, Jian; Pierce, William M.; Bredesen, Dale E.

    2012-01-01

    Abstract The single methionine (Met/M) residue of amyloid-beta (Aβ) peptide, at position 35 of the 42-mer, has important relevance for Aβ-induced oxidative stress and neurotoxicity. Recent in vivo brain studies in a transgenic (Tg) Alzheimer disease (AD) mouse model with Swedish and Indiana familial AD mutations in human amyloid precursor protein (APP) (referred to as the J20 Tg mouse) demonstrated increased levels of oxidative stress. However, the substitution of the Met631 residue of APP to leucine (Leu/L) (M631L in human APP numbering, referred to as M631L Tg and corresponding to residue 35 of Aβ1–42) resulted in no significant in vivo oxidative stress levels, thereby supporting the hypothesis that Met-35 of Aβ contributes to oxidative insult in the AD brain. It is conceivable that oxidative stress mediated by Met-35 of Aβ is important in regulating numerous downstream effects, leading to differential levels of relevant biochemical pathways in AD. Therefore, in the current study using proteomics, we tested the hypothesis that several brain proteins involved in pathways such as energy and metabolism, antioxidant activity, proteasome degradation, and pH regulation are altered in J20Tg versus M631L Tg AD mice. Antioxid. Redox Signal. 17, 1507–1514. PMID:22500616

  4. Contribution of human smooth muscle cells to amyloid angiopathy in AL (light-chain) amyloidosis.

    PubMed

    Vora, Moiz; Kevil, Christopher G; Herrera, Guillermo A

    2017-01-01

    Amyloid light-chain (AL) amyloidosis is a disease process that often compromises the peripheral vascular system and leads to systemic end-organ dysfunction. Although amyloid formation in vessel walls is a multifaceted process, the assembly of the native light chains (LCs) into amyloid fibrils is central to its pathogenesis. Recent evidence suggests that endocytosis and endolysosomal processing of immunoglobin LCs by host cells is essential to the formation of amyloid fibrils that are deposited in at least some tissues. The aim of this study was to elucidate the role of vascular smooth muscle in amyloid angiopathy. Human coronary artery smooth muscle cells (SMCs) were grown on coverslips, four chamber glass slides, and growth factor-reduced Matrigel matrix in the presence of 10 µg/ml of ALs (λ and κ isotypes), nonamyloidogenic LCs, and culture medium (negative control) for 48 and 72 hours. Thereafter, a detailed light microscopic, immunohistochemical, and ultrastructural evaluation was conducted to verify amyloid deposition and characterize the role of SMCs in the formation of amyloid deposits in the various experimental conditions. Amyloid deposits were detected extracellulary as early as 48 hours after exposure of vascular smooth muscle cells (VSMCs) to AL-LCs (amyloidogenic light chains) as confirmed by affinity to Congo red dye, thioflavin T fluorescence, and transmission electron microscopy. No amyloid was present in the cultures of SMCs treated with medium alone or nonamyloidogenic LCs. SMCs associated with amyloid deposits exhibited CD68, lysosome-associated membrane protein 1-1, and intracellular lambda light chain expression and only focal smooth muscle actin and muscle-specific actin positivity. Electron microscopy revealed these cells to have an expanded mature lysosomal compartment closely associated with deposits of newly formed amyloid fibrils. The interaction of amyloidogenic LCs with VSMCs is necessary for the formation of amyloid fibrils that are

  5. Alzheimer's abeta(1-40) amyloid fibrils feature size-dependent mechanical properties.

    PubMed

    Xu, Zhiping; Paparcone, Raffaella; Buehler, Markus J

    2010-05-19

    Amyloid fibrils are highly ordered protein aggregates that are associated with several pathological processes, including prion propagation and Alzheimer's disease. A key issue in amyloid science is the need to understand the mechanical properties of amyloid fibrils and fibers to quantify biomechanical interactions with surrounding tissues, and to identify mechanobiological mechanisms associated with changes of material properties as amyloid fibrils grow from nanoscale to microscale structures. Here we report a series of computational studies in which atomistic simulation, elastic network modeling, and finite element simulation are utilized to elucidate the mechanical properties of Alzheimer's Abeta(1-40) amyloid fibrils as a function of the length of the protein filament for both twofold and threefold symmetric amyloid fibrils. We calculate the elastic constants associated with torsional, bending, and tensile deformation as a function of the size of the amyloid fibril, covering fibril lengths ranging from nanometers to micrometers. The resulting Young's moduli are found to be consistent with available experimental measurements obtained from long amyloid fibrils, and predicted to be in the range of 20-31 GPa. Our results show that Abeta(1-40) amyloid fibrils feature a remarkable structural stability and mechanical rigidity for fibrils longer than approximately 100 nm. However, local instabilities that emerge at the ends of short fibrils (on the order of tens of nanometers) reduce their stability and contribute to their disassociation under extreme mechanical or chemical conditions, suggesting that longer amyloid fibrils are more stable. Moreover, we find that amyloids with lengths shorter than the periodicity of their helical pitch, typically between 90 and 130 nm, feature significant size effects of their bending stiffness due the anisotropy in the fibril's cross section. At even smaller lengths (50 nm), shear effects dominate lateral deformation of amyloid fibrils

  6. Hyperhidrosis (Excessive Sweating)

    MedlinePlus

    ... a cause (Alzheimer’s Association) Iontophoresis (the no-sweat machine) If excessive sweating affects your hands, feet, or ... this is an option, the dermatologist uses a machine that emits electromagnetic energy. This energy destroys the ...

  7. Amyloid-β Oligomers Interact with Neurexin and Diminish Neurexin-mediated Excitatory Presynaptic Organization

    PubMed Central

    Naito, Yusuke; Tanabe, Yuko; Lee, Alfred Kihoon; Hamel, Edith; Takahashi, Hideto

    2017-01-01

    Alzheimer’s disease (AD) is characterized by excessive production and deposition of amyloid-beta (Aβ) proteins as well as synapse dysfunction and loss. While soluble Aβ oligomers (AβOs) have deleterious effects on synapse function and reduce synapse number, the underlying molecular mechanisms are not well understood. Here we screened synaptic organizer proteins for cell-surface interaction with AβOs and identified a novel interaction between neurexins (NRXs) and AβOs. AβOs bind to NRXs via the N-terminal histidine-rich domain (HRD) of β-NRX1/2/3 and alternatively-spliced inserts at splicing site 4 of NRX1/2. In artificial synapse-formation assays, AβOs diminish excitatory presynaptic differentiation induced by NRX-interacting proteins including neuroligin1/2 (NLG1/2) and the leucine-rich repeat transmembrane protein LRRTM2. Although AβOs do not interfere with the binding of NRX1β to NLG1 or LRRTM2, time-lapse imaging revealed that AβO treatment reduces surface expression of NRX1β on axons and that this reduction depends on the NRX1β HRD. In transgenic mice expressing mutated human amyloid precursor protein, synaptic expression of β-NRXs, but not α-NRXs, decreases. Thus our data indicate that AβOs interact with NRXs and that this interaction inhibits NRX-mediated presynaptic differentiation by reducing surface expression of axonal β-NRXs, providing molecular and mechanistic insights into how AβOs lead to synaptic pathology in AD. PMID:28211900

  8. Centella asiatica extract selectively decreases amyloid beta levels in hippocampus of Alzheimer's disease animal model.

    PubMed

    Dhanasekaran, Muralikrishnan; Holcomb, Leigh A; Hitt, Angie R; Tharakan, Binu; Porter, Jami W; Young, Keith A; Manyam, Bala V

    2009-01-01

    PSAPP mice expressing the 'Swedish' amyloid precursor protein and the M146L presenilin 1 mutations are a well-characterized model for spontaneous amyloid beta plaque formation. Centella asiatica has a long history of use in India as a memory enhancing drug in Ayurvedic literature. The study investigated whether Centella asiatica extract (CaE) can alter the amyloid pathology in PSAPP mice by administering CaE (2.5 or 5.0 g/kg/day) starting at 2 months of age prior to the onset of detectable amyloid deposition and continued for either 2 months or 8 months. A significant decrease in amyloid beta 1-40 and 1-42 was detectable by ELISA following an 8 month treatment with 2.5 mg/kg of CaE. A reduction in Congo Red stained fibrillar amyloid plaques was detected with the 5.0 mg/kg CaE dose and long-term treatment regimen. It was also confirmed that CaE functions as an antioxidant in vitro, scavenging free radicals, reducing lipid peroxidation and protecting against DNA damage. The data indicate that CaE can impact the amyloid cascade altering amyloid beta pathology in the brains of PSAPP mice and modulating components of the oxidative stress response that has been implicated in the neurodegenerative changes that occur with Alzheimer's disease. Copyright 2008 John Wiley & Sons, Ltd.

  9. Porcine prion protein amyloid

    PubMed Central

    Hammarström, Per; Nyström, Sofie

    2015-01-01

    ABSTRACT Mammalian prions are composed of misfolded aggregated prion protein (PrP) with amyloid-like features. Prions are zoonotic disease agents that infect a wide variety of mammalian species including humans. Mammals and by-products thereof which are frequently encountered in daily life are most important for human health. It is established that bovine prions (BSE) can infect humans while there is no such evidence for any other prion susceptible species in the human food chain (sheep, goat, elk, deer) and largely prion resistant species (pig) or susceptible and resistant pets (cat and dogs, respectively). PrPs from these species have been characterized using biochemistry, biophysics and neurobiology. Recently we studied PrPs from several mammals in vitro and found evidence for generic amyloidogenicity as well as cross-seeding fibril formation activity of all PrPs on the human PrP sequence regardless if the original species was resistant or susceptible to prion disease. Porcine PrP amyloidogenicity was among the studied. Experimentally inoculated pigs as well as transgenic mouse lines overexpressing porcine PrP have, in the past, been used to investigate the possibility of prion transmission in pigs. The pig is a species with extraordinarily wide use within human daily life with over a billion pigs harvested for human consumption each year. Here we discuss the possibility that the largely prion disease resistant pig can be a clinically silent carrier of replicating prions. PMID:26218890

  10. Porcine prion protein amyloid.

    PubMed

    Hammarström, Per; Nyström, Sofie

    2015-01-01

    Mammalian prions are composed of misfolded aggregated prion protein (PrP) with amyloid-like features. Prions are zoonotic disease agents that infect a wide variety of mammalian species including humans. Mammals and by-products thereof which are frequently encountered in daily life are most important for human health. It is established that bovine prions (BSE) can infect humans while there is no such evidence for any other prion susceptible species in the human food chain (sheep, goat, elk, deer) and largely prion resistant species (pig) or susceptible and resistant pets (cat and dogs, respectively). PrPs from these species have been characterized using biochemistry, biophysics and neurobiology. Recently we studied PrPs from several mammals in vitro and found evidence for generic amyloidogenicity as well as cross-seeding fibril formation activity of all PrPs on the human PrP sequence regardless if the original species was resistant or susceptible to prion disease. Porcine PrP amyloidogenicity was among the studied. Experimentally inoculated pigs as well as transgenic mouse lines overexpressing porcine PrP have, in the past, been used to investigate the possibility of prion transmission in pigs. The pig is a species with extraordinarily wide use within human daily life with over a billion pigs harvested for human consumption each year. Here we discuss the possibility that the largely prion disease resistant pig can be a clinically silent carrier of replicating prions.

  11. Non-pharmacological interventions designed to reduce health risks due to unhealthy eating behaviour and linked risky or excessive drinking in adults aged 18-25 years: a systematic review protocol.

    PubMed

    Scott, Stephanie; Parkinson, Kathryn; Kaner, Eileen; Robalino, Shannon; Stead, Martine; Power, Christine; Fitzgerald, Niamh; Wrieden, Wendy; Adamson, Ashley

    2017-03-03

    Excess body weight and heavy alcohol consumption are two of the greatest contributors to global disease. Alcohol use peaks in early adulthood. Alcohol consumption can also exacerbate weight gain. A high body mass index and heavy drinking are independently associated with liver disease but, in combination, they produce an intensified risk of damage, with individuals from lower socio-economic status groups disproportionately affected. We will conduct searches in MEDLINE, Embase, PubMed, PsycINFO, ERIC, ASSIA, Web of Knowledge (WoK), Scopus, CINAHL via EBSCO, LILACS, CENTRAL and ProQuest Dissertations and Theses for studies that assess targeted preventative interventions of any length of time or duration of follow-up that are focused on reducing unhealthy eating behaviour and linked risky alcohol use in 18-25-year-olds. Primary outcomes will be reported changes in: (1) dietary, nutritional or energy intake and (2) alcohol consumption. We will include all randomised controlled trials (RCTs) including cluster RCTs; randomised trials; non-randomised controlled trials; interrupted time series; quasi-experimental; cohort involving concurrent or historical controls and controlled before and after studies. Database searches will be supplemented with searches of Google Scholar, hand searches of key journals and backward and forward citation searches of reference lists of identified papers. Search records will be independently screened by two researchers, with full-text copies of potentially relevant papers retrieved for in-depth review against the inclusion criteria. Methodological quality of RCTs will be evaluated using the Cochrane risk of bias tool. Other study designs will be evaluated using the Cochrane Public Health Review Group's recommended Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies. Studies will be pooled by meta-analysis and/or narrative synthesis as appropriate for the nature of the data retrieved. It is anticipated

  12. Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people

    PubMed Central

    Bennett, D; Schneider, J; Wilson, R; Bienias, J; Berry-Kravis, E; Arnold, S

    2005-01-01

    Background: The neurobiological changes underlying the association of the apolipoprotein E (APOE) e4 allele with level of cognition are poorly understood. Objective: To test the hypothesis that amyloid load can account for (mediate) the association of the APOE e4 allele with level of cognition assessed proximate to death. Methods: There were 44 subjects with clinically diagnosed Alzheimer's disease and 50 without dementia, who had participated in the Religious Orders Study. They underwent determination of APOE allele status, had comprehensive cognitive testing in the last year of life, and brain autopsy at death. The percentage area of cortex occupied by amyloid beta and the density of tau positive neurofibrillary tangles were quantified from six brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multiple regression analyses were used to examine whether amyloid load could account for the effect of allele status on level of cognition, controlling for age, sex, and education. Results: Possession of at least one APOE e4 allele was associated with lower level of cognitive function proximate to death (p = 0.04). The effect of the e4 allele was reduced by nearly 60% and was no longer significant after controlling for the effect of amyloid load, whereas there was a robust inverse association between amyloid and cognition (p = 0.001). Because prior work had suggested that neurofibrillary tangles could account for the association of amyloid on cognition, we next examined whether amyloid could account for the effect of allele status on tangles. In a series of regression analyses, e4 was associated with density of tangles (p = 0.002), but the effect of the e4 allele was reduced by more than 50% and was no longer significant after controlling for the effect of amyloid load. Conclusion: These findings are consistent with a sequence of events whereby the e4 allele works through amyloid deposition and subsequent tangle formation to

  13. Within-patient correspondence of amyloid-β and intrinsic network connectivity in Alzheimer’s disease

    PubMed Central

    Pasquini, Lorenzo; Göttler, Jens; Grimmer, Timo; Koch, Kathrin; Ortner, Marion; Neitzel, Julia; Mühlau, Mark; Förster, Stefan; Kurz, Alexander; Förstl, Hans; Zimmer, Claus; Wohlschläger, Afra M.; Riedl, Valentin; Drzezga, Alexander; Sorg, Christian

    2014-01-01

    intrinsic connectivity, indicating that amyloid-β pathology adversely reduces connectivity anywhere in an affected network as a function of local amyloid-β-plaque concentration. The local negative association between amyloid-β and intrinsic connectivity was much more pronounced than conventional group comparisons of intrinsic connectivity would suggest. Our findings indicate that the negative impact of amyloid-β on intrinsic connectivity in heteromodal networks is underestimated by conventional analyses. Moreover, our results provide first within-patient evidence for correspondent patterns of amyloid-β and intrinsic connectivity, with the distribution of amyloid-β pathology following functional connectivity gradients within and across intrinsic networks. PMID:24771519

  14. Study of amyloids using yeast

    PubMed Central

    Wickner, Reed B.; Kryndushkin, Dmitry; Shewmaker, Frank; McGlinchey, Ryan; Edskes, Herman K.

    2012-01-01

    Summary Saccharomyces cerevisiae has been a useful model organism in such fields as the cell cycle, regulation of transcription, protein trafficking and cell biology, primarily because of its ease of genetic manipulation. This is no less so in the area of amyloid studies. The endogenous yeast amyloids described to date include prions, infectious proteins (Table 1), and some cell wall proteins (1). and amyloids of humans and a fungal prion have also been studied using the yeast system. Accordingly, the emphasis of this chapter will be on genetic, biochemical, cell biological and physical methods particularly useful in the study of yeast prions and other amyloids studied in yeast. We limit our description of these methods to those aspects which have been most useful in studying yeast prions, citing more detailed expositions in the literature. Volumes on yeast genetics methods (2–4), and on amyloids and prions (5, 6) are useful, and Masison has edited a volume of Methods on “Identification, analysis and characterization of fungal prions” which covers some of this territory (7). We also outline some useful physical methods, pointing the reader to more extensive and authoratative descriptions. PMID:22528100

  15. Islet amyloid polypeptide (IAPP): a second amyloid in Alzheimer's disease.

    PubMed

    Fawver, Janelle N; Ghiwot, Yonatan; Koola, Catherine; Carrera, Wesley; Rodriguez-Rivera, Jennifer; Hernandez, Caterina; Dineley, Kelly T; Kong, Yu; Li, Jianrong; Jhamandas, Jack; Perry, George; Murray, Ian V J

    2014-01-01

    Amyloid formation is the pathological hallmark of type 2 diabetes (T2D) and Alzheimer's disease (AD). These diseases are marked by extracellular amyloid deposits of islet amyloid polypeptide (IAPP) in the pancreas and amyloid β (Aβ) in the brain. Since IAPP may enter the brain and disparate amyloids can cross-seed each other to augment amyloid formation, we hypothesized that pancreatic derived IAPP may enter the brain to augment misfolding of Aβ in AD. The corollaries for validity of this hypothesis are that IAPP [1] enters the brain, [2] augments Aβ misfolding, [3] associates with Aβ plaques, and most importantly [4] plasma levels correlate with AD diagnosis. We demonstrate the first 3 corollaries that: (1) IAPP is present in the brain in human cerebrospinal fluid (CSF), (2) synthetic IAPP promoted oligomerization of Aβ in vitro, and (3) endogenous IAPP localized to Aβ oligomers and plaques. For the 4th corollary, we did not observe correlation of peripheral IAPP levels with AD pathology in either an African American cohort or AD transgenic mice. In the African American cohort, with increased risk for both T2D and AD, peripheral IAPP levels were not significantly different in samples with no disease, T2D, AD, or both T2D and AD. In the Tg2576 AD mouse model, IAPP plasma levels were not significantly elevated at an age where the mice exhibit the glucose intolerance of pre-diabetes. Based on this negative data, it appears unlikely that peripheral IAPP cross-seeds or "infects" Aβ pathology in AD brain. However, we provide novel and additional data which demonstrate that IAPP protein is present in astrocytes in murine brain and secreted from primary cultured astrocytes. This preliminary report suggests a potential and novel association between brain derived IAPP and AD, however whether astrocytic derived IAPP cross-seeds Aβ in the brain requires further research.

  16. In Vivo Detection of Amyloid Plaques by Gadolinium-Stained MRI Can Be Used to Demonstrate the Efficacy of an Anti-amyloid Immunotherapy

    PubMed Central

    Santin, Mathieu D.; Vandenberghe, Michel E.; Herard, Anne-Sophie; Pradier, Laurent; Cohen, Caroline; Debeir, Thomas; Delzescaux, Thierry; Rooney, Thomas; Dhenain, Marc

    2016-01-01

    Extracellular deposition of β amyloid plaques is an early event associated to Alzheimer’s disease. Here, we have used in vivo gadolinium-stained high resolution (29∗29∗117 μm3) magnetic resonance imaging (MRI) to follow-up in a longitudinal way individual amyloid plaques in APP/PS1 mice and evaluate the efficacy of a new immunotherapy (SAR255952) directed against protofibrillar and fibrillary forms of Aβ. APP/PS1 mice were treated for 5 months between the age of 3.5 and 8.5 months. SAR255952 reduced amyloid load in 8.5-months-old animals, but not in 5.5-months animals compared to mice treated with a control antibody (DM4). Histological evaluation confirmed the reduction of amyloid load and revealed a lower density of amyloid plaques in 8.5-months SAR255952-treated animals. The longitudinal follow-up of individual amyloid plaques by MRI revealed that plaques that were visible at 5.5 months were still visible at 8.5 months in both SAR255952 and DM4-treated mice. This suggests that the amyloid load reduction induced by SAR255952 is related to a slowing down in the formation of new plaques rather than to the clearance of already formed plaques. PMID:27047372

  17. Reduction of Amyloid-β Plasma Levels by Hemodialysis: An Anti-Amyloid Treatment Strategy?

    PubMed

    Tholen, Susanne; Schmaderer, Christoph; Chmielewski, Stefan; Förstl, Hans; Heemann, Uwe; Baumann, Marcus; Steubl, Dominik; Grimmer, Timo

    2016-01-01

    Cognitive impairment in hemodialysis patients is common, but the underlying pathogenesis remains unclear. Alzheimer's disease is the most common cause of dementia in the general elderly population. Histopathological hallmarks are, among others, senile plaques, which consist of amyloid-β (Aβ). To measure plasma levels of Aβ42 and Aβ40 during hemodialysis and to examine potential associations with cognitive performance in cognitively impaired hemodialysis patients. Plasma samples of 26 hemodialysis patients were collected shortly before, after 50% of dialysis time, and at the end of a dialysis session. Aβ42 and Aβ40 levels were measured by a high-sensitivity ELISA for human amyloid-β. Cognition was tested under standardized conditions using the Montreal Cognitive Assessment (MoCA) as proposed previously. Clearance rates of both peptides during one dialysis session were 22% and 35% for Aβ42 and Aβ40, respectively. Aβ42 but not Aβ40 baseline levels were significantly associated with MoCA test results (r = 0.654, p = 0.001). In cognitively impaired hemodialysis patients plasma Aβ42 levels were associated with cognitive performance and both Aβ42 and Aβ40 plasma levels could be effectively reduced by dialysis. By inducing peripheral Aβ sink, hemodialysis may be considered as an anti-amyloid treatment strategy.

  18. Blocking the Apolipoprotein E/Amyloid β Interaction in Triple Transgenic Mice Ameliorates Alzheimer’s Disease Related Amyloid β and Tau Pathology

    PubMed Central

    Liu, Shan; Breitbart, Ariel; Sun, Yanjie; Mehta, Pankaj D.; Boutajangout, Allal; Scholtzova, Henrieta; Wisniewski, Thomas

    2013-01-01

    Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late-onset Alzheimer’s disease (AD). Studies have shown that the binding between apoE and amyloid-β (Aβ) peptides occurs at residues 244–272 of apoE and residues 12–28 of Aβ. ApoE4 has been implicated in promoting Aβ deposition and impairing clearance of Aβ. We hypothesized that blocking the apoE/Aβ interaction would serve as an effective new approach to AD therapy. We have previously shown that treatment with Aβ12–28P can reduce amyloid plaques in APP/PS1 transgenic (Tg) mice and vascular amyloid in TgSwDI mice with congophilic amyloid angiopathy (CAA). In the present study, we investigated whether the Aβ12–28P elicits a therapeutic effect on tau-related pathology in addition to amyloid pathology using old triple transgenic Alzheimer’s disease mice (3xTg, with PS1M146V, APPSwe and tauP30IL transgenes) with established pathology from the ages of 21 to 26 months. We show that treatment with Aβ12–28P substantially reduces tau pathology both immunohistochemically and biochemically, as well as reducing the amyloid burden and suppressing the activation of astrocytes and microglia. These affects correlate with a behavioral amelioration in the treated Tg mice. PMID:24117759

  19. RESTORED STREAMS ENHANCE ABILITY TO REMOVE EXCESS NITROGEN

    EPA Science Inventory

    Issue: Excess nitrogen from fertilizer, septic tanks, animal feedlots, and runoff from pavement can threaten human and aquatic ecosystem health. Furthermore, degraded ecosystems like those impacted by urbanization have reduced ability to process and remove excess nitrogen from t...

  20. RESTORED STREAMS ENHANCE ABILITY TO REMOVE EXCESS NITROGEN

    EPA Science Inventory

    Issue: Excess nitrogen from fertilizer, septic tanks, animal feedlots, and runoff from pavement can threaten human and aquatic ecosystem health. Furthermore, degraded ecosystems like those impacted by urbanization have reduced ability to process and remove excess nitrogen from t...

  1. A randomized, comparative pilot trial of family-based interpersonal psychotherapy for reducing psychosocial symptoms, disordered-eating, and excess weight gain in at-risk preadolescents with loss-of-control-eating.

    PubMed

    Shomaker, Lauren B; Tanofsky-Kraff, Marian; Matherne, Camden E; Mehari, Rim D; Olsen, Cara H; Marwitz, Shannon E; Bakalar, Jennifer L; Ranzenhofer, Lisa M; Kelly, Nichole R; Schvey, Natasha A; Burke, Natasha L; Cassidy, Omni; Brady, Sheila M; Dietz, Laura J; Wilfley, Denise E; Yanovski, Susan Z; Yanovski, Jack A

    2017-09-01

    Preadolescent loss-of-control-eating (LOC-eating) is a risk factor for excess weight gain and binge-eating-disorder. We evaluated feasibility and acceptability of a preventive family-based interpersonal psychotherapy (FB-IPT) program. FB-IPT was compared to family-based health education (FB-HE) to evaluate changes in children's psychosocial functioning, LOC-eating, and body mass. A randomized, controlled pilot trial was conducted with 29 children, 8 to 13 years who had overweight/obesity and LOC-eating. Youth-parent dyads were randomized to 12-week FB-IPT (n = 15) or FB-HE (n = 14) and evaluated at post-treatment, six-months, and one-year. Changes in child psychosocial functioning, LOC-eating, BMI, and adiposity by dual-energy-X-ray-absorptiometry were assessed. Missing follow-up data were multiply imputed. FB-IPT feasibility and acceptability were indicated by good attendance (83%) and perceived benefits to social interactions and eating. Follow-up assessments were completed by 73% FB-IPT and 86% FB-HE at post-treatment, 60% and 64% at six-months, and 47% and 57% at one-year. At post-treatment, children in FB-IPT reported greater decreases in depression (95% CI -7.23, -2.01, Cohen's d = 1.23) and anxiety (95% CI -6.08, -0.70, Cohen's d = .79) and less odds of LOC-eating (95% CI -3.93, -0.03, Cohen's d = .38) than FB-HE. At six-months, children in FB-IPT had greater reductions in disordered-eating attitudes (95% CI -0.72, -0.05, Cohen's d = .66) and at one-year, tended to have greater decreases in depressive symptoms (95% CI -8.82, 0.44, Cohen's d = .69) than FB-HE. There was no difference in BMI gain between the groups. Family-based approaches that address interpersonal and emotional underpinnings of LOC-eating in preadolescents with overweight/obesity show preliminary promise, particularly for reducing internalizing symptoms. Whether observed psychological benefits translate into sustained prevention of disordered-eating or excess

  2. Deamidation accelerates amyloid formation and alters amylin fiber structure

    PubMed Central

    Dunkelberger, Emily B.; Buchanan, Lauren E.; Marek, Peter; Cao, Ping; Raleigh, Daniel P.; Zanni, Martin T.

    2012-01-01

    Deamidation of asparagine and glutamine is the most common non-enzymatic, post-translational modification. Deamidation can influence the structure, stability, folding, and aggregation of proteins and has been proposed to play a role in amyloid formation. However there are no structural studies of the consequences of deamidation on amyloid fibers, in large part because of the difficulty of studying these materials using conventional methods. Here we examine the effects of deamidation on the kinetics of amyloid formation by amylin, the causative agent of type 2 diabetes. We find that deamidation accelerates amyloid formation and the deamidated material is able to seed amyloid formation by unmodified amylin. Using site-specific isotope labeling and two-dimensional infrared (2D IR) spectroscopy, we show that fibers formed by samples that contain deamidated polypeptide contain reduced amounts of β-sheet. Deamidation leads to disruption of the N-terminal β-sheet between Ala-8 and Ala-13, but β-sheet is still retained near Leu-16. The C-terminal sheet is disrupted near Leu-27. Analysis of potential sites of deamidation together with structural models of amylin fibers reveals that deamidation in the N-terminal β-sheet region may be the cause for the disruption of the fiber structure at both the N- and C-terminal β-sheet. Thus, deamidation is a post-translational modification that creates fibers which have an altered structure, but can still act as a template for amylin aggregation. Deamidation is very difficult to detect with standard methods used to follow amyloid formation, but isotope labeled IR spectroscopy provides a means for monitoring sample degradation and investigating the structural consequences of deamidation. PMID:22734583

  3. The biochemical aftermath of anti-amyloid immunotherapy

    PubMed Central

    2010-01-01

    Background Active and passive immunotherapy in both amyloid-beta precursor protein (APP) transgenic mice and Alzheimer's Disease (AD) patients have resulted in remarkable reductions in amyloid plaque accumulation, although the degree of amyloid regression has been highly variable. Nine individuals with a clinical diagnosis of AD dementia were actively immunized with the Aβ peptide 1-42 (AN-1792) and subjected to detailed postmortem biochemical analyses. These patients were compared to 6 non-immunized AD cases and 5 non-demented control (NDC) cases. Results All patients were assessed for the presence of AD pathology including amyloid plaques, neurofibrillary tangles and vascular amyloidosis. This effort revealed that two immunotherapy recipients had dementia as a consequence of diseases other than AD. Direct neuropathological examination consistently demonstrated small to extensive areas in which amyloid plaques apparently were disrupted. Characterization of Aβ species remnants by ELISA suggested that total Aβ levels may have been reduced, although because the amounts of Aβ peptides among treated individuals were extremely variable, those data must be regarded as tentative. Chromatographic analysis and Western blots revealed abundant dimeric Aβ peptides. SELDI-TOF mass spectrometry demonstrated a substantive number of Aβ-related peptides, some of them with elongated C-terminal sequences. Pro-inflammatory TNF-α levels were significantly increased in the gray matter of immunized AD cases compared to the NDC and non-immunized AD groups. Conclusions Immunotherapy responses were characterized by extreme variability. Considering the broad range of biological variation that characterizes aging and complicates the recognition of reliable AD biomarkers, such disparities will make the interpretation of outcomes derived from epidemiologic and therapeutic investigations challenging. Although in some cases the apparent removal of amyloid plaques by AN-1792 was impressive

  4. Microcin E492 Amyloid Formation Is Retarded by Posttranslational Modification

    PubMed Central

    Marcoleta, Andrés; Marín, Macarena; Mercado, Gabriela; Valpuesta, José María; Monasterio, Octavio

    2013-01-01

    Microcin E492, a channel-forming bacteriocin with the ability to form amyloid fibers, is exported as a mixture of two forms: unmodified (inactive) and posttranslationally modified at the C terminus with a salmochelin-like molecule, which is an essential modification for conferring antibacterial activity. During the stationary phase, the unmodified form accumulates because expression of the maturation genes mceIJ is turned off, and microcin E492 is rapidly inactivated. The aim of this work was to demonstrate that the increase in the proportion of unmodified microcin E492 augments the ability of this bacteriocin to form amyloid fibers, which in turn decreases antibacterial activity. To this end, strains with altered proportions of the two forms were constructed. The increase in the expression of the maturation genes augmented the antibacterial activity during all growth phases and delayed the loss of activity in the stationary phase, while the ability to form amyloid fibers was markedly reduced. Conversely, a higher expression of microcin E492 protein produced concomitant decreases in the levels of the modified form and in antibacterial activity and a substantial increase in the ability to form amyloid fibers. The same morphology for these fibers, including those formed by only the unmodified version, was observed. Moreover, seeds formed using exclusively the nonmodified form were remarkably more efficient in amyloid formation with a shorter lag phase, indicating that the nucleation process is probably improved. Unmodified microcin E492 incorporation into amyloid fibers was kinetically more efficient than the modified form, probably due to the existence of a conformation that favors this process. PMID:23836864

  5. A novel retro-inverso peptide inhibitor reduces amyloid deposition, oxidation and inflammation and stimulates neurogenesis in the APPswe/PS1ΔE9 mouse model of Alzheimer's disease.

    PubMed

    Parthsarathy, Vadivel; McClean, Paula L; Hölscher, Christian; Taylor, Mark; Tinker, Claire; Jones, Glynn; Kolosov, Oleg; Salvati, Elisa; Gregori, Maria; Masserini, Massimo; Allsop, David

    2013-01-01

    Previously, we have developed a retro-inverso peptide inhibitor (RI-OR2, rGffvlkGr) that blocks the in vitro formation and toxicity of the Aβ oligomers which are thought to be a cause of neurodegeneration and memory loss in Alzheimer's disease. We have now attached a retro-inverted version of the HIV protein transduction domain 'TAT' to RI-OR2 to target this new inhibitor (RI-OR2-TAT, Ac-rGffvlkGrrrrqrrkkrGy-NH(2)) into the brain. Following its peripheral injection, a fluorescein-labelled version of RI-OR2-TAT was found to cross the blood brain barrier and bind to the amyloid plaques and activated microglial cells present in the cerebral cortex of 17-months-old APPswe/PS1ΔE9 transgenic mice. Daily intraperitoneal injection of RI-OR2-TAT (at 100 nmol/kg) for 21 days into 10-months-old APPswe/PS1ΔE9 mice resulted in a 25% reduction (p<0.01) in the cerebral cortex of Aβ oligomer levels, a 32% reduction (p<0.0001) of β-amyloid plaque count, a 44% reduction (p<0.0001) in the numbers of activated microglial cells, and a 25% reduction (p<0.0001) in oxidative damage, while the number of young neurons in the dentate gyrus was increased by 210% (p<0.0001), all compared to control APPswe/PS1ΔE9 mice injected with vehicle (saline) alone. Our data suggest that oxidative damage, inflammation, and inhibition of neurogenesis are all a downstream consequence of Aβ aggregation, and identify a novel brain-penetrant retro-inverso peptide inhibitor of Aβ oligomer formation for further testing in humans as a potential disease-modifying treatment for Alzheimer's disease.

  6. [Excessive daytime sleepiness].

    PubMed

    Bittencourt, Lia Rita Azeredo; Silva, Rogério Santos; Santos, Ruth Ferreira; Pires, Maria Laura Nogueira; Mello, Marco Túlio de

    2005-05-01

    Sleepiness is a physiological function, and can be defined as increased propension to fall asleep. However, excessive sleepiness (ES) or hypersomnia refer to an abnormal increase in the probability to fall asleep, to take involuntary naps, or to have sleep atacks, when sleep is not desired. The main causes of excessive sleepiness is chronic sleep deprivation, sleep apnea syndrome, narcolepsy, movement disorders during sleep, circadian sleep disorders, use of drugs and medications, or idiopathic hypersomnia. Social, familial, work, and cognitive impairment are among the consequences of hypersomnia. Moreover, it has also been reported increased risk of accidents. The treatment of excessive sleepiness includes treating the primary cause, whenever identified. Sleep hygiene for sleep deprivation, positive pressure (CPAP) for sleep apnea, dopaminergic agents and exercises for sleep-related movement disorders, phototherapy and/or melatonin for circadian disorders, and use of stimulants are the treatment modalities of first choice.

  7. Interactions between a luminescent conjugated polyelectrolyte and amyloid fibrils investigated with flow linear dichroism spectroscopy.

    PubMed

    Wigenius, Jens; Andersson, Mats R; Esbjörner, Elin K; Westerlund, Fredrik

    2011-04-29

    Luminescent conjugated polyelectrolytes (LCPs) have emerged as novel stains to detect and distinguish between various amyloidogenic species, including prefibrillar aggregates and mature fibril deposits, both in vitro and in histological tissue samples, offering advantages over traditional amyloid stains. We here use linear dichroism (LD) spectroscopy under shear alignment to characterize interactions between the LCP poly(3-thiophene acetic acid) (PTAA) and amyloid fibrils. The positive signature in the LD spectrum of amyloid-bound PTAA suggests that it binds in the grooves between adjacent protein side-chains in the amyloid fibril core, parallel to the fibril axis, similar to thioflavin-T and congo red. Moreover, using LD we record the absorption spectrum of amyloid-bound PTAA in isolation from free dye showing a red-shift by ca 30 nm compared to in solution. This has important implications for the use of PTAA as an amyloid probe in situ and in vitro and we demonstrate how to obtain optimal amyloid-specific fluorescence read-outs using PTAA. We use the shift in maximum absorption to estimate the fraction of bound PTAA at a given concentration. PTAA binding reaches saturation when added in 36 times excess and at this concentration the PTAA density is 4-5 monomer units per insulin monomer in the fibril. Finally, we demonstrate that changes in LD intensity can be related to alterations in persistence length of amyloid fibrils resulting from changes in solution conditions, showing that this technique is useful to assess macroscopic properties of these biopolymers. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease

    PubMed Central

    Insel, Philip S.; Donohue, Michael; Landau, Susan; Jagust, William J.; Shaw, Leslie M.; Trojanowski, John Q.; Zetterberg, Henrik; Blennow, Kaj; Weiner, Michael W.

    2015-01-01

    Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal fluid total-tau and phosphorylated-tau levels (cross-sectionally); and hippocampal volume, fluorodeoxyglucose positron emission tomography results and Alzheimer's Disease Assessment Scale-cognitive subscale scores (longitudinally). Cerebrospinal fluid and positron emission tomography amyloid-β were highly correlated, but adjusting one of these predictors for the other revealed that they both provided partially independent information when predicting diagnosis, APOE ε4, hippocampal volume, metabolism, cognition, total-tau and phosphorylated-tau (the 95% confidence intervals of the adjusted effects did not include zero). Cerebrospinal fluid amyloid-β was more strongly related to APOE ε4 whereas positron emission tomography amyloid-β was more strongly related to tau levels (P < 0.05). Discordance (mainly isolated cerebrospinal fluid amyloid-β positivity) differed by diagnostic group (P < 0.001) and was seen in 21% of cognitively healthy people but only 6% in dementia patients. The finding that

  9. Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease.

    PubMed

    Mattsson, Niklas; Insel, Philip S; Donohue, Michael; Landau, Susan; Jagust, William J; Shaw, Leslie M; Trojanowski, John Q; Zetterberg, Henrik; Blennow, Kaj; Weiner, Michael W

    2015-03-01

    Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal fluid total-tau and phosphorylated-tau levels (cross-sectionally); and hippocampal volume, fluorodeoxyglucose positron emission tomography results and Alzheimer's Disease Assessment Scale-cognitive subscale scores (longitudinally). Cerebrospinal fluid and positron emission tomography amyloid-β were highly correlated, but adjusting one of these predictors for the other revealed that they both provided partially independent information when predicting diagnosis, APOE ε4, hippocampal volume, metabolism, cognition, total-tau and phosphorylated-tau (the 95% confidence intervals of the adjusted effects did not include zero). Cerebrospinal fluid amyloid-β was more strongly related to APOE ε4 whereas positron emission tomography amyloid-β was more strongly related to tau levels (P < 0.05). Discordance (mainly isolated cerebrospinal fluid amyloid-β positivity) differed by diagnostic group (P < 0.001) and was seen in 21% of cognitively healthy people but only 6% in dementia patients. The finding that

  10. Imaging of amyloid burden and distribution in cerebral amyloid angiopathy.

    PubMed

    Johnson, Keith A; Gregas, Matt; Becker, John A; Kinnecom, Catherine; Salat, David H; Moran, Erin K; Smith, Erin E; Rosand, Jonathan; Rentz, Dorene M; Klunk, William E; Mathis, Chester A; Price, Julie C; Dekosky, Steven T; Fischman, Alan J; Greenberg, Steven M

    2007-09-01

    Cerebrovascular deposition of beta-amyloid (cerebral amyloid angiopathy [CAA]) is a major cause of hemorrhagic stroke and a likely contributor to vascular cognitive impairment. We evaluated positron emission tomographic imaging with the beta-amyloid-binding compound Pittsburgh Compound B (PiB) as a potential noninvasive method for detection of CAA. We hypothesized that amyloid deposition would be observed with PiB in CAA, and based on the occipital predilection of CAA pathology and associated hemorrhages, that specific PiB retention would be disproportionately greater in occipital lobes. We compared specific cortical PiB retention in 6 nondemented subjects diagnosed with probable CAA with 15 healthy control subjects and 9 patients with probable Alzheimer's disease (AD). All CAA and AD subjects were PiB-positive, both by distribution volume ratio measurements and by visual inspection of positron emission tomographic images. Global cortical PiB retention was significantly increased in CAA (distribution volume ratio 1.18 +/- 0.06) relative to healthy control subjects (1.04 +/- 0.10; p = 0.0009), but was lower in CAA than in AD subjects (1.41 +/- 0.17; p = 0.002). The occipital-to-global PiB ratio, however, was significantly greater in CAA than in AD subjects (0.99 +/- 0.07 vs 0.86 +/- 0.05; p = 0.003). We conclude that PiB-positron emission tomography can detect cerebrovascular beta-amyloid and may serve as a method for identifying the extent of CAA in living subjects.

  11. Functional amyloid formation within mammalian tissue.

    PubMed

    Fowler, Douglas M; Koulov, Atanas V; Alory-Jost, Christelle; Marks, Michael S; Balch, William E; Kelly, Jeffery W

    2006-01-01

    Amyloid is a generally insoluble, fibrous cross-beta sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin-a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin) may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology.

  12. Nanomechanical properties of single amyloid fibrils

    NASA Astrophysics Data System (ADS)

    Sweers, K. K. M.; Bennink, M. L.; Subramaniam, V.

    2012-06-01

    Amyloid fibrils are traditionally associated with neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease or Creutzfeldt-Jakob disease. However, the ability to form amyloid fibrils appears to be a more generic property of proteins. While disease-related, or pathological, amyloid fibrils are relevant for understanding the pathology and course of the disease, functional amyloids are involved, for example, in the exceptionally strong adhesive properties of natural adhesives. Amyloid fibrils are thus becoming increasingly interesting as versatile nanobiomaterials for applications in biotechnology. In the last decade a number of studies have reported on the intriguing mechanical characteristics of amyloid fibrils. In most of these studies atomic force microscopy (AFM) and atomic force spectroscopy play a central role. AFM techniques make it possible to probe, at nanometer length scales, and with exquisite control over the applied forces, biological samples in different environmental conditions. In this review we describe the different AFM techniques used for probing mechanical properties of single amyloid fibrils on the nanoscale. An overview is given of the existing mechanical studies on amyloid. We discuss the difficulties encountered with respect to the small fibril sizes and polymorphic behavior of amyloid fibrils. In particular, the different conformational packing of monomers within the fibrils leads to a heterogeneity in mechanical properties. We conclude with a brief outlook on how our knowledge of these mechanical properties of the amyloid fibrils can be exploited in the construction of nanomaterials from amyloid fibrils.

  13. HIV Excess Cancers JNCI

    Cancer.gov

    In 2010, an estimated 7,760 new cancers were diagnosed among the nearly 900,000 Americans known to be living with HIV infection. According to the first comprehensive study in the United States, approximately half of these cancers were in excess of what wo

  14. Addiction as excessive appetite.

    PubMed

    Orford, J

    2001-01-01

    The excessive appetite model of addiction is summarized. The paper begins by considering the forms of excessive appetite which a comprehensive model should account for: principally, excessive drinking, smoking, gambling, eating, sex and a diverse range of drugs including at least heroin, cocaine and cannabis. The model rests, therefore, upon a broader concept of what constitutes addiction than the traditional, more restricted, and arguably misleading definition. The core elements of the model include: very skewed consumption distribution curves; restraint, control or deterrence; positive incentive learning mechanisms which highlight varied forms of rapid emotional change as rewards, and wide cue conditioning; complex memory schemata; secondary, acquired emotional regulation cycles, of which 'chasing', 'the abstinence violation effect' and neuroadaptation are examples; and the consequences of conflict. These primary and secondary processes, occurring within diverse sociocultural contexts, are sufficient to account for the development of a strong attachment to an appetitive activity, such that self-control is diminished, and behaviour may appear to be disease-like. Giving up excess is a natural consequence of conflict arising from strong and troublesome appetite. There is much supportive evidence that change occurs outside expert treatment, and that when it occurs within treatment the change processes are more basic and universal than those espoused by fashionable expert theories.

  15. Induction of murine AA amyloidosis by various homogeneous amyloid fibrils and amyloid-like synthetic peptides.

    PubMed

    Liu, Y; Cui, D; Hoshii, Y; Kawano, H; Une, Y; Gondo, T; Ishihara, T

    2007-11-01

    We investigated amyloid-enhancing factor (AEF) activity of amyloid fibrils extracted from amyloid-laden livers of mice, cow, cheetah, cat and swan. All amyloid fibrils were confirmed to be amyloid protein A (AA) by an immunohistochemical analysis. We found that these fibrils accelerated the deposition of amyloid in an experimental mouse model of AA amyloidosis. Furthermore, the degree of deposition was dependent on the concentration of fibrils. When we compared the minimal concentration of amyloid fibrils needed to induce deposition, we found that these fibrils showed different efficiencies. Murine amyloid fibril induced amyloid deposition more efficiently than cow, cat, cheetah or swan amyloid fibrils. These data suggest that amyloid deposition is preferentially induced by amyloid fibrils with the same primary sequence as the endogenous amyloid protein. We then analysed the AEF activity of synthetic peptides, synthesized corresponding to amino acids 1-15 of mouse SAA (mSAA), 2-15 of cow SAA (bSAA), 1-15 of cat SAA (cSAA), which was the same as cheetah, and the common amino acids 33-45 of these four SAA (aSAA). We found that mSAA, bSAA and cSAA formed amyloid-like fibrils in morphology and showed similar AEF properties to those of native amyloid fibrils. Although aSAA also formed highly ordered amyloid-like fibrils, it showed weaker AEF activity than the other synthetic fibrils. Our results indicate that amyloidosis is transmissible between species under certain conditions; however, the efficiency of amyloid deposition is species-specific and appears to be related to the primary amino acid sequence, especially the N-terminal segment of the amyloid protein.

  16. Molecular recycling within amyloid fibrils.

    PubMed

    Carulla, Natàlia; Caddy, Gemma L; Hall, Damien R; Zurdo, Jesús; Gairí, Margarida; Feliz, Miguel; Giralt, Ernest; Robinson, Carol V; Dobson, Christopher M

    2005-07-28

    Amyloid fibrils are thread-like protein aggregates with a core region formed from repetitive arrays of beta-sheets oriented parallel to the fibril axis. Such structures were first recognized in clinical disorders, but more recently have also been linked to a variety of non-pathogenic phenomena ranging from the transfer of genetic information to synaptic changes associated with memory. The observation that many proteins can convert into similar structures in vitro has suggested that this ability is a generic feature of polypeptide chains. Here we have probed the nature of the amyloid structure by monitoring hydrogen/deuterium exchange in fibrils formed from an SH3 domain using a combination of nuclear magnetic resonance spectroscopy and electrospray ionization mass spectrometry. The results reveal that under the conditions used in this study, exchange is dominated by a mechanism of dissociation and re-association that results in the recycling of molecules within the fibril population. This insight into the dynamic nature of amyloid fibrils, and the ability to determine the parameters that define this behaviour, have important implications for the design of therapeutic strategies directed against amyloid disease.

  17. Copernicus revisited: amyloid beta in Alzheimer's disease.

    PubMed

    Joseph, J; Shukitt-Hale, B; Denisova, N A; Martin, A; Perry, G; Smith, M A

    2001-01-01

    The beta-amyloid hypothesis of Alzheimer's Disease (AD) has dominated the thinking and research in this area for over a decade and a half. While there has been a great deal of effort in attempting to prove its centrality in this devastating disease, and while an enormous amount has been learned about its properties (e.g., putative toxicity, processing and signaling), Abeta has not proven to be both necessary and sufficient for the development, neurotoxicity, and cognitive deficits associated with this disease. Instead, the few treatments that are available have emerged from aging research and are primarily directed toward modification of acetylcholine levels. Clearly, it is time to rethink this position and to propose instead that future approaches should focus upon altering the age-related sensitivity of the neuronal environment to insults involving such factors as inflammation and oxidative stress. In other words "solve the problems of aging and by extension those of AD will also be reduced." This review is being submitted as a rather Lutherian attempt to "nail an alternative thesis" to the gate of the Church of the Holy Amyloid to open its doors to the idea that aging is the most pervasive element in this disease and Abeta is merely one of the planets.

  18. The otherness of sexuality: excess.

    PubMed

    Stein, Ruth

    2008-03-01

    The present essay, the second of a series of three, aims at developing an experience-near account of sexuality by rehabilitating the idea of excess and its place in sexual experience. It is suggested that various types of excess, such as excess of excitation (Freud), the excess of the other (Laplanche), excess beyond symbolization and the excess of the forbidden object of desire (Leviticus; Lacan) work synergistically to constitute the compelling power of sexuality. In addition to these notions, further notions of excess touch on its transformative potential. Such notions address excess that shatters psychic structures and that is actively sought so as to enable new ones to evolve (Bersani). Work is quoted that regards excess as a way of dealing with our lonely, discontinuous being by using the "excessive" cosmic energy circulating through us to achieve continuity against death (Bataille). Two contemporary analytic thinkers are engaged who deal with the object-relational and intersubjective vicissitudes of excess.

  19. An energy-reduced dietary pattern, including moderate protein and increased nonfat dairy intake combined with walking promotes beneficial body composition and metabolic changes in women with excess adiposity: a randomized comparative trial

    PubMed Central

    Shlisky, Julie D; Durward, Carrie M; Zack, Melissa K; Gugger, Carolyn K; Campbell, Jessica K; Nickols-Richardson, Sharon M

    2015-01-01

    Moderate protein and nonfat dairy intake within an energy-reduced diet (ERD) may contribute to health benefits achieved with body weight (BW) loss. The current study examined the effectiveness of a weight-loss/weight-loss maintenance intervention using an ERD with moderate dietary protein (30% of kcals) and increased nonfat dairy intake (4–5 svg/d), including yogurt (INT group) and daily walking compared to an ERD with standard protein (16–17% of kcals) and standard nonfat dairy intake (3 svg/d) (COM group) with daily walking. A randomized comparative trial with 104 healthy premenopausal women with overweight/obesity was conducted in a university setting. Women were randomized to INT group or COM group. Anthropometric measurements, as well as dietary intake, selected vital signs, resting energy expenditure, blood lipids, glucose, insulin, and selected adipose-derived hormones were measured at baseline, and weeks 2, 12, and 24. Targets for dietary protein and nonfat dairy intake, while initially achieved, were not sustained in the INT group. There were no significant effects of diet group on anthropometric measurements. Women in the INT group and COM group, respectively, reduced BW (−4.9 ± 3.2 and −4.3 ± 3.3 kg, P < 0.001) and fat mass (−3.0 ± 2.2 and −2.3 ± 2.3 kg, P < 0.001) during the 12-week weight-loss phase and maintained these losses at 24 weeks. Both groups experienced significant decreases in body mass index, fat-free soft tissue mass, body fat percentage, waist and hip circumferences and serum triglycerides, total cholesterol, and leptin (all P < 0.001). Healthy premenopausal women with excess adiposity effectively lost BW and fat mass and improved some metabolic risk factors following an ERD with approximately 20% protein and 3 svg/d of nonfat dairy intake. PMID:26405524

  20. Three-year follow-up of a randomised controlled trial to reduce excessive weight gain in the first two years of life: protocol for the POI follow-up study.

    PubMed

    Taylor, Rachael W; Heath, Anne-Louise M; Galland, Barbara C; Cameron, Sonya L; Lawrence, Julie A; Gray, Andrew R; Tannock, Gerald W; Lawley, Blair; Healey, Dione; Sayers, Rachel M; Hanna, Maha; Meredith-Jones, Kim; Hatch, Burt; Taylor, Barry J

    2016-08-11

    The Prevention of Overweight in Infancy (POI) study was a four-arm randomised controlled trial (RCT) in 802 families which assessed whether additional education and support on sleep (Sleep group); food, physical activity and breastfeeding (FAB group); or both (Combination group), reduced excessive weight gain from birth to 2 years of age, compared to usual care (Control group). The study had high uptake at recruitment (58 %) and retention at 2 years (86 %). Although the FAB intervention produced no significant effect on BMI or weight status at 2 years, the odds of obesity were halved in those who received the sleep intervention, despite no apparent effect on sleep duration. We speculate that enhanced self-regulatory behaviours may exist in the Sleep group. Self-regulation was not measured in our initial intervention, but extensive measures have been included in this follow-up study. Thus, the overall aim of the POI follow-up is to determine the extent to which augmented parental support and education on infant sleep, feeding, diet, and physical activity in the first 2 years of life reduces BMI at 3.5 and 5 years of age, and to determine the role of self-regulation in any such relationship. We will contact all 802 families and seek renewed consent to participate in the follow-up study. The families have received no POI intervention since the RCT finished at 2 years of age. Follow-up data collection will occur when the children are aged 3.5 and 5 years (i.e. up to 3 years post-intervention). Outcomes of interest include child anthropometry, body composition (DXA scan), diet (validated food frequency questionnaire), physical activity (accelerometry), sleep (questionnaire and accelerometry), and self-regulation (questionnaires and neuropsychological assessment). Our follow-up study has been designed primarily to enable us to determine whether the intriguing benefit of the sleep intervention suggested at 2 years of age remains as children approach school age

  1. An energy-reduced dietary pattern, including moderate protein and increased nonfat dairy intake combined with walking promotes beneficial body composition and metabolic changes in women with excess adiposity: a randomized comparative trial.

    PubMed

    Shlisky, Julie D; Durward, Carrie M; Zack, Melissa K; Gugger, Carolyn K; Campbell, Jessica K; Nickols-Richardson, Sharon M

    2015-09-01

    Moderate protein and nonfat dairy intake within an energy-reduced diet (ERD) may contribute to health benefits achieved with body weight (BW) loss. The current study examined the effectiveness of a weight-loss/weight-loss maintenance intervention using an ERD with moderate dietary protein (30% of kcals) and increased nonfat dairy intake (4-5 svg/d), including yogurt (INT group) and daily walking compared to an ERD with standard protein (16-17% of kcals) and standard nonfat dairy intake (3 svg/d) (COM group) with daily walking. A randomized comparative trial with 104 healthy premenopausal women with overweight/obesity was conducted in a university setting. Women were randomized to INT group or COM group. Anthropometric measurements, as well as dietary intake, selected vital signs, resting energy expenditure, blood lipids, glucose, insulin, and selected adipose-derived hormones were measured at baseline, and weeks 2, 12, and 24. Targets for dietary protein and nonfat dairy intake, while initially achieved, were not sustained in the INT group. There were no significant effects of diet group on anthropometric measurements. Women in the INT group and COM group, respectively, reduced BW (-4.9 ± 3.2 and -4.3 ± 3.3 kg, P < 0.001) and fat mass (-3.0 ± 2.2 and -2.3 ± 2.3 kg, P < 0.001) during the 12-week weight-loss phase and maintained these losses at 24 weeks. Both groups experienced significant decreases in body mass index, fat-free soft tissue mass, body fat percentage, waist and hip circumferences and serum triglycerides, total cholesterol, and leptin (all P < 0.001). Healthy premenopausal women with excess adiposity effectively lost BW and fat mass and improved some metabolic risk factors following an ERD with approximately 20% protein and 3 svg/d of nonfat dairy intake.

  2. Disruption of Functional Connectivity in Clinically Normal Older Adults Harboring Amyloid Burden

    PubMed Central

    Hedden, Trey; Van Dijk, Koene R. A.; Becker, J. Alex; Mehta, Angel; Sperling, Reisa A.; Johnson, Keith A.; Buckner, Randy L.

    2009-01-01

    Amyloid deposition is present in 20–50% of nondemented older adults yet the functional consequences remain unclear. The current study found that amyloid accumulation is correlated with functional disruption of the default network as measured by intrinsic activity correlations. Clinically normal participants (n=38, aged 60–88) were characterized using [11C]-Pittsburgh Compound B (PiB) PET imaging to estimate fibrillar amyloid burden and, separately, underwent functional MRI (fMRI). The integrity of the default network was estimated by correlating rest-state fMRI time courses extracted from a priori regions including the posterior cingulate, lateral parietal, and medial prefrontal cortices. Clinically normal participants with high amyloid burden displayed significantly reduced functional correlations within the default network relative to participants with low amyloid burden. These reductions were also observed when amyloid burden was treated as a continuous, rather than a dichotomous, measure and when controlling for age and structural atrophy. Whole-brain analyses initiated by seeding the posterior cingulate cortex, a region of high amyloid burden in Alzheimer1s disease (AD), revealed significant disruption in the default network including functional disconnection of the hippocampal formation. PMID:19812343

  3. Amyloid Features and Neuronal Toxicity of Mature Prion Fibrils Are Highly Sensitive to High Pressure*

    PubMed Central

    El Moustaine, Driss; Perrier, Veronique; Van Ba, Isabelle Acquatella-Tran; Meersman, Filip; Ostapchenko, Valeriy G.; Baskakov, Ilia V.; Lange, Reinhard; Torrent, Joan

    2011-01-01

    Prion proteins (PrP) can aggregate into toxic and possibly infectious amyloid fibrils. This particular macrostructure confers on them an extreme and still unexplained stability. To provide mechanistic insights into this self-assembly process, we used high pressure as a thermodynamic tool for perturbing the structure of mature amyloid fibrils that were prepared from recombinant full-length mouse PrP. Application of high pressure led to irreversible loss of several specific amyloid features, such as thioflavin T and 8-anilino-1-naphthalene sulfonate binding, alteration of the characteristic proteinase K digestion pattern, and a significant decrease in the β-sheet structure and cytotoxicity of amyloid fibrils. Partial disaggregation of the mature fibrils into monomeric soluble PrP was observed. The remaining amyloid fibrils underwent a change in secondary structure that led to morphologically different fibrils composed of a reduced number of proto-filaments. The kinetics of these reactions was studied by recording the pressure-induced dissociation of thioflavin T from the amyloid fibrils. Analysis of the pressure and temperature dependence of the relaxation rates revealed partly unstructured and hydrated kinetic transition states and highlighted the importance of collapsing and hydrating inter- and intramolecular cavities to overcome the high free energy barrier that stabilizes amyloid fibrils. PMID:21357423

  4. The contribution of neuroinflammation to amyloid toxicity in Alzheimer's disease.

    PubMed

    Minter, Myles R; Taylor, Juliet M; Crack, Peter J

    2016-02-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. Deposition of amyloid-β (Aβ) remains a hallmark feature of the disease, yet the precise mechanism(s) by which this peptide induces neurotoxicity remain unknown. Neuroinflammation has long been implicated in AD pathology, yet its contribution to disease progression is still not understood. Recent evidence suggests that various Aβ complexes interact with microglial and astrocytic expressed pattern recognition receptors that initiate innate immunity. This process involves secretion of pro-inflammatory cytokines, chemokines and generation of reactive oxygen species that, in excess, drive a dysregulated immune response that contributes to neurodegeneration. The mechanisms by which a neuroinflammatory response can influence Aβ production, aggregation and eventual clearance are now becoming key areas where future therapeutic intervention may slow progression of AD. This review will focus on evidence supporting the combined neuroinflammatory-amyloid hypothesis for pathogenesis of AD, describing the key cell types, pathways and mediators involved. Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. Deposition of intracellular plaques containing amyloid-beta (Aβ) is a hallmark proteinopathy of the disease yet the precise mechanisms by which this peptide induces neurotoxicity remains unknown. A neuroinflammatory response involving polarized microglial activity, enhanced astrocyte reactivity and elevated pro-inflammatory cytokine and chemokine load has long been implicated in AD and proposed to facilitate neurodegeneration. In this issue we discuss key receptor systems of innate immunity that detect Aβ, drive pro-inflammatory cytokine and chemokine production and influence Aβ aggregation and clearance. Evidence summarized in this review supports the combined neuroinflammatory-amyloid hypothesis for

  5. β-cell loss and β-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition.

    PubMed

    Jurgens, Catherine A; Toukatly, Mirna N; Fligner, Corinne L; Udayasankar, Jayalakshmi; Subramanian, Shoba L; Zraika, Sakeneh; Aston-Mourney, Kathryn; Carr, Darcy B; Westermark, Per; Westermark, Gunilla T; Kahn, Steven E; Hull, Rebecca L

    2011-06-01

    Amyloid deposition and reduced β-cell mass are pathological hallmarks of the pancreatic islet in type 2 diabetes; however, whether the extent of amyloid deposition is associated with decreased β-cell mass is debated. We investigated the possible relationship and, for the first time, determined whether increased islet amyloid and/or decreased β-cell area quantified on histological sections is correlated with increased β-cell apoptosis. Formalin-fixed, paraffin-embedded human pancreas sections from subjects with (n = 29) and without (n = 39) diabetes were obtained at autopsy (64 ± 2 and 70 ± 4 islets/subject, respectively). Amyloid and β cells were visualized by thioflavin S and insulin immunolabeling. Apoptotic β cells were detected by colabeling for insulin and by TUNEL. Diabetes was associated with increased amyloid deposition, decreased β-cell area, and increased β-cell apoptosis, as expected. There was a strong inverse correlation between β-cell area and amyloid deposition (r = -0.42, P < 0.001). β-Cell area was selectively reduced in individual amyloid-containing islets from diabetic subjects, compared with control subjects, but amyloid-free islets had β-cell area equivalent to islets from control subjects. Increased amyloid deposition was associated with β-cell apoptosis (r = 0.56, P < 0.01). Thus, islet amyloid is associated with decreased β-cell area and increased β-cell apoptosis, suggesting that islet amyloid deposition contributes to the decreased β-cell mass that characterizes type 2 diabetes. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  6. Long-Term Treatment of Thalidomide Ameliorates Amyloid-Like Pathology through Inhibition of β-Secretase in a Mouse Model of Alzheimer’s Disease

    PubMed Central

    He, Ping; Cheng, Xin; Staufenbiel, Matthias; Li, Rena; Shen, Yong

    2013-01-01

    Thalidomide is a tumor necrosis factor alpha (TNFα) inhibitor which has been found to have abilities against tumor growth, angiogenesis and inflammation. Recently, it has been applied in clinic for the treatment of multiple myeloma as well as some inflammatory diseases. However, whether thalidomide has any therapeutic effects on neurodegenerative disorders, i.e. Alzheimer’s disease (AD) is not clear. AD is characterized by excessive amount of amyloid β peptides (Aβ), which results in a significant release of inflammatory factors, including TNFα in the brain. Studies have shown that inhibition of TNFα reduces amyloid-associated pathology, prevents neuron loss and improves cognition. Our recent report showed that genetic inhibition of TNFα/TNF receptor signal transduction down-regulates β amyloid cleavage enzyme 1 (BACE1) activity, reduces Aβ generation and improves learning and memory deficits. However, the mechanism of thalidomide involving in the mitigation of AD neuropathological features remains unclear. Here, we chronically administrated thalidomide on human APPswedish mutation transgenic (APP23) mice from 9 months old (an onset of Aβ deposits and early stage of AD-like changes) to 12 months old. We found that, in addition of dramatic decrease in the activation of both astrocytes and microglia, thalidomide significantly reduces Aβ load and plaque formation. Furthermore, we found a significant decrease in BACE1 level and activity with long-term thalidomide application. Interestingly, these findings cannot be observed in the brains of 12-month-old APP23 mice with short-term treatment of thalidomide (3 days). These results suggest that chronic thalidomide administration is an alternative approach for AD prevention and therapeutics. PMID:23405115

  7. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus.

    PubMed

    Westermark, Per; Andersson, Arne; Westermark, Gunilla T

    2011-07-01

    Islet amyloid polypeptide (IAPP, or amylin) is one of the major secretory products of β-cells of the pancreatic islets of Langerhans. It is a regulatory peptide with putative function both locally in the islets, where it inhibits insulin and glucagon secretion, and at distant targets. It has binding sites in the brain, possibly contributing also to satiety regulation and inhibits gastric emptying. Effects on several other organs have also been described. IAPP was discovered through its ability to aggregate into pancreatic islet amyloid deposits, which are seen particularly in association with type 2 diabetes in humans and with diabetes in a few other mammalian species, especially monkeys and cats. Aggregated IAPP has cytotoxic properties and is believed to be of critical importance for the loss of β-cells in type 2 diabetes and also in pancreatic islets transplanted into individuals with type 1 diabetes. This review deals both with physiological aspects of IAPP and with the pathophysiological role of aggregated forms of IAPP, including mechanisms whereby human IAPP forms toxic aggregates and amyloid fibrils.

  8. Early identification of amyloid heart disease by technetium-99m-pyrophosphate scintigraphy: a study with familial amyloid polyneuropathy

    SciTech Connect

    Hongo, M.; Hirayama, J.; Fujii, T.; Yamada, H.; Okubo, S.; Kusama, S.; Ikeda, S.

    1987-03-01

    To determine whether technetium-99m-pyrophosphate (Tc-99m-PYP) scanning or two-dimensional echocardiography can detect amyloid heart disease in an earlier stage of familial amyloid polyneuropathy, 15 patients were examined. Although 10 of the 15 patients had no clinical evidence of congestive heart failure, as well as normal ventricular wall thickness and normal values for left ventricular systolic function, five (50%) of them showed mild or moderate myocardial uptake. On the other hand, none had characteristic highly refractile myocardial echoes on the two-dimensional echocardiographic images (p less than 0.01), and values for diastolic function were reduced in four of the five and normal in the remaining one. In 85 control subjects, diffuse positive pyrophosphate scans of the heart were found in four (5%) of them (three with dilated cardiomyopathy and one with sarcoidosis), and highly refractile granular sparkling echoes were observed in nine (11%) (five with hypertrophic cardiomyopathy, three with aortic stenosis, and one with hypereosinophilic syndrome). We conclude that Tc-99m-PYP scanning is a more sensitive and specific method and may have the potential ability to detect amyloid heart disease in the earlier stage of familial amyloid polyneuropathy than two-dimensional echocardiography.

  9. PSD-93 Attenuates Amyloid-β-Mediated Cognitive Dysfunction by Promoting the Catabolism of Amyloid-β.

    PubMed

    Yu, Linjie; Liu, Yi; Yang, Hui; Zhu, Xiaolei; Cao, Xiang; Gao, Jun; Zhao, Hui; Xu, Yun

    2017-01-01

    Amyloid-β (Aβ) is a key neuropathological hallmark of Alzheimer's disease (AD). Postsynaptic density protein 93 (PSD-93) is a key scaffolding protein enriched at postsynaptic sites. The aim of the present study was to examine whether PSD-93 overexpression could alleviate Aβ-induced cognitive dysfunction in APPswe/PS1dE9 (APP/PS1) mice by reducing Aβ levels in the brain. The level of PSD-93 was significantly decreased in the hippocampus of 6-month-old APP/PS1 mice compared with that in wild-type mice. Following lentivirus-mediated PSD-93 overexpression, cognitive function, synaptic function, and amyloid burden were investigated. The open field test, Morris water maze test, and fear condition test revealed that PSD-93 overexpression ameliorated spatial memory deficits in APP/PS1 mice. The facilitation of long-term potentiation induction was observed in APP/PS1 mice after PSD-93 overexpression. The expression of somatostatin receptor 4 (SSTR4) and neprilysin was increased, while the amyloid plaque load and Aβ levels were decreased in the brains of APP/PS1 mice. Moreover, PSD-93 interacted with SSTR4 and affected the level of SSTR4 on cell membrane, which was associated with the ubiquitination. Together, these findings suggest that PSD-93 attenuates spatial memory deficits and decreases amyloid levels in APP/PS1 mice, which might be associated with Aβ catabolism, and overexpression of PSD-93 might be a potential therapy for AD.

  10. Diagnostic performance of amyloid A protein quantification in fat tissue of patients with clinical AA amyloidosis.

    PubMed

    Hazenberg, Bouke P C; Bijzet, Johan; Limburg, Pieter C; Skinner, Martha; Hawkins, Philip N; Butrimiene, Irena; Livneh, Avi; Lesnyak, Olga; Nasonov, Evgeney L; Filipowicz-Sosnowska, Anna; Gül, Ahmet; Merlini, Giampaolo; Wiland, Piotr; Ozdogan, Huri; Gorevic, Peter D; Maïz, Hédi Ben; Benson, Merrill D; Direskeneli, Haner; Kaarela, Kalevi; Garceau, Denis; Hauck, Wendy; Van Rijswijk, Martin H

    2007-06-01

    Amyloid A protein quantification in fat tissue is a new immunochemical method for detecting AA amyloidosis, a rare but serious disease. The objective was to assess diagnostic performance in clinical AA amyloidosis. Abdominal subcutaneous fat tissue of patients with AA amyloidosis was studied at the start of an international clinical trial with eprodisate (NC-503; 1,3-propanedisulfonate; Kiacta), an antiamyloid compound. All patients had renal findings, i.e. proteinuria (> or =1 g/day) or reduced creatinine clearance (20 - 60 ml/min). Controls were patients with other types of amyloidosis and arthritic patients without amyloidosis. Amyloid A protein was quantified by ELISA using monoclonal antihuman serum amyloid A antibodies. Congo red stained slides were scored by light microscopy in a semiquantitative way (0 to 4+). Ample fat tissue (>50 mg) was available for analysis in 154 of 183 patients with AA amyloidosis and in 354 controls. The sensitivity of amyloid A protein quantification for detection of AA amyloidosis (>11.6 ng/mg fat tissue) was 84% (95% CI: 77 - 89%) and specificity 99% (95% CI: 98 - 100%). Amyloid A protein quantification and semiquantitative Congo red scoring were concordant. Men had lower amyloid A protein values than women (p < 0.0001) and patients with familial Mediterranean fever had lower values than patients with arthritis (p < 0.001) or other inflammatory diseases (p < 0.01). Amyloid A protein quantification in fat tissue is a sensitive and specific method for detection of clinical AA amyloidosis. Advantages are independence from staining quality and observer experience, direct confirmation of amyloid AA type, and potential for quantitative monitoring of tissue amyloid over time.

  11. Attenuation of β-Amyloid Deposition and Neurotoxicity by Chemogenetic Modulation of Neural Activity.

    PubMed

    Yuan, Peng; Grutzendler, Jaime

    2016-01-13

    Aberrant neural hyperactivity has been observed in early stages of Alzheimer's disease (AD) and may be a driving force in the progression of amyloid pathology. Evidence for this includes the findings that neural activity may modulate β-amyloid (Aβ) peptide secretion and experimental stimulation of neural activity can increase amyloid deposition. However, whether long-term attenuation of neural activity prevents the buildup of amyloid plaques and associated neural pathologies remains unknown. Using viral-mediated delivery of designer receptors exclusively activated by designer drugs (DREADDs), we show in two AD-like mouse models that chronic intermittent increases or reductions of activity have opposite effects on Aβ deposition. Neural activity reduction markedly decreases Aβ aggregation in regions containing axons or dendrites of DREADD-expressing neurons, suggesting the involvement of synaptic and nonsynaptic Aβ release mechanisms. Importantly, activity attenuation is associated with a reduction in axonal dystrophy and synaptic loss around amyloid plaques. Thus, modulation of neural activity could constitute a potential therapeutic strategy for ameliorating amyloid-induced pathology in AD. A novel chemogenetic approach to upregulate and downregulate neuronal activity in Alzheimer's disease (AD) mice was implemented. This led to the first demonstration that chronic intermittent attenuation of neuronal activity in vivo significantly reduces amyloid deposition. The study also demonstrates that modulation of β-amyloid (Aβ) release can occur at both axonal and dendritic fields, suggesting the involvement of synaptic and nonsynaptic Aβ release mechanisms. Activity reductions also led to attenuation of the synaptic pathology associated with amyloid plaques. Therefore, chronic attenuation of neuronal activity could constitute a novel therapeutic approach for AD. Copyright © 2016 the authors 0270-6474/16/360632-10$15.00/0.

  12. Attenuation of β-Amyloid Deposition and Neurotoxicity by Chemogenetic Modulation of Neural Activity

    PubMed Central

    Yuan, Peng

    2016-01-01

    Aberrant neural hyperactivity has been observed in early stages of Alzheimer's disease (AD) and may be a driving force in the progression of amyloid pathology. Evidence for this includes the findings that neural activity may modulate β-amyloid (Aβ) peptide secretion and experimental stimulation of neural activity can increase amyloid deposition. However, whether long-term attenuation of neural activity prevents the buildup of amyloid plaques and associated neural pathologies remains unknown. Using viral-mediated delivery of designer receptors exclusively activated by designer drugs (DREADDs), we show in two AD-like mouse models that chronic intermittent increases or reductions of activity have opposite effects on Aβ deposition. Neural activity reduction markedly decreases Aβ aggregation in regions containing axons or dendrites of DREADD-expressing neurons, suggesting the involvement of synaptic and nonsynaptic Aβ release mechanisms. Importantly, activity attenuation is associated with a reduction in axonal dystrophy and synaptic loss around amyloid plaques. Thus, modulation of neural activity could constitute a potential therapeutic strategy for ameliorating amyloid-induced pathology in AD. SIGNIFICANCE STATEMENT A novel chemogenetic approach to upregulate and downregulate neuronal activity in Alzheimer's disease (AD) mice was implemented. This led to the first demonstration that chronic intermittent attenuation of neuronal activity in vivo significantly reduces amyloid deposition. The study also demonstrates that modulation of β-amyloid (Aβ) release can occur at both axonal and dendritic fields, suggesting the involvement of synaptic and nonsynaptic Aβ release mechanisms. Activity reductions also led to attenuation of the synaptic pathology associated with amyloid plaques. Therefore, chronic attenuation of neuronal activity could constitute a novel therapeutic approach for AD. PMID:26758850

  13. Amyloid deposition in 2 feline thymomas.

    PubMed

    Burrough, E R; Myers, R K; Hostetter, S J; Fox, L E; Bayer, B J; Felz, C L; Waller, K R; Whitley, E M

    2012-07-01

    Two cases of feline thymoma with amyloid deposition were encountered between 1982 and 2010. Neoplastic cells were separated by abundant, pale eosinophilic, homogeneous material that was congophilic and birefringent. Ultrastructurally, the neoplastic cells were connected by desmosomes, and the extracellular deposits were composed of nonbranching, hollow-cored fibrils, 8-10 nm in diameter. In the case with sufficient archived tissue for additional sections, the amyloid remained congophilic following potassium permanganate incubation, and the neoplastic cells were immunoreactive for pancytokeratin. The histologic, histochemical, ultrastructural, and immunohistochemical features of both neoplasms are consistent with epithelial-predominant thymoma with the unusual feature of intratumoral amyloid deposition. The affinity of the amyloid for Congo red following potassium permanganate incubation is consistent with non-AA amyloid. The ultrastructural findings were consistent with amyloid production by the neoplastic epithelial cells.

  14. Insight into Amyloid Structure Using Chemical Probes

    PubMed Central

    Reinke, Ashley A.; Gestwicki, Jason E.

    2011-01-01

    Alzheimer’s disease (AD) is a common neurodegenerative disorder characterized by the deposition of amyloids in the brain. One prominent form of amyloid is composed of repeating units of the amyloid-β (Aβ) peptide. Over the past decade, it has become clear that these Aβ amyloids are not homogeneous; rather, they are composed of a series of structures varying in their overall size and shape and the number of Aβ peptides they contain. Recent theories suggest that these different amyloid conformations may play distinct roles in disease, although their relative contributions are still being discovered. Here, we review how chemical probes, such as congo red, thioflavin T and their derivatives, have been powerful tools for better understanding amyloid structure and function. Moreover, we discuss how design and deployment of conformationally selective probes might be used to test emerging models of AD. PMID:21457473

  15. Amyloid Structures as Biofilm Matrix Scaffolds

    PubMed Central

    Taglialegna, Agustina; Lasa, Iñigo

    2016-01-01

    Recent insights into bacterial biofilm matrix structures have induced a paradigm shift toward the recognition of amyloid fibers as common building block structures that confer stability to the exopolysaccharide matrix. Here we describe the functional amyloid systems related to biofilm matrix formation in both Gram-negative and Gram-positive bacteria and recent knowledge regarding the interaction of amyloids with other biofilm matrix components such as extracellular DNA (eDNA) and the host immune system. In addition, we summarize the efforts to identify compounds that target amyloid fibers for therapeutic purposes and recent developments that take advantage of the amyloid structure to engineer amyloid fibers of bacterial biofilm matrices for biotechnological applications. PMID:27185827

  16. Towards a Pharmacophore for Amyloid

    PubMed Central

    Landau, Meytal; Sawaya, Michael R.; Faull, Kym F.; Laganowsky, Arthur; Jiang, Lin; Sievers, Stuart A.; Liu, Jie; Barrio, Jorge R.; Eisenberg, David

    2011-01-01

    Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of β-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. PMID:21695112

  17. Towards a pharmacophore for amyloid.

    PubMed

    Landau, Meytal; Sawaya, Michael R; Faull, Kym F; Laganowsky, Arthur; Jiang, Lin; Sievers, Stuart A; Liu, Jie; Barrio, Jorge R; Eisenberg, David

    2011-06-01

    Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of β-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases.

  18. Surgical considerations about amyloid goiter.

    PubMed

    García Villanueva, Augusto; García Villanueva, María Jesús; García Villanueva, Mercedes; Rojo Blanco, Roberto; Collado Guirao, María Vicenta; Cabañas Montero, Jacobo; Beni Pérez, Rafael; Moreno Montes, Irene

    2013-05-01

    Amyloidosis is an uncommon syndrome consisting of a number of disorders having in common an extracellular deposit of fibrillary proteins. This results in functional and structural changes in the affected organs, depending on deposit location and severity. Amyloid infiltration of the thyroid gland may occur in 50% and up to 80% of patients with primary and secondary amyloidosis respectively. Amyloid goiter (AG) is a true rarity, usually found associated to secondary amyloidosis. AG may require surgical excision, usually because of compressive symptoms. We report the case of a patient with a big AG occurring in the course of a secondary amyloidosis associated to polyarticular onset juvenile idiopathic arthritis who underwent total thyroidectomy. Current literature is reviewed, an attempt is made to provide action guidelines, and some surgical considerations on this rare condition are given.

  19. The yin and yang of amyloid aggregation

    PubMed Central

    Falsone, S Fabio

    2015-01-01

    Intra- and extra-cellular amyloid protein fibers are traditionally coupled to a series of devastating and incurable neurodegenerative disorders. Since the discovery of physiologically useful amyloids, our attention has been shifting from pure pathology to function, as amyloid aggregation seems to constitute a basis for the functional and dynamic assembly of biological structures. The following article summarizes how the cell profits from such an unconventional high-risk aggregation at the rim of physiologic utility and pathologic catastrophe. PMID:28031869

  20. The Human Disease-Associated Aβ Amyloid Core Sequence Forms Functional Amyloids in a Fungal Adhesin

    PubMed Central

    Rameau, Rachele D.; Jackson, Desmond N.; Beaussart, Audrey; Dufrêne, Yves F.

    2016-01-01

    ABSTRACT There is increasing evidence that many amyloids in living cells have physiological functions. On the surfaces of fungal cells, amyloid core sequences in adhesins can aggregate into 100- to 1,000-nm-wide patches to form high-avidity adhesion nanodomains on the cell surface. The nanodomains form through interactions that have amyloid-like properties: binding of amyloid dyes, perturbation by antiamyloid agents, and interaction with homologous sequences. To test whether these functional interactions are mediated by typical amyloid interactions, we substituted an amyloid core sequence, LVFFA, from human Aβ protein for the native sequence IVIVA in the 1,419-residue Candida albicans adhesin Als5p. The chimeric protein formed cell surface nanodomains and mediated cellular aggregation. The native sequence and chimeric adhesins responded similarly to the amyloid dye thioflavin T and to amyloid perturbants. However, unlike the native protein, the nanodomains formed by the chimeric protein were not force activated and formed less-robust aggregates under flow. These results showed the similarity of amyloid interactions in the amyloid core sequences of native Als5p and Aβ, but they also highlighted emergent properties of the native sequence. Also, a peptide composed of the Aβ amyloid sequence flanked by amino acids from the adhesin formed two-dimensional sheets with sizes similar to the cell surface patches of the adhesins. These results inform an initial model for the structure of fungal cell surface amyloid nanodomains. PMID:26758179

  1. Excess flow shutoff valve

    DOEpatents

    Kiffer, Micah S.; Tentarelli, Stephen Clyde

    2016-02-09

    Excess flow shutoff valve comprising a valve body, a valve plug, a partition, and an activation component where the valve plug, the partition, and activation component are disposed within the valve body. A suitable flow restriction is provided to create a pressure difference between the upstream end of the valve plug and the downstream end of the valve plug when fluid flows through the valve body. The pressure difference exceeds a target pressure difference needed to activate the activation component when fluid flow through the valve body is higher than a desired rate, and thereby closes the valve.

  2. The Common Inhalational Anesthetic Sevoflurane Induces Apoptosis and Increases β-Amyloid Protein Levels

    PubMed Central

    Dong, Yuanlin; Zhang, Guohua; Zhang, Bin; Moir, Robert D.; Xia, Weiming; Marcantonio, Edward R.; Culley, Deborah J.; Crosby, Gregory; Tanzi, Rudolph E.; Xie, Zhongcong

    2009-01-01

    Objective: To assess the effects of sevoflurane, the most commonly used inhalation anesthetic, on apoptosis and β-amyloid protein (Aβ) levels in vitro and in vivo. Subjects: Naive mice, H4 human neuroglioma cells, and H4 human neuroglioma cells stably transfected to express full-length amyloid precursor protein. Interventions: Human H4 neuroglioma cells stably transfected to express full-length amyloid precursor protein were exposed to 4.1% sevoflurane for 6 hours. Mice received 2.5% sevoflurane for 2 hours. Caspase-3 activation, apoptosis, and Aβ levels were assessed. Results: Sevoflurane induced apoptosis and elevated levels of β-site amyloid precursor protein-cleaving enzyme and Aβ in vitro and in vivo. The caspase inhibitor Z-VAD decreased the effects of sevoflurane on apoptosis and Aβ. Sevoflurane-induced caspase-3 activation was attenuated by the γ-secretase inhibitor L-685,458 and was potentiated by Aβ. These results suggest that sevoflurane induces caspase activation which, in turn, enhances β-site amyloid precursor protein–cleaving enzyme and Aβ levels. Increased Aβ levels then induce further rounds of apoptosis. Conclusions: These results suggest that inhalational anesthetic sevoflurane may promote Alzheimer disease neuropathogenesis. If confirmed in human subjects, it may be prudent to caution against the use of sevoflurane as an anesthetic, especially in those suspected of possessing excessive levels of cerebral Aβ. PMID:19433662

  3. Genetics Home Reference: hereditary cerebral amyloid angiopathy

    MedlinePlus

    ... Testing Registry: Dementia, familial Danish Genetic Testing Registry: Hereditary cerebral amyloid angiopathy, Icelandic type Other Diagnosis and Management Resources (2 links) Johns Hopkins Medicine: ...

  4. Amyloid imaging: the court of public opinion.

    PubMed

    Lerner, Alan J

    2013-09-24

    Human amyloid imaging is one of the great recent translational medicine stories. Beginning with the recognition that Thioflavin T derivatives could be used as PET tracers, through development of Pittsburgh compound B, to Food and Drug Administration (FDA) approval of Florbetapir in 2012, human amyloid imaging has held great promise to allow in vivo inclusive diagnosis of Alzheimer disease (AD), even though the first principle of amyloid PET is that it functions as a surrogate for β-amyloid pathology, and not necessarily as a surrogate for the diagnosis of AD.(1,2.)

  5. Epigallocatechin Gallate Remodels Overexpressed Functional Amyloids in Pseudomonas aeruginosa and Increases Biofilm Susceptibility to Antibiotic Treatment.

    PubMed

    Stenvang, Marcel; Dueholm, Morten S; Vad, Brian S; Seviour, Thomas; Zeng, Guanghong; Geifman-Shochat, Susana; Søndergaard, Mads T; Christiansen, Gunna; Meyer, Rikke Louise; Kjelleberg, Staffan; Nielsen, Per Halkjær; Otzen, Daniel E

    2016-12-16

    Epigallocatechin-3-gallate (EGCG) is the major polyphenol in green tea. It has antimicrobial properties and disrupts the ordered structure of amyloid fibrils involved in human disease. The antimicrobial effect of EGCG against the opportunistic pathogen Pseudomonas aeruginosa has been shown to involve disruption of quorum sensing (QS). Functional amyloid fibrils in P. aeruginosa (Fap) are able to bind and retain quorum-sensing molecules, suggesting that EGCG interferes with QS through structural remodeling of amyloid fibrils. Here we show that EGCG inhibits the ability of Fap to form fibrils; instead, EGCG stabilizes protein oligomers. Existing fibrils are remodeled by EGCG into non-amyloid aggregates. This fibril remodeling increases the binding of pyocyanin, demonstrating a mechanism by which EGCG can affect the QS function of functional amyloid. EGCG reduced the amyloid-specific fluorescent thioflavin T signal in P. aeruginosa biofilms at concentrations known to exert an antimicrobial effect. Nanoindentation studies showed that EGCG reduced the stiffness of biofilm containing Fap fibrils but not in biofilm with little Fap. In a combination treatment with EGCG and tobramycin, EGCG had a moderate effect on the minimum bactericidal eradication concentration against wild-type P. aeruginosa biofilms, whereas EGCG had a more pronounced effect when Fap was overexpressed. Our results provide a direct molecular explanation for the ability of EGCG to disrupt P. aeruginosa QS and modify its biofilm and strengthens the case for EGCG as a candidate in multidrug treatment of persistent biofilm infections.

  6. Optimal parameters for near infrared fluorescence imaging of amyloid plaques in Alzheimer's disease mouse models

    NASA Astrophysics Data System (ADS)

    Raymond, S. B.; Kumar, A. T. N.; Boas, D. A.; Bacskai, B. J.

    2009-10-01

    Amyloid-β plaques are an Alzheimer's disease biomarker which present unique challenges for near-infrared fluorescence tomography because of size (<50 µm diameter) and distribution. We used high-resolution simulations of fluorescence in a digital Alzheimer's disease mouse model to investigate the optimal fluorophore and imaging parameters for near-infrared fluorescence tomography of amyloid plaques. Fluorescence was simulated for amyloid-targeted probes with emission at 630 and 800 nm, plaque-to-background ratios from 1-1000, amyloid burden from 0-10%, and for transmission and reflection measurement geometries. Fluorophores with high plaque-to-background contrast ratios and 800 nm emission performed significantly better than current amyloid imaging probes. We tested idealized fluorophores in transmission and full-angle tomographic measurement schemes (900 source-detector pairs), with and without anatomical priors. Transmission reconstructions demonstrated strong linear correlation with increasing amyloid burden, but underestimated fluorescence yield and suffered from localization artifacts. Full-angle measurements did not improve upon the transmission reconstruction qualitatively or in semi-quantitative measures of accuracy; anatomical and initial-value priors did improve reconstruction localization and accuracy for both transmission and full-angle schemes. Region-based reconstructions, in which the unknowns were reduced to a few distinct anatomical regions, produced highly accurate yield estimates for cortex, hippocampus and brain regions, even with a reduced number of measurements (144 source-detector pairs).

  7. Cortical amyloid accumulation is associated with alterations of structural integrity in older people with subjective memory complaints.

    PubMed

    Teipel, Stefan J; Cavedo, Enrica; Weschke, Sarah; Grothe, Michel J; Rojkova, Katrine; Fontaine, Gaëlle; Dauphinot, Luce; Gonzalez-Escamilla, Gabriel; Potier, Marie-Claude; Bertin, Hugo; Habert, Marie-Odile; Dubois, Bruno; Hampel, Harald

    2017-09-01

    We determined the effect of cortical amyloid load using (18)F-florbetapir PET on cognitive performance and gray matter structural integrity derived from MRI in 318 cognitively normally performing older people with subjective memory impairment from the INSIGHT-preAD cohort using multivariate partial least squares regression. Amyloid uptake was associated with reduced gray matter structural integrity in hippocampus, entorhinal and cingulate cortex, middle temporal gyrus, prefrontal cortex, and lentiform nucleus (p < 0.01, permutation test). Higher amyloid load was associated with poorer global cognitive performance, delayed recall and attention (p < 0.05), independently of its effects on gray matter connectivity. These findings agree with the assumption of a two-stage effect of amyloid on cognition, (1) an early direct effect in the preclinical stages of Alzheimer's disease and (2) a delayed effect mediated by downstream effects of amyloid accumulation, such as gray matter connectivity decline. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Excess mortality in Harlem.

    PubMed

    McCord, C; Freeman, H P

    1990-01-18

    In recent decades mortality rates have declined for both white and nonwhite Americans, but national averages obscure the extremely high mortality rates in many inner-city communities. Using data from the 1980 census and from death certificates in 1979, 1980, and 1981, we examined mortality rates in New York City's Central Harlem health district, where 96 percent of the inhabitants are black and 41 percent live below the poverty line. For Harlem, the age-adjusted rate of mortality from all causes was the highest in New York City, more than double that of U.S. whites and 50 percent higher than that of U.S. blacks. Almost all the excess mortality was among those less than 65 years old. With rates for the white population as the basis for comparison, the standardized (adjusted for age) mortality ratios (SMRs) for deaths under the age of 65 in Harlem were 2.91 for male residents and 2.70 for female residents. The highest ratios were for women 25 to 34 years old (SMR, 6.13) and men 35 to 44 years old (SMR, 5.98). The chief causes of this excess mortality were cardiovascular disease (23.5 percent of the excess deaths; SMR, 2.23), cirrhosis (17.9 percent; SMR, 10.5), homicide (14.9 percent; SMR, 14.2), and neoplasms (12.6 percent; SMR, 1.77). Survival analysis showed that black men in Harlem were less likely to reach the age of 65 than men in Bangladesh. Of the 353 health areas in New York, 54 (with a total population of 650,000) had mortality rates for persons under 65 years old that were at lest twice the expected rate. All but one of these areas of high mortality were predominantly black or Hispanic. We conclude that Harlem and probably other inner-city areas with largely black populations have extremely high mortality rates that justify special consideration analogous to that given to natural-disaster areas.

  9. Bacterial Chaperones CsgE and CsgC Differentially Modulate Human α-Synuclein Amyloid Formation via Transient Contacts

    PubMed Central

    Evans, Margery L.; Jain, Neha; Götheson, Anna; Åden, Jörgen; Chapman, Matthew R.; Almqvist, Fredrik; Wittung-Stafshede, Pernilla

    2015-01-01

    Amyloid formation is historically associated with cytotoxicity, but many organisms produce functional amyloid fibers (e.g., curli) as a normal part of cell biology. Two E. coli genes in the curli operon encode the chaperone-like proteins CsgC and CsgE that both can reduce in vitro amyloid formation by CsgA. CsgC was also found to arrest amyloid formation of the human amyloidogenic protein α-synuclein, which is involved in Parkinson’s disease. Here, we report that the inhibitory effects of CsgC arise due to transient interactions that promote the formation of spherical α-synuclein oligomers. We find that CsgE also modulates α-synuclein amyloid formation through transient contacts but, in contrast to CsgC, CsgE accelerates α-synuclein amyloid formation. Our results demonstrate the significance of transient protein interactions in amyloid regulation and emphasize that the same protein may inhibit one type of amyloid while accelerating another. PMID:26465894

  10. Review: history of the amyloid fibril.

    PubMed

    Sipe, J D; Cohen, A S

    2000-06-01

    Rudolph Virchow, in 1854, introduced and popularized the term amyloid to denote a macroscopic tissue abnormality that exhibited a positive iodine staining reaction. Subsequent light microscopic studies with polarizing optics demonstrated the inherent birefringence of amyloid deposits, a property that increased intensely after staining with Congo red dye. In 1959, electron microscopic examination of ultrathin sections of amyloidotic tissues revealed the presence of fibrils, indeterminate in length and, invariably, 80 to 100 A in width. Using the criteria of Congophilia and fibrillar morphology, 20 or more biochemically distinct forms of amyloid have been identified throughout the animal kingdom; each is specifically associated with a unique clinical syndrome. Fibrils, also 80 to 100 A in width, have been isolated from tissue homogenates using differential sedimentation or solubility. X-ray diffraction analysis revealed the fibrils to be ordered in the beta pleated sheet conformation, with the direction of the polypeptide backbone perpendicular to the fibril axis (cross beta structure). Because of the similar dimensions and tinctorial properties of the fibrils extracted from amyloid-laden tissues and amyloid fibrils in tissue sections, they have been assumed to be identical. However, the spatial relationship of proteoglycans and amyloid P component (AP), common to all forms of amyloid, to the putative protein only fibrils in tissues, has been unclear. Recently, it has been suggested that, in situ, amyloid fibrils are composed of proteoglycans and AP as well as amyloid proteins and thus resemble connective tissue microfibrils. Chemical and physical definition of the fibrils in tissues will be needed to relate the in vitro properties of amyloid protein fibrils to the pathogenesis of amyloid fibril formation in vivo.

  11. Consequences of excess iodine

    PubMed Central

    Leung, Angela M.; Braverman, Lewis E.

    2014-01-01

    Iodine is a micronutrient that is essential for the production of thyroid hormones. The primary source of iodine is the diet via consumption of foods that have been fortified with iodine, including salt, dairy products and bread, or that are naturally abundant in the micronutrient, such as seafood. Recommended daily iodine intake is 150 μg in adults who are not pregnant or lactating. Ingestion of iodine or exposure above this threshold is generally well-tolerated. However, in certain susceptible individuals, including those with pre-existing thyroid disease, the elderly, fetuses and neonates, or patients with other risk factors, the risk of developing iodine-induced thyroid dysfunction might be increased. Hypothyroidism or hyperthyroidism as a result of supraphysiologic iodine exposure might be either subclinical or overt, and the source of the excess iodine might not be readily apparent. PMID:24342882

  12. USE OF FUSED CIRCULATIONS TO INVESTIGATE THE ROLE OF APOLIPOPROTEIN E AS AMYLOID CATALYST AND PERIPHERAL SINK IN ALZHEIMER'S DISEASE

    PubMed Central

    Nilsson, Lars N. G.; Gografe, Sylvia; Costa, David A.; Hughes, Tiffany; Dressler, David; Potter, Huntington

    2013-01-01

    Apolipoprotein E (apoE) synthesized in liver and brain plays a key role in both cholesterol transport and Alzheimer's disease (AD): apoE-knockout mice develop hypercholesterolemia and atherosclerosis and cannot support AD amyloid deposition. The ApoE4 allele is the strongest genetic risk factor for late-onset AD, and apoE4 protein preferentially catalyzes amyloid-beta (Aβ) peptide fibrillization in vitro and amyloid plaque deposition in vivo. Circulating apoE may also have the potential to draw Aβ from the brain and reduce amyloid deposition. We used parabiosis to determine how circulating apoE impacts brain amyloid deposition and blood cholesterol levels in transgenic mice carrying AD-promoting APP and PS1 human transgenes—either with or without the endogenous mouse apoE gene. ApoE transferred through the joined circulations from WT to parabiosed APP+/+,PS1+/−,apoE-KO mice prevented hypercholesterolemia and reduced already low brain amyloid deposition. The findings indicate that apoE synthesis in the brain itself is necessary for amyloid accumulation. Furthermore, plasma apoE can both normalize cholesterol levels in apoE-KO mice and act as a peripheral sink to induce net efflux of Aβ peptide from the brain. The therapeutic implication is that inhibiting Alzheimer's disease neuropathology may be accomplished by either reducing apoE in the brain or increasing apoE in the blood. PMID:23626867

  13. The influence of biological and technical factors on quantitative analysis of amyloid PET: Points to consider and recommendations for controlling variability in longitudinal data.

    PubMed

    Schmidt, Mark E; Chiao, Ping; Klein, Gregory; Matthews, Dawn; Thurfjell, Lennart; Cole, Patricia E; Margolin, Richard; Landau, Susan; Foster, Norman L; Mason, N Scott; De Santi, Susan; Suhy, Joyce; Koeppe, Robert A; Jagust, William

    2015-09-01

    In vivo imaging of amyloid burden with positron emission tomography (PET) provides a means for studying the pathophysiology of Alzheimer's and related diseases. Measurement of subtle changes in amyloid burden requires quantitative analysis of image data. Reliable quantitative analysis of amyloid PET scans acquired at multiple sites and over time requires rigorous standardization of acquisition protocols, subject management, tracer administration, image quality control, and image processing and analysis methods. We review critical points in the acquisition and analysis of amyloid PET, identify ways in which technical factors can contribute to measurement variability, and suggest methods for mitigating these sources of noise. Improved quantitative accuracy could reduce the sample size necessary to detect intervention effects when amyloid PET is used as a treatment end point and allow more reliable interpretation of change in amyloid burden and its relationship to clinical course.

  14. Characterization of Amyloid Cores in Prion Domains

    PubMed Central

    Sant’Anna, Ricardo; Fernández, Maria Rosario; Batlle, Cristina; Navarro, Susanna; de Groot, Natalia S.; Serpell, Louise; Ventura, Salvador

    2016-01-01

    Amyloids consist of repetitions of a specific polypeptide chain in a regular cross-β-sheet conformation. Amyloid propensity is largely determined by the protein sequence, the aggregation process being nucleated by specific and short segments. Prions are special amyloids that become self-perpetuating after aggregation. Prions are responsible for neuropathology in mammals, but they can also be functional, as in yeast prions. The conversion of these last proteins to the prion state is driven by prion forming domains (PFDs), which are generally large, intrinsically disordered, enriched in glutamines/asparagines and depleted in hydrophobic residues. The self-assembly of PFDs has been thought to rely mostly on their particular amino acid composition, rather than on their sequence. Instead, we have recently proposed that specific amyloid-prone sequences within PFDs might be key to their prion behaviour. Here, we demonstrate experimentally the existence of these amyloid stretches inside the PFDs of the canonical Sup35, Swi1, Mot3 and Ure2 prions. These sequences self-assemble efficiently into highly ordered amyloid fibrils, that are functionally competent, being able to promote the PFD amyloid conversion in vitro and in vivo. Computational analyses indicate that these kind of amyloid stretches may act as typical nucleating signals in a number of different prion domains. PMID:27686217

  15. ESCRTs regulate amyloid precursor protein sorting in multivesicular bodies and intracellular amyloid-β accumulation.

    PubMed

    Edgar, James R; Willén, Katarina; Gouras, Gunnar K; Futter, Clare E

    2015-07-15

    Intracellular amyloid-β (Aβ) accumulation is a key feature of early Alzheimer's disease and precedes the appearance of Aβ in extracellular plaques. Aβ is generated through proteolytic processing of amyloid precursor protein (APP), but the intracellular site of Aβ production is unclear. APP has been localized to multivesicular bodies (MVBs) where sorting of APP onto intraluminal vesicles (ILVs) could promote amyloidogenic processing, or reduce Aβ production or accumulation by sorting APP and processing products to lysosomes for degradation. Here, we show that APP localizes to the ILVs of a subset of MVBs that also traffic EGF receptor (EGFR), and that it is delivered to lysosomes for degradation. Depletion of the endosomal sorting complexes required for transport (ESCRT) components, Hrs (also known as Hgs) or Tsg101, inhibited targeting of APP to ILVs and the subsequent delivery to lysosomes, and led to increased intracellular Aβ accumulation. This was accompanied by dramatically decreased Aβ secretion. Thus, the early ESCRT machinery has a dual role in limiting intracellular Aβ accumulation through targeting of APP and processing products to the lysosome for degradation, and promoting Aβ secretion.

  16. Intracellular cleavage of amyloid β by a viral protease NIa prevents amyloid β-mediated cytotoxicity.

    PubMed

    Shin, Baehyun; Oh, Hyejin; Park, Sang Min; Han, Hye-Eun; Ye, Michael; Song, Woo Keun; Park, Woo Jin

    2014-01-01

    Nuclear inclusion a (NIa) of turnip mosaic virus is a cytosolic protease that cleaves amyloid β (Aβ) when heterologously overexpressed. Lentivirus-mediated expression of NIa in the brains of APP(sw)/PS1 mice significantly reduces cerebral Aβ levels and plaque depositions, and improves behavioral deficits. Here, the effects of NIa and neprilysin (NEP), a well-known Aβ-cleaving protease, on oligomeric Aβ-induced cell death were evaluated. NIa cleaved monomeric and oligomeric Aβ at a similar rate, whereas NEP only cleaved monomeric Aβ. Oligomeric Aβ-induced cytotoxicity and mitochondrial dysfunction were significantly ameliorated by NIa, but not by NEP. Endocytosed fluorescently-labeled Aβ localized to mitochondria, and this was significantly reduced by NIa, but not by NEP. These data suggest that NIa may exerts its protective roles by degrading Aβ and thus preventing mitochondrial deposition of Aβ.

  17. Intracellular Cleavage of Amyloid β by a Viral Protease NIa Prevents Amyloid β-Mediated Cytotoxicity

    PubMed Central

    Shin, Baehyun; Oh, Hyejin; Park, Sang Min; Han, Hye-Eun; Ye, Michael; Song, Woo Keun; Park, Woo Jin

    2014-01-01

    Nuclear inclusion a (NIa) of turnip mosaic virus is a cytosolic protease that cleaves amyloid β (Aβ) when heterologously overexpressed. Lentivirus-mediated expression of NIa in the brains of APP(sw)/PS1 mice significantly reduces cerebral Aβ levels and plaque depositions, and improves behavioral deficits. Here, the effects of NIa and neprilysin (NEP), a well-known Aβ-cleaving protease, on oligomeric Aβ-induced cell death were evaluated. NIa cleaved monomeric and oligomeric Aβ at a similar rate, whereas NEP only cleaved monomeric Aβ. Oligomeric Aβ-induced cytotoxicity and mitochondrial dysfunction were significantly ameliorated by NIa, but not by NEP. Endocytosed fluorescently-labeled Aβ localized to mitochondria, and this was significantly reduced by NIa, but not by NEP. These data suggest that NIa may exerts its protective roles by degrading Aβ and thus preventing mitochondrial deposition of Aβ. PMID:24915567

  18. Betaine suppressed Aβ generation by altering amyloid precursor protein processing.

    PubMed

    Liu, Xiu-Ping; Qian, Xiang; Xie, Yue; Qi, Yan; Peng, Min-Feng; Zhan, Bi-Cui; Lou, Zheng-Qing

    2014-07-01

    Betaine was an endogenous catabolite of choline, which could be isolated from vegetables and marine products. Betaine could promote the metabolism of homocysteine in healthy subjects and was used for hyperlipidemia, coronary atherosclerosis, and fatty liver in clinic. Recent findings shown that Betaine rescued neuronal damage due to homocysteine induced Alzheimer's disease (AD) like pathological cascade, including tau hyperphosphorylation and amyloid-β (Aβ) deposition. Aβ was derived from amyloid precursor protein (APP) processing, and was a triggering factor for AD pathological onset. Here, we demonstrated that Betaine reduced Aβ levels by altering APP processing in N2a cells stably expressing Swedish mutant of APP. Betaine increased α-secretase activity, but decreased β-secretase activity. Our data indicate that Betaine might play a protective role in Aβ production.

  19. Amyloid fibrils compared to peptide nanotubes.

    PubMed

    Zganec, Matjaž; Zerovnik, Eva

    2014-09-01

    Prefibrillar oligomeric states and amyloid fibrils of amyloid-forming proteins qualify as nanoparticles. We aim to predict what biophysical and biochemical properties they could share in common with better researched peptide nanotubes. We first describe what is known of amyloid fibrils and prefibrillar aggregates (oligomers and protofibrils): their structure, mechanisms of formation and putative mechanism of cytotoxicity. In distinction from other neuronal fibrillar constituents, amyloid fibrils are believed to cause pathology, however, some can also be functional. Second, we give a review of known biophysical properties of peptide nanotubes. Finally, we compare properties of these two macromolecular states side by side and discuss which measurements that have already been done with peptide nanotubes could be done with amyloid fibrils as well.

  20. 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.

  1. APP processing and amyloid deposition in mice haplo-insufficient for presenilin 1.

    PubMed

    Jankowsky, Joanna L; Slunt, Hilda H; Gonzales, Victoria; Jenkins, Nancy A; Copeland, Neal G; Borchelt, David R

    2004-08-01

    More than 70 different mutations in presenilin 1 (PS1) have been associated with inherited early onset Alzheimer's disease (AD). How all these different mutations cause disease has not been clearly delineated. Our laboratory has previously shown that co-expression of mutant PS1 in mice transgenic for amyloid precursor protein (APPswe) dramatically accelerates the rate of amyloid deposition in the brain. In our original animals mutant PS1 was substantially over-expressed, and the stabilized pool of mouse PS1 fragments was largely replaced by the human protein. In this setting the accelerated amyloid pathology in the double transgenic mice could have been due, in part, to decreased endogenous PS1 activity. To investigate this possibility, we generated APP transgenic mice with reduced levels of endogenous PS1. We find that mice harboring only one functional PS1 allele and co-expressing Mo/HuAPPswe do not develop amyloid deposits at ages comparable to mice expressing mutant PS1. We next tested whether hypo-expression of mutant PS1 could accelerate the rate of amyloid deposition using an unusual line of transgenic mice expressing PS1dE9 at low levels, finding no significant acceleration. Our findings demonstrate that the accelerated amyloid pathology, caused by so many different mutations in PS1, is clearly not a result of haplo-insufficiency that might result from inactivating mutations. Instead, our data are consistent with a gain of property mechanism.

  2. Soluble β-Amyloid Induction of Alzheimer's Phenotype for Human Fibroblast K^+ Channels

    NASA Astrophysics Data System (ADS)

    Etcheberrigaray, Rene; Ito, Etsuro; Kim, Christopher S.; Alkon, Daniel L.

    1994-04-01

    Although β-amyloid is the main constituent of neurite plaques and may play a role in the pathophysiology of Alzheimer's disease, mechanisms by which soluble β-amyloid might produce early symptoms such as memory loss before diffuse plaque deposition have not been implicated. Treatment of fibroblasts with β-amyloid (10 nM) induced the same potassium channel dysfunction previously shown to occur specifically in fibroblasts from patients with Alzheimer's disease-namely, the absence of a 113-picosiemen potassium channel. A tetraethylammonium-induced increase of intracellular concentrations of calcium, [Ca2+]_i, a response that depends on functional 113-picosiemen potassium channels, was also eliminated or markedly reduced by 10 nM β-amyloid. Increased [Ca2+]_i induced by high concentrations of extracellular potassium and 166-picosiemen potassium channels were unaffected by 10 nM β-amyloid. In Alzheimer's disease, then, β-amyloid might alter potassium channels and thus impair neuronal function to produce symptoms such as memory loss by a means other than plaque formation.

  3. β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation

    PubMed Central

    Mander, Bryce A.; Marks, Shawn M.; Vogel, Jacob W.; Rao, Vikram; Lu, Brandon; Saletin, Jared M.; Ancoli-Israel, Sonia; Jagust, William J.; Walker, Matthew P.

    2015-01-01

    Independent evidence associates β-amyloid pathology with both NREM sleep disruption and memory impairment in older adults. However, whether the influence of β-amyloid pathology on hippocampus-dependent memory is, in part, driven by impairments of NREM slow wave activity (SWA) and associated overnight memory consolidation is unknown. Here, we show that β-amyloid burden within medial prefrontal cortex (mPFC) is significantly correlated with the severity of impairment in NREM SWA generation. Moreover, reduced NREM SWA generation was further associated with impaired overnight memory consolidation and impoverished hippocampal-neocortical memory transformation. Furthermore, structural equation models revealed that the association between mPFC β-amyloid pathology and impaired hippocampus-dependent memory consolidation is not direct, but instead, statistically depends on the intermediary factor of diminished NREM SWA. By linking β-amyloid pathology with impaired NREM SWA, these data implicate sleep disruption as a novel mechanistic pathway through which β-amyloid pathology may contribute to hippocampus-dependent cognitive decline in the elderly. PMID:26030850

  4. Specific Amyloid Binding of Polybasic Peptides In Vivo Is Retained by β-Sheet Conformers but Lost in the Disrupted Coil and All D-Amino Acid Variants.

    PubMed

    Wall, Jonathan S; Williams, Angela; Richey, Tina; Stuckey, Alan; Wooliver, Craig; Christopher Scott, J; Donnell, Robert; Martin, Emily B; Kennel, Stephen J

    2017-02-22

    The heparin-reactive, helical peptide p5 is an effective amyloid imaging agent in mice with systemic amyloidosis. Analogs of p5 with modified secondary structure characteristics exhibited altered binding to heparin, synthetic amyloid fibrils, and amyloid extracts in vitro. Herein, we further study the effects of peptide helicity and chirality on specific amyloid binding using a mouse model of systemic inflammation-associated (AA) amyloidosis. Peptides with disrupted helical structure [p5(coil) and p5(Pro3)], with an extended sheet conformation [p5(sheet)] or an all-D enantiomer [p5(D)], were chemically synthesized, radioiodinated, and their biodistribution studied in WT mice as well as transgenic animals with severe systemic AA amyloidosis. Peptide binding was assessed qualitatively by using small animal single-photon emission computed tomography/x-ray computed tomography imaging and microautoradiography and quantitatively using tissue counting. Peptides with reduced helical propensity, p5(coil) and p5(Pro3), exhibited significantly reduced binding to AA amyloid-laden organs. In contrast, peptide p5(D) was retained by non-amyloid-related ligands in the liver and kidneys of both WT and AA mice, but it also bound AA amyloid in the spleen. The p5(sheet) peptide specifically bound AA amyloid in vivo and was not retained by healthy tissues in WT animals. Modification of amyloid-targeting peptides using D-amino acids should be performed cautiously due to the introduction of unexpected secondary pharmacologic effects. Peptides that adopt a helical structure, to align charged amino acid side chains along one face, exhibit specific reactivity with amyloid; however, polybasic peptides with a propensity for β-sheet conformation are also amyloid-reactive and may yield a novel class of amyloid-targeting agents for imaging and therapy.

  5. Scintigraphic characterization of amyloid cardiomyopathy

    SciTech Connect

    Li, C.K.; Rabinovitch, M.A.; Juni, J.E.; Thrall, J.H.; Pitt, B.; Das, S.K.; Abrams, G.D.; Helvie, M.

    1985-03-01

    Amyloidosis is an important entity in the differential diagnosis of cardiac failure of undetermined etiology. In this case report, the typical pattern of combined systolic and diastolic impairment in amyloid cardiomyopathy was demonstrated by analysis of the cardiac blood pool study. In addition, the patient described had mild uptake of Ga-67 citrate, as well as the characteristically intense myocardial uptake of Tc-99m pyrophosphate. Scintigraphic assessment may be particularly helpful when the diagnosis of amyloidosis is being considered in a patient with unexplained cardiac failure.

  6. Role of phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) in intracellular amyloid precursor protein (APP) processing and amyloid plaque pathogenesis.

    PubMed

    Xiao, Qingli; Gil, So-Chon; Yan, Ping; Wang, Yan; Han, Sharon; Gonzales, Ernie; Perez, Ronaldo; Cirrito, John R; Lee, Jin-Moo

    2012-06-15

    One of the pathological hallmarks of Alzheimer disease is the accumulation of amyloid plaques in the extracellular space in the brain. Amyloid plaques are primarily composed of aggregated amyloid β peptide (Aβ), a proteolytic fragment of the transmembrane amyloid precursor protein (APP). For APP to be proteolytically cleaved into Aβ, it must be internalized into the cell and trafficked to endosomes where specific protease complexes can cleave APP. Several recent genome-wide association studies have reported that several single nucleotide polymorphisms (SNPs) in the phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) gene were significantly associated with Alzheimer disease, suggesting a role in APP endocytosis and Aβ generation. Here, we show that PICALM co-localizes with APP in intracellular vesicles of N2a-APP cells after endocytosis is initiated. PICALM knockdown resulted in reduced APP internalization and Aβ generation. Conversely, PICALM overexpression increased APP internalization and Aβ production. In vivo, PICALM was found to be expressed in neurons and co-localized with APP throughout the cortex and hippocampus in APP/PS1 mice. PICALM expression was altered using AAV8 gene transfer of PICALM shRNA or PICALM cDNA into the hippocampus of 6-month-old APP/PS1 mice. PICALM knockdown decreased soluble and insoluble Aβ levels and amyloid plaque load in the hippocampus. Conversely, PICALM overexpression increased Aβ levels and amyloid plaque load. These data indicate that PICALM, an adaptor protein involved in clathrin-mediated endocytosis, regulates APP internalization and subsequent Aβ generation. PICALM contributes to amyloid plaque load in brain likely via its effect on Aβ metabolism.

  7. Role of Phosphatidylinositol Clathrin Assembly Lymphoid-Myeloid Leukemia (PICALM) in Intracellular Amyloid Precursor Protein (APP) Processing and Amyloid Plaque Pathogenesis*

    PubMed Central

    Xiao, Qingli; Gil, So-Chon; Yan, Ping; Wang, Yan; Han, Sharon; Gonzales, Ernie; Perez, Ronaldo; Cirrito, John R.; Lee, Jin-Moo

    2012-01-01

    One of the pathological hallmarks of Alzheimer disease is the accumulation of amyloid plaques in the extracellular space in the brain. Amyloid plaques are primarily composed of aggregated amyloid β peptide (Aβ), a proteolytic fragment of the transmembrane amyloid precursor protein (APP). For APP to be proteolytically cleaved into Aβ, it must be internalized into the cell and trafficked to endosomes where specific protease complexes can cleave APP. Several recent genome-wide association studies have reported that several single nucleotide polymorphisms (SNPs) in the phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) gene were significantly associated with Alzheimer disease, suggesting a role in APP endocytosis and Aβ generation. Here, we show that PICALM co-localizes with APP in intracellular vesicles of N2a-APP cells after endocytosis is initiated. PICALM knockdown resulted in reduced APP internalization and Aβ generation. Conversely, PICALM overexpression increased APP internalization and Aβ production. In vivo, PICALM was found to be expressed in neurons and co-localized with APP throughout the cortex and hippocampus in APP/PS1 mice. PICALM expression was altered using AAV8 gene transfer of PICALM shRNA or PICALM cDNA into the hippocampus of 6-month-old APP/PS1 mice. PICALM knockdown decreased soluble and insoluble Aβ levels and amyloid plaque load in the hippocampus. Conversely, PICALM overexpression increased Aβ levels and amyloid plaque load. These data indicate that PICALM, an adaptor protein involved in clathrin-mediated endocytosis, regulates APP internalization and subsequent Aβ generation. PICALM contributes to amyloid plaque load in brain likely via its effect on Aβ metabolism. PMID:22539346

  8. Amyloid beta peptide immunotherapy in Alzheimer disease.

    PubMed

    Delrieu, J; Ousset, P J; Voisin, T; Vellas, B

    2014-12-01

    Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid β peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  9. Amyloid imaging in mild cognitive impairment subtypes.

    PubMed

    Wolk, David A; Price, Julie C; Saxton, Judy A; Snitz, Beth E; James, Jeffrey A; Lopez, Oscar L; Aizenstein, Howard J; Cohen, Ann D; Weissfeld, Lisa A; Mathis, Chester A; Klunk, William E; De-Kosky, Steven T; DeKoskym, Steven T

    2009-05-01

    We utilized the amyloid imaging ligand Pittsburgh Compound B (PiB) to determine the presence of Alzheimer's disease (AD) pathology in different mild cognitive impairment (MCI) subtypes and to relate increased PiB binding to other markers of early AD and longitudinal outcome. Twenty-six patients with MCI (13 single-domain amnestic-MCI [a-MCI], 6 multidomain a-MCI, and 7 nonamnestic MCI) underwent PiB imaging. Twenty-three had clinical follow-up (21.2 +/- 16.0 [standard deviation] months) subsequent to their PiB scan. Using cutoffs established from a control cohort, we found that 14 (54%) patients had increased levels of PiB retention and were considered "amyloid-positive." All subtypes were associated with a significant proportion of amyloid-positive patients (6/13 single-domain a-MCI, 5/6 multidomain a-MCI, 3/7 nonamnestic MCI). There were no obvious differences in the distribution of PiB retention in the nonamnestic MCI group. Predictors of conversion to clinical AD in a-MCI, including poorer episodic memory, and medial temporal atrophy, were found in the amyloid-positive relative to amyloid-negative a-MCI patients. Longitudinal follow-up demonstrated 5 of 13 amyloid-positive patients, but 0 of 10 amyloid-negative patients, converted to clinical AD. Further, 3 of 10 amyloid-negative patients "reverted to normal." These data support the notion that amyloid-positive patients are likely to have early AD, and that the use of amyloid imaging may have an important role in determining which patients are likely to benefit from disease-specific therapies. In addition, our data are consistent with longitudinal studies that suggest a significant percentage of all MCI subtypes will develop AD.

  10. Chiral recognition in amyloid fiber growth.

    PubMed

    Torbeev, Vladimir; Grogg, Marcel; Ruiz, Jérémy; Boehringer, Régis; Schirer, Alicia; Hellwig, Petra; Jeschke, Gunnar; Hilvert, Donald

    2016-05-01

    Insoluble amyloid fibers represent a pathological signature of many human diseases. To treat such diseases, inhibition of amyloid formation has been proposed as a possible therapeutic strategy. d-Peptides, which possess high proteolytic stability and lessened immunogenicity, are attractive candidates in this context. However, a molecular understanding of chiral recognition phenomena for d-peptides and l-amyloids is currently incomplete. Here we report experiments on amyloid growth of individual enantiomers and their mixtures for two distinct polypeptide systems of different length and structural organization: a 44-residue covalently-linked dimer derived from a peptide corresponding to the [20-41]-fragment of human β2-microglobulin (β2m) and the 99-residue full-length protein. For the dimeric [20-41]β2m construct, a combination of electron paramagnetic resonance of nitroxide-labeled constructs and (13) C-isotope edited FT-IR spectroscopy of (13) C-labeled preparations was used to show that racemic mixtures precipitate as intact homochiral fibers, i.e. undergo spontaneous Pasteur-like resolution into a mixture of left- and right-handed amyloids. In the case of full-length β2m, the presence of the mirror-image d-protein affords morphologically distinct amyloids that are composed largely of enantiopure domains. Removal of the l-component from hybrid amyloids by proteolytic digestion results in their rapid transformation into characteristic long straight d-β2m amyloids. Furthermore, the full-length d-enantiomer of β2m was found to be an efficient inhibitor of l-β2m amyloid growth. This observation highlights the potential of longer d-polypeptides for future development into inhibitors of amyloid propagation. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  11. Early Detection of Autism (ASD) by a Non-invasive Quick Measurement of Markedly Reduced Acetylcholine & DHEA and Increased β-Amyloid (1-42), Asbestos (Chrysotile), Titanium Dioxide, Al, Hg & often Coexisting Virus Infections (CMV, HPV 16 and 18), Bacterial Infections etc. in the Brain and Corresponding Safe Individualized Effective Treatment.

    PubMed

    Omura, Yoshiaki; Lu, Dominic; Jones, Marilyn K; Nihrane, Ahdallah; Duvvi, Harsha; Shimotsuura, Yasuhiro; Ohki, Motomu

    2015-01-01

    A brief historical background on Autism & some of the important symptoms associated with Autism are summarized. Using strong Electro Magnetic Field Resonance Phenomenon between 2 identical molecules with identical weight (which received U.S. Patent) non-invasively & rapidly we can detect various molecules including neurotransmitters, bacteria, virus, fungus, metals & abnormal molecules. Simple non- invasive measurement of various molecules through pupils & head of diagnosed or suspected Autism patients indicated that in Autism patients following changes were often found: 1) Acetylcholine is markedly reduced; 2) Alzheimer's disease markers (i.e. β-Amyloid (1-42), Tau Protein, Apolipoprotein (Apo E4)) are markedly increased; 3) Chrysotile Asbestos is increased; 4) Titanium Dioxide (TiO2) is moderately increased; 5) Al is moderately increased; 6) Hg is moderately increased; 7) Dopamine, Serotonin & GABA are significantly reduced (up to about 1/10 of normal); 8) Often viral infections (such as CMV, HHV-6, HPV-16, HPV-18, etc.), and Bacterial infections (such as Chlamydia trachomatis, Mycobacterium TB, Borrelia Burgdorferi, etc.) coexist. Research by others on Autism spectrum disorder (ASD) shows that it is a group of complex neurodevelopmental disorders, with about 70% of ASD patients also suffering from gastro-intestinal problems. While Alzheimer disease (AD) is characterized by formation of 1) Amyloid plaques, 2) Neurofibrillary tangles inside of neurons, and 3) Loss of connections between neurons. More than 90% of AD develops in people over the age of 65. These 3 characteristics often progressively worsen over time. Although Autism Spectrum Disorder and Alzheimer's disease are completely different diseases they have some similar biochemical changes. Eight examples of such measurement & analysis are shown for comparison. Most of Autism patients improved significantly by removing the source or preventing intake of Asbestos, TiO2, Al & Hg or enhancing urinary output

  12. Thermodynamics and dynamics of amyloid peptide oligomerization are sequence dependent.

    PubMed

    Lu, Yan; Derreumaux, Philippe; Guo, Zhi; Mousseau, Normand; Wei, Guanghong

    2009-06-01

    Aggregation of the full-length amyloid-beta (Abeta) and beta2-microglobulin (beta2m) proteins is associated with Alzheimer's disease and dialysis-related amyloidosis, respectively. This assembly process is not restricted to full-length proteins, however, many short peptides also assemble into amyloid fibrils in vitro. Remarkably, the kinetics of amyloid-fibril formation of all these molecules is generally described by a nucleation-polymerization process characterized by a lag phase associated with the formation of a nucleus, after which fibril elongation occurs rapidly. In this study, we report using long molecular dynamics simulations with the OPEP coarse-grained force field, the thermodynamics and dynamics of the octamerization for two amyloid 7-residue peptides: the beta2m83-89 NHVTLSQ and Abeta16-22 KLVFFAE fragments. Based on multiple trajectories run at 310 K, totaling 2.2 mus (beta2m83-89) and 4.8 mus (Abeta16-22) and starting from random configurations and orientations of the chains, we find that the two peptides not only share common but also very different aggregation properties. Notably, an increase in the hydrophobic character of the peptide, as observed in Abeta16-22 with respect to beta2m83-89 impacts the thermodynamics by reducing the population of bilayer beta-sheet assemblies. Higher hydrophobicity is also found to slow down the dynamics of beta-sheet formation by enhancing the averaged lifetime of all configuration types (CT) and by reducing the complexity of the CT transition probability matrix. Proteins 2009. (c) 2008 Wiley-Liss, Inc.

  13. Amyloid and non-amyloid carpal tunnel syndrome in patients receiving chronic renal dialysis.

    PubMed

    Chary-Valckenaere, I; Kessler, M; Mainard, D; Schertz, L; Chanliau, J; Champigneulle, J; Pourel, J; Gaucher, A; Netter, P

    1998-06-01

    To determine the prevalence of amyloid deposits among patients with carpal tunnel syndrome (CTS) receiving dialysis, and to investigate the factors associated with amyloid and non-amyloid CTS. Subjects for this prospective study were dialysis patients who underwent surgery for CTS in the same surgical unit between 1989 and 1997. CTS was diagnosed from clinical and electromyographic (EMG) findings. Systematic standard radiographs and laboratory data were also obtained. Surgical investigations included systematic macroscopic examination and biopsy of the epineurium, flexor retinaculum, synovium, and flexor tendon sheaths. Samples were stained for amyloid and examined by plain and polarized light microscopy, immunohistochemistry, and electron microscopy. Forty-one samples from 30 patients (11 bilateral cases) were examined. Amyloid deposits were found in 26 samples from 18 patients (7 M, 11 F). Fifteen samples from 12 patients (3 M, 9 F) showed no amyloid deposits. Amyloid CTS was statistically significantly associated with arthralgia and longterm dialysis [mean 13.3 (range 5.5-23) vs 7.5 yrs (range 3 mo-14 yrs)] in non-amyloid CTS. Flexor tenosynovitis and carpal bone erosion occurred more frequently in amyloid CTS. There were no statistically significant differences between the 2 groups in clinical, laboratory or EMG findings, type of dialysis membrane, or frequency of ipsilateral fistula. Only amyloid CTS was recurrent. Amyloid deposits were confirmed microscopically in 63.4% of patients. The relatively large number of cases of non-amyloid CTS without signs of dialysis associated arthropathy suggests that CTS is not a satisfactory criterion for diagnosis of dialysis arthropathy or beta2-microglobulin amyloidosis unless the presence of amyloid has been confirmed or duration of dialysis treatment has been at least 15 years.

  14. Amyloid pore-channel hypothesis: effect of ethanol on aggregation state using frog oocytes for an Alzheimer's disease study.

    PubMed

    Parodi, Jorge; Ormeño, David; Ochoa-de la Paz, Lenin D

    2015-01-01

    Alzheimer's disease severely compromises cognitive function. One of the mechanisms to explain the pathology of Alzheimer's disease has been the hypotheses of amyloid-pore/channel formation by complex Aβ-aggregates. Clinical studies suggested the moderate alcohol consumption can reduces probability developing neurodegenerative pathologies. A recent report explored the ability of ethanol to disrupt the generation of complex Aβ in vitro and reduce the toxicity in two cell lines. Molecular dynamics simulations were applied to understand how ethanol blocks the aggregation of amyloid. On the other hand, the in silico modeling showed ethanol effect over the dynamics assembling for complex Aβ-aggregates mediated by break the hydrosaline bridges between Asp 23 and Lys 28, was are key element for amyloid dimerization. The amyloid pore/channel hypothesis has been explored only in neuronal models, however recently experiments suggested the frog oocytes such an excellent model to explore the mechanism of the amyloid pore/channel hypothesis. So, the used of frog oocytes to explored the mechanism of amyloid aggregates is new, mainly for amyloid/pore hypothesis. Therefore, this experimental model is a powerful tool to explore the mechanism implicates in the Alzheimer's disease pathology and also suggests a model to prevent the Alzheimer's disease pathology.

  15. Intermediate Tyrosyl Radical and Amyloid Structure in Peroxide-Activated Cytoglobin.

    PubMed

    Ferreira, Juliana C; Marcondes, Marcelo F; Icimoto, Marcelo Y; Cardoso, Thyago H S; Tofanello, Aryane; Pessoto, Felipe S; Miranda, Erica G A; Prieto, Tatiana; Nascimento, Otaciro R; Oliveira, Vitor; Nantes, Iseli L

    2015-01-01

    We characterized the peroxidase mechanism of recombinant rat brain cytoglobin (Cygb) challenged by hydrogen peroxide, tert-butylhydroperoxide and by cumene hydroperoxide. The peroxidase mechanism of Cygb is similar to that of myoglobin. Cygb challenged by hydrogen peroxide is converted to a Fe4+ oxoferryl π cation, which is converted to Fe4+ oxoferryl and tyrosyl radical detected by direct continuous wave-electron paramagnetic resonance and by 3,5-dibromo-4-nitrosobenzene sulfonate spin trapping. When organic peroxides are used as substrates at initial reaction times, and given an excess of peroxide present, the EPR signals of the corresponding peroxyl radicals precede those of the direct tyrosyl radical. This result is consistent with the use of peroxide as a reducing agent for the recycling of Cygb high-valence species. Furthermore, we found that the Cygb oxidation by peroxides leads to the formation of amyloid fibrils. This result suggests that Cygb possibly participates in the development of degenerative diseases; our findings also support the possible biological role of Cygb related to peroxidase activity.

  16. Intermediate Tyrosyl Radical and Amyloid Structure in Peroxide-Activated Cytoglobin

    PubMed Central

    Ferreira, Juliana C.; Marcondes, Marcelo F.; Icimoto, Marcelo Y.; Cardoso, Thyago H. S.; Tofanello, Aryane; Pessoto, Felipe S.; Miranda, Erica G. A.; Prieto, Tatiana; Nascimento, Otaciro R.; Oliveira, Vitor; Nantes, Iseli L.

    2015-01-01

    We characterized the peroxidase mechanism of recombinant rat brain cytoglobin (Cygb) challenged by hydrogen peroxide, tert-butylhydroperoxide and by cumene hydroperoxide. The peroxidase mechanism of Cygb is similar to that of myoglobin. Cygb challenged by hydrogen peroxide is converted to a Fe4+ oxoferryl π cation, which is converted to Fe4+ oxoferryl and tyrosyl radical detected by direct continuous wave-electron paramagnetic resonance and by 3,5-dibromo-4-nitrosobenzene sulfonate spin trapping. When organic peroxides are used as substrates at initial reaction times, and given an excess of peroxide present, the EPR signals of the corresponding peroxyl radicals precede those of the direct tyrosyl radical. This result is consistent with the use of peroxide as a reducing agent for the recycling of Cygb high-valence species. Furthermore, we found that the Cygb oxidation by peroxides leads to the formation of amyloid fibrils. This result suggests that Cygb possibly participates in the development of degenerative diseases; our findings also support the possible biological role of Cygb related to peroxidase activity. PMID:26312997

  17. Self-Assembly of Large Amyloid Fibers

    NASA Astrophysics Data System (ADS)

    Ridgley, Devin M.

    Functional amyloids found throughout nature have demonstrated that amyloid fibers are potential industrial biomaterials. This work introduces a new "template plus adder" cooperative mechanism for the spontaneous self-assembly of micrometer sized amyloid fibers. A short hydrophobic template peptide induces a conformation change within a highly alpha-helical adder protein to form beta-sheets that continue to assemble into micrometer sized amyloid fibers. This study utilizes a variety of proteins that have template or adder characteristics which suggests that this mechanism may be employed throughout nature. Depending on the amino acid composition of the proteins used the mixtures form amyloid fibers of a cylindrical ( 10 mum diameter, 2 GPa Young's modulus) or tape (5- 10 mum height, 10-20 mum width and 100-200 MPa Young's modulus) morphology. Processing conditions are altered to manipulate the morphology and structural characteristics of the fibers. Spectroscopy is utilized to identify certain amino acid groups that contribute to the self-assembly process. Aliphatic amino acids (A, I, V and L) are responsible for initiating conformation change of the adder proteins to assemble into amyloid tapes. Additional polyglutamine segments (Q-blocks) within the protein mixtures will form Q hydrogen bonds to reinforce the amyloid structure and form a cylindrical fiber of higher modulus. Atomic force microscopy is utilized to delineate the self-assembly of amyloid tapes and cylindrical fibers from protofibrils (15-30 nm width) to fibers (10-20 mum width) spanning three orders of magnitude. The aliphatic amino acid content of the adder proteins' alpha-helices is a good predictor of high density beta-sheet formation within the protein mixture. Thus, it is possible to predict the propensity of a protein to undergo conformation change into amyloid structures. Finally, Escherichia coli is genetically engineered to express a template protein which self-assembles into large amyloid

  18. Anti-amyloid precursor protein immunoglobulins inhibit amyloid-β production by steric hindrance.

    PubMed

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

    2011-01-01

    The cleavage of amyloid precursor protein (APP) by β- and γ-secretases results in the production of amyloid-β (Aβ) in Alzheimer's disease. We raised two monoclonal antibodies, 2B3 and 2B12, that recognize the β-secretase cleavage site on APP but not Aβ. We hypothesized 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 nonamyloidogenic 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, whereas 2B12 bound slightly upstream. Both of these factors probably contribute to its greater effect on Aβ levels. After 60 min 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 the effects of antibody internalization and intracellular degradation were excluded. 2B3 virtually abolished this cleavage. In addition, levels of C-terminal APP fragments, generated following β-secretase cleavage (βCTF), were significantly reduced in cells after incubation with 2B3. These results strongly suggest that anti-cleavage site IgGs can generically reduce Aβ levels via inhibition of β-secretase by steric hindrance and may provide a novel alternative therapy for Alzheimer's disease.

  19. 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

  20. Photoreceptor damage following exposure to excess riboflavin.

    PubMed

    Eckhert, C D; Hsu, M H; Pang, N

    1993-12-15

    Flavins generate oxidants during metabolism and when exposed to light. Here we report that the photoreceptor layer of retinas from black-eyed rats is reduced in size by a dietary regime containing excess riboflavin. The effect of excess riboflavin was dose-dependent and was manifested by a decrease in photoreceptor length. This decrease was due in part to a reduction in the thickness of the outer nuclear layer, a structure formed from stacked photoreceptor nuclei. These changes were accompanied by an increase in photoreceptor outer segment autofluorescence following illumination at 328 nm, a wavelength that corresponds to the excitation maxima of oxidized lipopigments of the retinal pigment epithelium.

  1. Hacking the Code of Amyloid Formation

    PubMed Central

    Pastor, M Teresa; Esteras-Chopo, Alexandra

    2007-01-01

    Many research efforts in the last years have been directed towards understanding the factors determining protein misfolding and amyloid formation. Protein stability and amino acid composition have been identified as the two major factors in vitro. The research of our group has been focused on understanding the relationship between amino acid sequence and amyloid formation. Our approach has been the design of simple model systems that reproduce the biophysical properties of natural amyloids. An amyloid sequence pattern was extracted that can be used to detect amyloidogenic hexapeptide stretches in proteins. We have added evidence supporting that these amyloidogenic stretches can trigger amyloid formation by nonamyloidogenic proteins. Some experimental results in other amyloid proteins will be analyzed under the conclusions obtained in these studies. Our conclusions together with evidences from other groups suggest that amyloid formation is the result of the interplay between a decrease of protein stability, and the presence of highly amyloidogenic regions in proteins. As many of these results have been obtained in vitro, the challenge for the next years will be to demonstrate their validity in in vivo systems. PMID:19164912

  2. Glutamate carboxypeptidase II does not process amyloid-β peptide.

    PubMed

    Sedlák, František; Šácha, Pavel; Blechová, Miroslava; Březinová, Anna; Šafařík, Martin; Šebestík, Jaroslav; Konvalinka, Jan

    2013-07-01

    The accumulation of amyloid-β (Aβ) peptide is thought to be a major causative mechanism of Alzheimer's disease. Aβ accumulation could be caused by dysregulated processing of amyloid precursor protein, yielding excessive amounts of Aβ, and/or by inefficient proteolytic degradation of the peptide itself. Several proteases have been described as Aβ degradation enzymes, most notably metalloendopeptidases, aspartic endopeptidases, and some exopeptidases. Recently a report suggested that another metallopeptidase, glutamate carboxypeptidase II (GCPII), can also cleave Aβ. GCPII is a zinc exopeptidase that cleaves glutamate from N-acetyl-L-aspartyl-L-glutamate in the central nervous system and from pteroylpoly-γ-glutamate in the jejunum. GCPII has been proposed as a promising therapeutic target for disorders caused by glutamate neurotoxicity. However, an Aβ-degrading activity of GCPII would compromise potential pharmaceutical use of GCPII inhibitors, because the enzyme inhibition might lead to increased Aβ levels and consequently to Alzheimer's disease. Therefore, we analyzed the reported Aβ-degrading activity of GCPII using highly purified recombinant enzyme and synthetic Aβ. We did not detect any Aβ degradation activity of GCPII or its homologue even under prolonged incubation at a high enzyme to substrate ratio. These results are in good agreement with the current detailed structural understanding of the substrate specificity and enzyme-ligand interactions of GCPII.

  3. Neuronal membrane cholesterol loss enhances amyloid peptide generation

    PubMed Central

    Abad-Rodriguez, Jose; Ledesma, Maria Dolores; Craessaerts, Katleen; Perga, Simona; Medina, Miguel; Delacourte, Andre; Dingwall, Colin; De Strooper, Bart; Dotti, Carlos G.

    2004-01-01

    Recent experimental and clinical retrospective studies support the view that reduction of brain cholesterol protects against Alzheimer's disease (AD). However, genetic and pharmacological evidence indicates that low brain cholesterol leads to neurodegeneration. This apparent contradiction prompted us to analyze the role of neuronal cholesterol in amyloid peptide generation in experimental systems that closely resemble physiological and pathological situations. We show that, in the hippocampus of control human and transgenic mice, only a small pool of endogenous APP and its β-secretase, BACE 1, are found in the same membrane environment. Much higher levels of BACE 1–APP colocalization is found in hippocampal membranes from AD patients or in rodent hippocampal neurons with a moderate reduction of membrane cholesterol. Their increased colocalization is associated with elevated production of amyloid peptide. These results suggest that loss of neuronal membrane cholesterol contributes to excessive amyloidogenesis in AD and pave the way for the identification of the cause of cholesterol loss and for the development of specific therapeutic strategies. PMID:15583033

  4. Hunger, escaping excess.

    PubMed

    Gardner, G; Halweil, B

    2000-01-01

    According to the WHO, in spite of decades of global food surpluses, half of humanity, in both rich and poor nations, is still malnourished. Malnutrition has become a significant impediment to development in rich and poor countries, alike. At the individual level, both hunger and poor eating habits reduce a person's physical fitness, increase susceptibility to illness, and shorten lifespan. In addition, children deprived of adequate nutrients during development can suffer from permanently reduced mental capacity. At the national level, poor eating hampers educational performance, curtails economic productivity, increases the burden on health care, and reduces well-being. Confronting this epidemic of poor eating will have widespread benefits, but the myths and misconceptions permeating humanity¿s understanding of malnutrition should be addressed first. It is noted that the major cause of hunger is poverty, not scarcity of food; it is the lack of access to the goods and services essential for a healthy life. On the other hand, for those who have access to plenty of food, dietary intake includes meat, dairy products, and highly processed items loaded with fat and sugar. This leads to the problem of obesity, a condition that increases susceptibility to disease and disability, reduces worker productivity, and shortens lifespan. In view of this, efforts to improve nutrition should focus on poverty eradication, health education, agricultural change, and policy change towards promotion of good nutrition.

  5. Magnetic Fluids Have Ability to Decrease Amyloid Aggregation Associated with Amyloid-Related Diseases

    NASA Astrophysics Data System (ADS)

    Antosova, Andrea; Koneracka, Martina; Siposova, Katarina; Zavisova, Vlasta; Daxnerova, Zuzana; Vavra, Ivo; Fabian, Martin; Kopcansky, Peter; Gazova, Zuzana

    2010-12-01

    At least twenty human proteins can fold abnormally to form pathological deposits that are associated with several amyloid-related diseases. We have investigated the effect of four magnetic fluids (MFs)—electrostatically stabilized Fe3O4 magnetic nanoparticles (MF1) and sterically stabilized Fe3O4 magnetic nanoparticles by sodium oleate (MF2, MF3 and MF4) with adsorbed BSA (MF2) or dextran (MF4)—on amyloid aggregation of two proteins, human insulin and chicken egg lysozyme. The morphology, particle size and size distribution of the prepared magnetic fluids were characterized. We have found that MFs are able to decrease amyloid aggregation of both studied proteins and the extent of depolymerization depended on the MF properties. The most effective reduction was observed for MF4 as 90% decrease of amyloids was detected for insulin and lysozyme amyloid aggregates. Our findings indicate that MFs have potential to be used for treatment of amyloid diseases.

  6. Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695.

    PubMed

    Chishti, M A; Yang, D S; Janus, C; Phinney, A L; Horne, P; Pearson, J; Strome, R; Zuker, N; Loukides, J; French, J; Turner, S; Lozza, G; Grilli, M; Kunicki, S; Morissette, C; Paquette, J; Gervais, F; Bergeron, C; Fraser, P E; Carlson, G A; George-Hyslop, P S; Westaway, D

    2001-06-15

    We have created early-onset transgenic (Tg) models by exploiting the synergistic effects of familial Alzheimer's disease mutations on amyloid beta-peptide (Abeta) biogenesis. TgCRND8 mice encode a double mutant form of amyloid precursor protein 695 (KM670/671NL+V717F) under the control of the PrP gene promoter. Thioflavine S-positive Abeta amyloid deposits are present at 3 months, with dense-cored plaques and neuritic pathology evident from 5 months of age. TgCRND8 mice exhibit 3,200-4,600 pmol of Abeta42 per g brain at age 6 months, with an excess of Abeta42 over Abeta40. High level production of the pathogenic Abeta42 form of Abeta peptide was associated with an early impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of age. Notably, learning impairment in young mice was offset by immunization against Abeta42 (Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T. J., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., St. George-Hyslop, P., and Westaway, D. (2000) Nature 408, 979-982). Amyloid deposition in TgCRND8 mice was enhanced by the expression of presenilin 1 transgenes including familial Alzheimer's disease mutations; for mice also expressing a M146L+L286V presenilin 1 transgene, amyloid deposits were apparent by 1 month of age. The Tg mice described here suggest a potential to investigate aspects of Alzheimer's disease pathogenesis, prophylaxis, and therapy within short time frames.

  7. Amyloid-beta fibrillogenesis: structural insight and therapeutic intervention.

    PubMed

    Dasilva, Kevin A; Shaw, James E; McLaurin, Joanne

    2010-06-01

    Structural insight into the conformational changes associated with aggregation and assembly of fibrils has provided a number of targets for therapeutic intervention. Solid-state NMR, hydrogen/deuterium exchange and mutagenesis strategies have been used to probe the secondary and tertiary structure of amyloid fibrils and key intermediates. Rational design of peptide inhibitors directed against key residues important for aggregation and stabilization of fibrils has demonstrated effectiveness at inhibiting fibrillogenesis. Studies on the interaction between Abeta and cell membranes led to the discovery that inositol, the head group of phosphatidylinositol, inhibits fibrillogenesis. As a result, scyllo-inositol is currently in clinical trials for the treatment of AD. Additional small-molecule inhibitors, including polyphenolic compounds such as curcumin, (-)-epigallocatechin gallate (EGCG), and grape seed extract have been shown to attenuate Abeta aggregation through distinct mechanisms, and have shown effectiveness at reducing amyloid levels when administered to transgenic mouse models of AD. Although the results of ongoing clinical trials remain to be seen, these compounds represent the first generation of amyloid-based therapeutics, with the potential to alter the progression of AD and, when used prophylactically, alleviate the deposition of Abeta.

  8. Development of amyloid burden in African green monkeys

    PubMed Central

    Kalinin, Sergey; Willard, Stephanie L.; Shively, Carol A; Kaplan, Jay R; Register, Tom; Jorgensen, Matthew J; Polak, Paul E; Rubinstein, Israel; Feinstein, Douglas L

    2013-01-01

    The vervet is an old world monkey increasingly being used as a model for human diseases. In addition to plaques and tangles, an additional hallmark of Alzheimer’s disease is damage to neurons that synthesize noradrenaline (NA). We characterized amyloid burden in the posterior temporal lobe of young and aged vervets, and compared that to changes in NA levels and astrocyte activation. Total Aβ40 and Aβ42 levels were increased in the aged group, as were numbers of amyloid plaques detected using antibody 6E10. Low levels of Aβ42 were detected in 1 of 5 younger animals, although diffusely stained plaques were observed in 4 of these. Increased GFAP staining and mRNA levels were significantly correlated with increased age, as were cortical NA levels. Levels of Aβ42 and Aβ40, and the number of 6E10+ plaques, were correlated with NA levels. Interestingly mRNA levels of glial derived neurotrophic factor, important for noradrenergic neuronal survival, were reduced with age. These findings suggest that amyloid pathology in aged vervets is associated with astrocyte activation and higher NA levels. PMID:23601810

  9. Imaging beta-amyloid burden in aging and dementia.

    PubMed

    Rowe, C C; Ng, S; Ackermann, U; Gong, S J; Pike, K; Savage, G; Cowie, T F; Dickinson, K L; Maruff, P; Darby, D; Smith, C; Woodward, M; Merory, J; Tochon-Danguy, H; O'Keefe, G; Klunk, W E; Mathis, C A; Price, J C; Masters, C L; Villemagne, V L

    2007-05-15

    To compare brain beta-amyloid (Abeta) burden measured with [(11)C]Pittsburgh Compound B (PIB) PET in normal aging, Alzheimer disease (AD), and other dementias. Thirty-three subjects with dementia (17 AD, 10 dementia with Lewy bodies [DLB], 6 frontotemporal dementia [FTD]), 9 subjects with mild cognitive impairment (MCI), and 27 age-matched healthy control subjects (HCs) were studied. Abeta burden was quantified using PIB distribution volume ratio. Cortical PIB binding was markedly elevated in every AD subject regardless of disease severity, generally lower and more variable in DLB, and absent in FTD, whereas subjects with MCI presented either an "AD-like" (60%) or normal pattern. Binding was greatest in the precuneus/posterior cingulate, frontal cortex, and caudate nuclei, followed by lateral temporal and parietal cortex. Six HCs (22%) showed cortical uptake despite normal neuropsychological scores. PIB binding did not correlate with dementia severity in AD or DLB but was higher in subjects with an APOE-epsilon4 allele. In DLB, binding correlated inversely with the interval from onset of cognitive impairment to diagnosis. Pittsburgh Compound B PET findings match histopathologic reports of beta-amyloid (Abeta) distribution in aging and dementia. Noninvasive longitudinal studies to better understand the role of amyloid deposition in the course of neurodegeneration and to determine if Abeta deposition in nondemented subjects is preclinical AD are now feasible. Our findings also suggest that Abeta may influence the development of dementia with Lewy bodies, and therefore strategies to reduce Abeta may benefit this condition.

  10. Cognitive and cortical plasticity deficits correlate with altered amyloid-β CSF levels in multiple sclerosis.

    PubMed

    Mori, Francesco; Rossi, Silvia; Sancesario, Giulia; Codecà, Claudia; Mataluni, Giorgia; Monteleone, Fabrizia; Buttari, Fabio; Kusayanagi, Hajime; Castelli, Maura; Motta, Caterina; Studer, Valeria; Bernardi, Giorgio; Koch, Giacomo; Bernardini, Sergio; Centonze, Diego

    2011-02-01

    Cognitive dysfunction is of frequent observation in multiple sclerosis (MS). It is associated with gray matter pathology, brain atrophy, and altered connectivity, and recent evidence showed that acute inflammation can exacerbate mental deficits independently of the primary functional system involved. In this study, we measured cerebrospinal fluid (CSF) levels of amyloid-β(1-42) and τ protein in MS and in clinically isolated syndrome patients, as both proteins have been associated with cognitive decline in Alzheimer's disease (AD). In AD, amyloid-β(1-42) accumulates in the brain as insoluble extracellular plaques, possibly explaining why soluble amyloid-β(1-42) is reduced in the CSF of these patients. In our sample of MS patients, amyloid-β(1-42) levels were significantly lower in patients cognitively impaired (CI) and were inversely correlated with the number of Gadolinium-enhancing (Gd+) lesions at the magnetic resonance imaging (MRI). Positive correlations between amyloid-β(1-42) levels and measures of attention and concentration were also found. Furthermore, abnormal neuroplasticity of the cerebral cortex, explored with θ burst stimulation (TBS), was observed in CI patients, and a positive correlation was found between amyloid-β(1-42) CSF contents and the magnitude of long-term potentiation-like effects induced by TBS. No correlation was conversely found between τ protein concentrations and MRI findings, cognitive parameters, and TBS effects in these patients. Together, our results indicate that in MS, central inflammation is able to alter amyloid-β metabolism by reducing its concentration in the CSF and leading to impairment of synaptic plasticity and cognitive function.

  11. Modeling of chemical inhibition from amyloid protein aggregation kinetics

    PubMed Central

    2014-01-01

    Backgrounds The process of amyloid proteins aggregation causes several human neuropathologies. In some cases, e.g. fibrillar deposits of insulin, the problems are generated in the processes of production and purification of protein and in the pump devices or injectable preparations for diabetics. Experimental kinetics and adequate modelling of chemical inhibition from amyloid aggregation are of practical importance in order to study the viable processing, formulation and storage as well as to predict and optimize the best conditions to reduce the effect of protein nucleation. Results In this manuscript, experimental data of insulin, Aβ42 amyloid protein and apomyoglobin fibrillation from recent bibliography were selected to evaluate the capability of a bivariate sigmoid equation to model them. The mathematical functions (logistic combined with Weibull equation) were used in reparameterized form and the effect of inhibitor concentrations on kinetic parameters from logistic equation were perfectly defined and explained. The surfaces of data were accurately described by proposed model and the presented analysis characterized the inhibitory influence on the protein aggregation by several chemicals. Discrimination between true and apparent inhibitors was also confirmed by the bivariate equation. EGCG for insulin (working at pH = 7.4/T = 37°C) and taiwaniaflavone for Aβ42 were the compounds studied that shown the greatest inhibition capacity. Conclusions An accurate, simple and effective model to investigate the inhibition of chemicals on amyloid protein aggregation has been developed. The equation could be useful for the clear quantification of inhibitor potential of chemicals and rigorous comparison among them. PMID:24572069

  12. [A subacute dementia: Inflammatory cerebral amyloid angiopathy].

    PubMed

    Charef, S; Leblanc, A; Guibourg, B; Quintin-Roue, I; Ben Salem, D; Zagnoli, F

    2015-12-01

    We report a case of inflammatory cerebral amyloid angiopathy (CAA) that led to rapid cognitive decline, seizures, visual hallucinations, hyperproteinorrachia and right hemispheric leukopathy. Brain biopsy gave the diagnosis of CAA. Although no inflammatory infiltrate was found in the biopsy sample, corticosteroids led to a regression of the radiological lesions without significant clinical improvement. CAA is a rare disease, defined by lesions of classical cerebral amyloid angiopathy and perivascular infiltrates in contact with the affected vessels. In cases of rapidly progressive dementia associated with leukopathy, inflammatory amyloid angiopathy should be considered as cognitive disorders may improve after immunosuppressive therapy. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  13. Glutamine Acts as a Neuroprotectant against DNA Damage, Beta-Amyloid and H2O2-Induced Stress

    PubMed Central

    Chen, Jianmin; Herrup, Karl

    2012-01-01

    Glutamine is the most abundant free amino acid in the human blood stream and is ‘conditionally essential’ to cells. Its intracellular levels are regulated both by the uptake of extracellular glutamine via specific transport systems and by its intracellular synthesis by glutamine synthetase (GS). Adding to the regulatory complexity, when extracellular glutamine is reduced GS protein levels rise. Unfortunately, this excess GS can be maladaptive. GS overexpression is neurotoxic especially if the cells are in a low-glutamine medium. Similarly, in low glutamine, the levels of multiple stress response proteins are reduced rendering cells hypersensitive to H2O2, zinc salts and DNA damage. These altered responses may have particular relevance to neurodegenerative diseases of aging. GS activity and glutamine levels are lower in the Alzheimer's disease (AD) brain, and a fraction of AD hippocampal neurons have dramatically increased GS levels compared with control subjects. We validated the importance of these observations by showing that raising glutamine levels in the medium protects cultured neuronal cells against the amyloid peptide, Aβ. Further, a 10-day course of dietary glutamine supplementation reduced inflammation-induced neuronal cell cycle activation, tau phosphorylation and ATM-activation in two different mouse models of familial AD while raising the levels of two synaptic proteins, VAMP2 and synaptophysin. Together, our observations suggest that healthy neuronal cells require both intracellular and extracellular glutamine, and that the neuroprotective effects of glutamine supplementation may prove beneficial in the treatment of AD. PMID:22413000

  14. Amyloid domains in the cell nucleus controlled by nucleoskeletal protein lamin B1 reveal a new pathway of mercury neurotoxicity

    PubMed Central

    Arnhold, Florian; Gührs, Karl-Heinz

    2015-01-01

    Mercury (Hg) is a bioaccumulating trace metal that globally circulates the atmosphere and waters in its elemental, inorganic and organic chemical forms. While Hg represents a notorious neurotoxicant, the underlying cellular pathways are insufficiently understood. We identify amyloid protein aggregation in the cell nucleus as a novel pathway of Hg-bio-interactions. By mass spectrometry of purified protein aggregates, a subset of spliceosomal components and nucleoskeletal protein lamin B1 were detected as constituent parts of an Hg-induced nuclear aggregome network. The aggregome network was located by confocal imaging of amyloid-specific antibodies and dyes to amyloid cores within splicing-speckles that additionally recruit components of the ubiquitin-proteasome system. Hg significantly enhances global proteasomal activity in the nucleus, suggesting that formation of amyloid speckles plays a role in maintenance of protein homeostasis. RNAi knock down showed that lamin B1 for its part regulates amyloid speckle formation and thus likewise participates in nuclear protein homeostasis. As the Hg-induced cascade of interactions between the nucleoskeleton and protein homeostasis reduces neuronal signalling, amyloid fibrillation in the cell nucleus is introduced as a feature of Hg-neurotoxicity that opens new avenues of future research. Similar to protein aggregation events in the cytoplasm that are controlled by the cytoskeleton, amyloid fibrillation of nuclear proteins may be driven by the nucleoskeleton. PMID:25699204

  15. Autophagy impairment by caspase-1-dependent inflammation mediates memory loss in response to β-Amyloid peptide accumulation.

    PubMed

    Álvarez-Arellano, Lourdes; Pedraza-Escalona, Martha; Blanco-Ayala, Tonali; Camacho-Concha, Nohemí; Cortés-Mendoza, Javier; Pérez-Martínez, Leonor; Pedraza-Alva, Gustavo

    2017-08-12

    β-Amyloid peptide accumulation in the cortex and in the hippocampus results in neurodegeneration and memory loss. Recently, it became evident that the inflammatory response triggered by β-Amyloid peptides promotes neuronal cell death and degeneration. In addition to inflammation, β-Amyloid peptides also induce alterations in neuronal autophagy, eventually leading to neuronal cell death. Thus, here we evaluated whether the inflammatory response induced by the β-Amyloid peptides impairs memory via disrupting the autophagic flux. We show that male mice overexpressing β-Amyloid peptides (5XFAD) but lacking caspase-1, presented reduced β-Amyloid plaques in the cortex and in the hippocampus; restored brain autophagic flux and improved learning and memory capacity. At the molecular level, inhibition of the inflammatory response in the 5XFAD mice restored LC3-II levels and prevented the accumulation of oligomeric p62 and ubiquitylated proteins. Furthermore, caspase-1 deficiency reinstates activation of the AMPK/Raptor pathway while down-regulating AKT/mTOR pathway. Consistent with this, we found an inverse correlation between the increase of autophagolysosomes in the cortex of 5XFAD mice lacking caspase-1 and the presence of mitochondria with altered morphology. Together our results indicate that β-Amyloid peptide-induced caspase-1 activation, disrupts autophagy in the cortex and in the hippocampus resulting in neurodegeneration and memory loss. © 2017 Wiley Periodicals, Inc.

  16. Amyloid domains in the cell nucleus controlled by nucleoskeletal protein lamin B1 reveal a new pathway of mercury neurotoxicity.

    PubMed

    Arnhold, Florian; Gührs, Karl-Heinz; von Mikecz, Anna

    2015-01-01

    Mercury (Hg) is a bioaccumulating trace metal that globally circulates the atmosphere and waters in its elemental, inorganic and organic chemical forms. While Hg represents a notorious neurotoxicant, the underlying cellular pathways are insufficiently understood. We identify amyloid protein aggregation in the cell nucleus as a novel pathway of Hg-bio-interactions. By mass spectrometry of purified protein aggregates, a subset of spliceosomal components and nucleoskeletal protein lamin B1 were detected as constituent parts of an Hg-induced nuclear aggregome network. The aggregome network was located by confocal imaging of amyloid-specific antibodies and dyes to amyloid cores within splicing-speckles that additionally recruit components of the ubiquitin-proteasome system. Hg significantly enhances global proteasomal activity in the nucleus, suggesting that formation of amyloid speckles plays a role in maintenance of protein homeostasis. RNAi knock down showed that lamin B1 for its part regulates amyloid speckle formation and thus likewise participates in nuclear protein homeostasis. As the Hg-induced cascade of interactions between the nucleoskeleton and protein homeostasis reduces neuronal signalling, amyloid fibrillation in the cell nucleus is introduced as a feature of Hg-neurotoxicity that opens new avenues of future research. Similar to protein aggregation events in the cytoplasm that are controlled by the cytoskeleton, amyloid fibrillation of nuclear proteins may be driven by the nucleoskeleton.

  17. Presynaptic localization of neprilysin contributes to efficient clearance of amyloid-beta peptide in mouse brain.

    PubMed

    Iwata, Nobuhisa; Mizukami, Hiroaki; Shirotani, Keiro; Takaki, Yoshie; Muramatsu, Shin-ichi; Lu, Bao; Gerard, Norma P; Gerard, Craig; Ozawa, Keiya; Saido, Takaomi C

    2004-01-28

    A local increase in amyloid-beta peptide (Abeta) is closely associated with synaptic dysfunction in the brain in Alzheimer's disease. Here, we report on the catabolic mechanism of Abeta at the presynaptic sites. Neprilysin, an Abeta-degrading enzyme, expressed by recombinant adeno-associated viral vector-mediated gene transfer, was axonally transported to presynaptic sites through afferent projections of neuronal circuits. This gene transfer abolished the increase in Abeta levels in the hippocampal formations of neprilysin-deficient mice and also reduced the increase in young mutant amyloid precursor protein transgenic mice. In the latter case, Abeta levels in the hippocampal formation contralateral to the vector-injected side were also significantly reduced as a result of transport of neprilysin from the ipsilateral side, and in both sides soluble Abeta was degraded more efficiently than insoluble Abeta. Furthermore, amyloid deposition in aged mutant amyloid precursor protein transgenic mice was remarkably decelerated. Thus, presynaptic neprilysin has been demonstrated to degrade Abeta efficiently and to retard development of amyloid pathology.

  18. Emerging roles for the amyloid precursor protein and derived peptides in the regulation of cellular and systemic metabolism.

    PubMed

    Czeczor, Juliane K; McGee, Sean L

    2017-03-28

    The amyloid precursor protein (APP) is a transmembrane protein that can be cleaved by proteases through two different pathways to yield a number of small peptides, each with distinct physiological properties and functions. It has been extensively studied in the context of Alzheimer's disease, with the APP-derived amyloid beta (Aβ) peptide being a major constituent of the amyloid plaques observed in this disease. It has been known for some time that APP can regulate neuronal metabolism, however this review will examine evidence that APP and its peptides can also regulate key metabolic processes such as insulin action, lipid synthesis and storage and mitochondrial function in peripheral tissues. This review will present a hypothesis that amyloidogenic processing of APP in peripheral tissues plays a key role in the response to nutrient excess and that this could contribute to the pathogenesis of metabolic diseases such as obesity and type 2 diabetes (T2D). This article is protected by copyright. All rights reserved.

  19. Spatially controlled amyloid reactions using organic electronics.

    PubMed

    Gabrielsson, Erik O; Tybrandt, Klas; Hammarström, Per; Berggren, Magnus; Nilsson, K Peter R

    2010-10-04

    Abnormal protein aggregates, so called amyloid fibrils, are mainly known as pathological hallmarks of a wide range of diseases, but in addition these robust well-ordered self-assembled natural nanostructures can also be utilized for creating distinct nanomaterials for bioelectronic devices. However, current methods for producing amyloid fibrils in vitro offer no spatial control. Herein, we demonstrate a new way to produce and spatially control the assembly of amyloid-like structures using an organic electronic ion pump (OEIP) to pump distinct cations to a reservoir containing a negatively charged polypeptide. The morphology and kinetics of the created proteinaceous nanomaterials depends on the ion and current used, which we leveraged to create layers incorporating different conjugated thiophene derivatives, one fluorescent (p-FTAA) and one conducting (PEDOT-S). We anticipate that this new application for the OEIP will be useful for both biological studies of amyloid assembly and fibrillogenesis as well as for creating new bioelectronic nanomaterials and devices.

  20. Multiphoton absorption in amyloid protein fibres

    NASA Astrophysics Data System (ADS)

    Hanczyc, Piotr; Samoc, Marek; Norden, Bengt

    2013-12-01

    Fibrillization of peptides leads to the formation of amyloid fibres, which, when in large aggregates, are responsible for diseases such as Alzheimer's and Parkinson's. Here, we show that amyloids have strong nonlinear optical absorption, which is not present in native non-fibrillized protein. Z-scan and pump-probe experiments indicate that insulin and lysozyme β-amyloids, as well as α-synuclein fibres, exhibit either two-photon, three-photon or higher multiphoton absorption processes, depending on the wavelength of light. We propose that the enhanced multiphoton absorption is due to a cooperative mechanism involving through-space dipolar coupling between excited states of aromatic amino acids densely packed in the fibrous structures. This finding will provide the opportunity to develop nonlinear optical techniques to detect and study amyloid structures and also suggests that new protein-based materials with sizable multiphoton absorption could be designed for specific applications in nanotechnology, photonics and optoelectronics.

  1. Androgen excess in cystic acne.

    PubMed

    Marynick, S P; Chakmakjian, Z H; McCaffree, D L; Herndon, J H

    1983-04-28

    We measured hormone levels in 59 women and 32 men with longstanding cystic acne resistant to conventional therapy. Affected women had higher serum levels of dehydroepiandrosterone sulfate, testosterone, and luteinizing hormone and lower levels of sex-hormone-binding globulin than controls. Affected men had higher levels of serum dehydroepiandrosterone sulfate and 17-hydroxyprogesterone and lower levels of sex-hormone-binding globulin than controls. To lower dehydroepiandrosterone sulfate, dexamethasone was given to men, and dexamethasone or an oral contraceptive pill, Demulen (or both), was given to women. Of the patients treated for six months, 97 per cent of the women and 81 per cent of the men had resolution or marked improvement in their acne. The dose of dexamethasone required to reduce dehydroepiandrosterone sulfate levels was low, rarely exceeding the equivalent of 20 mg of hydrocortisone per day. We conclude that most patients with therapeutically resistant cystic acne have androgen excess and that lowering elevated dehydroepiandrosterone sulfate results in improvement or remission of acne in most instances.

  2. Functional amyloid formation by Streptococcus mutans

    PubMed Central

    Oli, M. W.; Otoo, H. N.; Crowley, P. J.; Heim, K. P.; Nascimento, M. M.; Ramsook, C. B.; Lipke, P. N.

    2012-01-01

    Dental caries is a common infectious disease associated with acidogenic and aciduric bacteria, including Streptococcus mutans. Organisms that cause cavities form recalcitrant biofilms, generate acids from dietary sugars and tolerate acid end products. It has recently been recognized that micro-organisms can produce functional amyloids that are integral to biofilm development. We now show that the S. mutans cell-surface-localized adhesin P1 (antigen I/II, PAc) is an amyloid-forming protein. This conclusion is based on the defining properties of amyloids, including binding by the amyloidophilic dyes Congo red (CR) and Thioflavin T (ThT), visualization of amyloid fibres by transmission electron microscopy and the green birefringent properties of CR-stained protein aggregates when viewed under cross-polarized light. We provide evidence that amyloid is present in human dental plaque and is produced by both laboratory strains and clinical isolates of S. mutans. We provide further evidence that amyloid formation is not limited to P1, since bacterial colonies without this adhesin demonstrate residual green birefringence. However, S. mutans lacking sortase, the transpeptidase enzyme that mediates the covalent linkage of its substrates to the cell-wall peptidoglycan, including P1 and five other proteins, is not birefringent when stained with CR and does not form biofilms. Biofilm formation is inhibited when S. mutans is cultured in the presence of known inhibitors of amyloid fibrillization, including CR, Thioflavin S and epigallocatechin-3-gallate, which also inhibited ThT uptake by S. mutans extracellular proteins. Taken together, these results indicate that S. mutans is an amyloid-forming organism and suggest that amyloidogenesis contributes to biofilm formation by this oral microbe. PMID:23082034

  3. Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer's disease and mild cognitive impairment.

    PubMed

    Mattsson, Niklas; Tosun, Duygu; Insel, Philip S; Simonson, Alix; Jack, Clifford R; Beckett, Laurel A; Donohue, Michael; Jagust, William; Schuff, Norbert; Weiner, Michael W

    2014-05-01

    Patients with Alzheimer's disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-β pathology. Using 182 subjects from the Alzheimer's Disease Neuroimaging Initiative we tested associations of amyloid-β with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer's disease with dementia (n = 24). Based on the theory that Alzheimer's disease starts with amyloid-β accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-β-negative controls and -positive subjects in different diagnostic groups, and if amyloid-β had different associations with cerebral blood flow and grey matter volume. Global amyloid-β load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-β load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-β-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-β with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-β being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-β pathology affects cerebral blood flow across the span from controls to

  4. Multimodal characterization of older APOE2 carriers reveals selective reduction of amyloid load.

    PubMed

    Grothe, Michel J; Villeneuve, Sylvia; Dyrba, Martin; Bartrés-Faz, David; Wirth, Miranka

    2017-02-07

    To comprehensively assess neurobiological effects of the protective APOE2 allele in the aged brain using a cross-sectional multimodal neuroimaging approach. Multimodal neuroimaging data were obtained from a total of 572 older individuals without dementia (cognitively normal and mild cognitive impairment) enrolled in the Alzheimer's Disease Neuroimaging Initiative and included assessments of regional amyloid load with AV45-PET, glucose metabolism with fluorodeoxyglucose-PET, and gray matter volume with structural MRI. Imaging indexes of APOE2 carriers were contrasted to risk-neutral APOE3 homozygotes, and analyses were controlled for age, sex, education, and clinical diagnosis. Additional models examined genotype-specific effects of age on the imaging markers. In region-of-interest-based analyses, APOE2 carriers had significantly less precuneal amyloid pathology and did not show the typical age-related increase in amyloid load, although the age × genotype interaction was only trend-level significant. In contrast, parietal metabolism and hippocampal volume did not differ between APOE2 and APOE3 genotypes, and both groups showed comparable negative effects of age on these markers. The amyloid specificity of APOE2-related brain changes was corroborated in 2 complementary analyses: spatially unbiased voxel-wise analyses showing widespread reductions in amyloid deposition but no differences in gray matter volume or metabolism and an analysis of CSF-based biomarkers showing a significant effect on amyloid but not on tau pathology. Regarding the range of Alzheimer disease biomarkers considered in the present study, the APOE2 allele appears to have a relatively selective effect on reduced accumulation of amyloid pathology in the aged brain. © 2017 American Academy of Neurology.

  5. The Luminescent Oligothiophene p-FTAA Converts Toxic Aβ1–42 Species into Nontoxic Amyloid Fibers with Altered Properties*

    PubMed Central

    Civitelli, Livia; Sandin, Linnea; Nelson, Erin; Khattak, Sikander Iqbal; Kågedal, Katarina

    2016-01-01

    Aggregation of the amyloid-β peptide (Aβ) in the brain leads to the formation of extracellular amyloid plaques, which is one of the pathological hallmarks of Alzheimer disease (AD). It is a general hypothesis that soluble prefibrillar assemblies of the Aβ peptide, rather than mature amyloid fibrils, cause neuronal dysfunction and memory impairment in AD. Thus, reducing the level of these prefibrillar species by using molecules that can interfere with the Aβ fibrillation pathway may be a valid approach to reduce Aβ cytotoxicity. Luminescent-conjugated oligothiophenes (LCOs) have amyloid binding properties and spectral properties that differ when they bind to protein aggregates with different morphologies and can therefore be used to visualize protein aggregates. In this study, cell toxicity experiments and biophysical studies demonstrated that the LCO p-FTAA was able to reduce the pool of soluble toxic Aβ species in favor of the formation of larger insoluble nontoxic amyloid fibrils, there by counteracting Aβ-mediated cytotoxicity. Moreover, p-FTAA bound to early formed Aβ species and induced a rapid formation of β-sheet structures. These p-FTAA generated amyloid fibrils were less hydrophobic and more resistant to proteolysis by proteinase K. In summary, our data show that p-FTAA promoted the formation of insoluble and stable Aβ species that were nontoxic which indicates that p-FTAA might have therapeutic potential. PMID:26907684

  6. Hybrid Amyloid Membranes for Continuous Flow Catalysis.

    PubMed

    Bolisetty, Sreenath; Arcari, Mario; Adamcik, Jozef; Mezzenga, Raffaele

    2015-12-29

    Amyloid fibrils are promising nanomaterials for technological applications such as biosensors, tissue engineering, drug delivery, and optoelectronics. Here we show that amyloid-metal nanoparticle hybrids can be used both as efficient active materials for wet catalysis and as membranes for continuous flow catalysis applications. Initially, amyloid fibrils generated in vitro from the nontoxic β-lactoglobulin protein act as templates for the synthesis of gold and palladium metal nanoparticles from salt precursors. The resulting hybrids possess catalytic features as demonstrated by evaluating their activity in a model catalytic reaction in water, e.g., the reduction of 4-nitrophenol into 4-aminophenol, with the rate constant of the reduction increasing with the concentration of amyloid-nanoparticle hybrids. Importantly, the same nanoparticles adsorbed onto fibrils surface show improved catalytic efficiency compared to the same unattached particles, pointing at the important role played by the amyloid fibril templates. Then, filter membranes are prepared from the metal nanoparticle-decorated amyloid fibrils by vacuum filtration. The resulting membranes serve as efficient flow catalysis active materials, with a complete catalytic conversion achieved within a single flow passage of a feeding solution through the membrane.

  7. Amyloid imaging in prodromal Alzheimer's disease

    PubMed Central

    2011-01-01

    Patients with mild cognitive impairment are at an increased risk of progression to Alzheimer's disease. However, not all patients with mild cognitive impairment progress, and it is difficult to accurately identify those patients who are in the prodromal stage of Alzheimer's disease. In a recent paper, Koivunen and colleagues report that Pittsburgh compound-B, an amyloid-beta positron emission tomography ligand, predicts the progression of patients with mild cognitive impairment to Alzheimer's disease. Of 29 subjects with mild cognitive impairment, 21 (72%) had a positive Pittsburgh compound-B positron emission tomography baseline scan. In their study, 15 of these 21 (71%) patients progressed to Alzheimer's disease, whilst only 1 out of 8 (12.5%) Pittsburgh compound-B-negative patients with mild cognitive impairment did so. Moreover, in these mild cognitive impairment patients, the overall amyloid burden increased approximately 2.5% during the follow-up period. This is consistent with other longitudinal amyloid imaging studies that found a similar increase in amyloid deposition over time in patients with mild cognitive impairment. These studies together challenge current theories that propose a flattening of the increase of brain amyloid deposition already in the preclinical stage of Alzheimer's disease. These findings may have important implications for the design of future clinical trials aimed at preventing progression to Alzheimer's disease by lowering the brain amyloid-beta burden in patients with mild cognitive impairment. PMID:21936965

  8. Supersaturation-limited and Unlimited Phase Transitions Compete to Produce the Pathway Complexity in Amyloid Fibrillation.

    PubMed

    Adachi, Masayuki; So, Masatomo; Sakurai, Kazumasa; Kardos, József; Goto, Yuji

    2015-07-17

    Although amyloid fibrils and amorphous aggregates are two types of aggregates formed by denatured proteins, their relationship currently remains unclear. We used β2-microglobulin (β2m), a protein responsible for dialysis-related amyloidosis, to clarify the mechanism by which proteins form either amyloid fibrils or amorphous aggregates. When ultrasonication was used to accelerate the spontaneous fibrillation of β2m at pH 2.0, the effects observed depended on ultrasonic power; although stronger ultrasonic power effectively accelerated fibrillation, excessively strong ultrasonic power decreased the amount of fibrils formed, as monitored by thioflavin T fluorescence. An analysis of the products formed indicated that excessively strong ultrasonic power generated fibrillar aggregates that retained β-structures but without high efficiency as seeds. On the other hand, when the spontaneous fibrillation of β2m was induced at higher concentrations of NaCl at pH 2.0 with stirring, amorphous aggregates became more dominant than amyloid fibrils. These apparent complexities in fibrillation were explained comprehensively by a competitive mechanism in which supersaturation-limited reactions competed with supersaturation-unlimited reactions. We link the kinetics of protein aggregation and a conformational phase diagram, in which supersaturation played important roles. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Supersaturation-limited and Unlimited Phase Transitions Compete to Produce the Pathway Complexity in Amyloid Fibrillation*

    PubMed Central

    Adachi, Masayuki; So, Masatomo; Sakurai, Kazumasa; Kardos, József; Goto, Yuji

    2015-01-01

    Although amyloid fibrils and amorphous aggregates are two types of aggregates formed by denatured proteins, their relationship currently remains unclear. We used β2-microglobulin (β2m), a protein responsible for dialysis-related amyloidosis, to clarify the mechanism by which proteins form either amyloid fibrils or amorphous aggregates. When ultrasonication was used to accelerate the spontaneous fibrillation of β2m at pH 2.0, the effects observed depended on ultrasonic power; although stronger ultrasonic power effectively accelerated fibrillation, excessively strong ultrasonic power decreased the amount of fibrils formed, as monitored by thioflavin T fluorescence. An analysis of the products formed indicated that excessively strong ultrasonic power generated fibrillar aggregates that retained β-structures but without high efficiency as seeds. On the other hand, when the spontaneous fibrillation of β2m was induced at higher concentrations of NaCl at pH 2.0 with stirring, amorphous aggregates became more dominant than amyloid fibrils. These apparent complexities in fibrillation were explained comprehensively by a competitive mechanism in which supersaturation-limited reactions competed with supersaturation-unlimited reactions. We link the kinetics of protein aggregation and a conformational phase diagram, in which supersaturation played important roles. PMID:26063798

  10. Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis.

    PubMed

    Luo, Jinghui; Wärmländer, Sebastian K T S; Gräslund, Astrid; Abrahams, Jan Pieter

    2016-08-05

    Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer disease amyloid-β (Aβ) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer disease should be expanded to include cross-interactions between Aβ and other amyloid proteins. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Primary amyloid goiter mimicking rapid growing thyroid malignancy.

    PubMed

    Joung, Kyong Hye; Park, Jae-Yong; Kim, Koon Soon; Koo, Bon Seok

    2014-02-01

    Amyloid accumulation in the thyroid gland leading to a clinically detectable mass, known as amyloid goiter, is a rare condition associated with primary amyloidosis. Moreover, a localized primary amyloid goiter involving only the thyroid gland is rarer still. Here, we report a patient with a localized primary amyloid goiter that had grown rapidly, causing dysphagia and dyspnea on exercise, and confused us with malignancy such as anaplastic carcinoma. After surgery, no further symptoms occurred. A diagnosis of amyloid goiter was established on microscopic examination. In patients with a rapidly enlarging thyroid gland presenting with dysphagia, dyspnea, or hoarseness, amyloid goiter and malignancy should both be suspected, even when systemic amyloidosis is not suspected.

  12. Ablation of TRPM5 in Mice Results in Reduced Body Weight Gain and Improved Glucose Tolerance and Protects from Excessive Consumption of Sweet Palatable Food when Fed High Caloric Diets

    PubMed Central

    Larsson, Marie H.; Håkansson, Pernilla; Jansen, Frank P.; Magnell, Kerstin; Brodin, Peter

    2015-01-01

    The calcium activated cation channel transient receptor potential channel type M5 (TRPM5) is part of the downstream machinery of the taste receptors and have been shown to play a central role in taste signalling. In addition it is also found in other types of chemosensory cells in various parts of the body as well as in pancreatic β-cells. The aim of this study was to investigate the effects of TRPM5 gene ablation on body weight, insulin sensitivity and other metabolic parameters in long-term high caloric diet induced obesity. Trpm5-/- mice gained significantly less body weight and fat mass on both palatable carbohydrate and fat rich cafeteria diet and 60% high fat diet (HFD) and developed less insulin resistance compared to wild type mice. A main finding was the clearly improved glucose tolerance in Trpm5-/- mice compared to wild type mice on cafeteria diet, which was independent of body weight. In addition, it was shown that Trpm5-/- mice consumed the same amount of calories when fed a HFD only or a HFD in combination with a palatable chocolate ball, which is in contrast to wild type mice that increased their caloric intake when fed the combination, mainly due to excessive consumption of the chocolate ball. Thus the palatable sugar containing diet induced overeating was prevented in Trpm5-/- mice. This indicates that sweet taste induced overeating may be a cause for the increased energy intake and glucose intolerance development seen for wild type mice on a sugar and high fat rich cafeteria diet compared to when on a high fat diet. This study point to an important role for the taste signalling system and TRPM5 in diet induced glucose intolerance. PMID:26397098

  13. Ablation of TRPM5 in Mice Results in Reduced Body Weight Gain and Improved Glucose Tolerance and Protects from Excessive Consumption of Sweet Palatable Food when Fed High Caloric Diets.

    PubMed

    Larsson, Marie H; Håkansson, Pernilla; Jansen, Frank P; Magnell, Kerstin; Brodin, Peter

    2015-01-01

    The calcium activated cation channel transient receptor potential channel type M5 (TRPM5) is part of the downstream machinery of the taste receptors and have been shown to play a central role in taste signalling. In addition it is also found in other types of chemosensory cells in various parts of the body as well as in pancreatic β-cells. The aim of this study was to investigate the effects of TRPM5 gene ablation on body weight, insulin sensitivity and other metabolic parameters in long-term high caloric diet induced obesity. Trpm5-/- mice gained significantly less body weight and fat mass on both palatable carbohydrate and fat rich cafeteria diet and 60% high fat diet (HFD) and developed less insulin resistance compared to wild type mice. A main finding was the clearly improved glucose tolerance in Trpm5-/- mice compared to wild type mice on cafeteria diet, which was independent of body weight. In addition, it was shown that Trpm5-/- mice consumed the same amount of calories when fed a HFD only or a HFD in combination with a palatable chocolate ball, which is in contrast to wild type mice that increased their caloric intake when fed the combination, mainly due to excessive consumption of the chocolate ball. Thus the palatable sugar containing diet induced overeating was prevented in Trpm5-/- mice. This indicates that sweet taste induced overeating may be a cause for the increased energy intake and glucose intolerance development seen for wild type mice on a sugar and high fat rich cafeteria diet compared to when on a high fat diet. This study point to an important role for the taste signalling system and TRPM5 in diet induced glucose intolerance.

  14. MR microscopy of human amyloid-β deposits: characterization of parenchymal amyloid, diffuse plaques, and vascular amyloid.

    PubMed

    Nabuurs, Rob J A; Natté, Remco; de Ronde, Fenna M; Hegeman-Kleinn, Ingrid; Dijkstra, Jouke; van Duinen, Sjoerd G; Webb, Andrew G; Rozemuller, Annemieke J; van Buchem, Mark A; van der Weerd, Louise

    2013-01-01

    Cerebral deposits of amyloid-β peptides (Aβ) form the neuropathological hallmarks of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In the brain, Aβ can aggregate as insoluble fibrils present in amyloid plaques and vascular amyloid, or as diffuse plaques consisting of mainly non-fibrillar Aβ. Previously, magnetic resonance imaging (MRI) has been shown to be capable of detecting individual amyloid plaques, not only via the associated iron, but also Aβ itself has been suggested to be responsible for a decrease in the image intensity. In this current study we aim to investigate the MRI properties of the different cerebral Aβ deposits including diffuse plaques and vascular amyloid. Postmortem 60-μm-thick brain sections of AD, CAA, and Down's syndrome patients, known to contain Aβ, were studied. High resolution T2*- and T2-weighted MRI scans and quantitative relaxation maps were acquired using a microcoil on a Bruker 9.4T MRI system. Specific MRI characteristics of each type of Aβ deposit were examined by co-registration of the MRI with Congo Red and Aβ-immunostainings of the same sections. Our results show that only fibrillar Aβ, present in both vascular and parenchymal amyloid, induced a significant change in T2* and T2 values. However, signal changes were not as consistent for all of the vessels affected by CAA, irrespective of possible dyshoric changes. In contrast, the non-fibrillar diffuse plaques did not create any detectable MRI signal changes. These findings are relevant for the interpretation and further development of (quantitative) MRI methods for the detection and follow-up of AD and CAA.

  15. Premium subsidies for health insurance: excessive coverage vs. adverse selection.

    PubMed

    Selden, T M

    1999-12-01

    The tax subsidy for employment-related health insurance can lead to excessive coverage and excessive spending on medical care. Yet, the potential also exists for adverse selection to result in the opposite problem-insufficient coverage and underconsumption of medical care. This paper uses the model of Rothschild and Stiglitz (R-S) to show that a simple linear premium subsidy can correct market failure due to adverse selection. The optimal linear subsidy balances welfare losses from excessive coverage against welfare gains from reduced adverse selection. Indeed, a capped premium subsidy may mitigate adverse selection without creating incentives for excessive coverage.

  16. Chronic copper exposure exacerbates both amyloid and tau pathology and selectively dysregulates cdk5 in a mouse model of AD.

    PubMed

    Kitazawa, Masashi; Cheng, David; Laferla, Frank M

    2009-03-01

    Excess copper exposure is thought to be linked to the development of Alzheimer's disease (AD) neuropathology. However, the mechanism by which copper affects the CNS remains unclear. To investigate the effect of chronic copper exposure on both beta-amyloid and tau pathologies, we treated young triple transgenic (3xTg-AD) mice with 250 ppm copper-containing water for a period of 3 or 9 months. Copper exposure resulted in altered amyloid precursor protein processing; increased accumulation of the amyloid precursor protein and its proteolytic product, C99 fragment, along with increased generation of amyloid-beta peptides and oligomers. These changes were found to be mediated via up-regulation of BACE1 as significant increases in BACE1 levels and deposits were detected around plaques in mice following copper exposure. Furthermore, tau pathology within hippocampal neurons was exacerbated in copper-exposed 3xTg-AD group. Increased tau phosphorylation was closely correlated with aberrant cdk5/p25 activation, suggesting a role for this kinase in the development of copper-induced tau pathology. Taken together, our data suggest that chronic copper exposure accelerates not only amyloid pathology but also tau pathology in a mouse model of AD.

  17. Amyloid Imaging in Mild Cognitive Impairment Subtypes

    PubMed Central

    Wolk, David A.; Price, Julie C.; Saxton, Judy A.; Snitz, Beth E.; James, Jeffrey A.; Lopez, Oscar L.; Aizenstein, Howard J.; Cohen, Ann D.; Weissfeld, Lisa A.; Mathis, Chester A.; Klunk, William E.; DeKosky, Steven T.

    2010-01-01

    Objective We utilized the amyloid imaging ligand Pittsburgh Compound-B (PiB) to determine the presence of AD pathology in different MCI subtypes and to relate elevated PiB binding to other markers of early AD and longitudinal outcome. Methods Twenty-six patients with MCI – 13 single domain amnestic-MCI (sd a-MCI), 6 multiple domain amnestic-MCI (md a-MCI), and 7 non-amnestic MCI (na-MCI) – underwent PiB imaging. Twenty-three had clinical follow-up [21.2 ± 16.0 (SD) months] subsequent to their PiB scan. Results Using cutoffs established from a control cohort, 14 (54%) had elevated levels of PiB retention and were considered “amyloid-positive.” All subtypes were associated with a significant proportion of amyloid-positive patients (6/13 sd a-MCI, 5/6 md a-MCI, 3/7 na-MCI). There were no obvious differences in the distribution of PiB retention in the na-MCI group despite their atypical early AD phenotype. Predictors of conversion to clinical AD in a-MCI, including poorer episodic memory, increased age, and medial temporal atrophy, were found in the amyloid-positive relative to amyloid-negative a-MCI patients. Longitudinal follow-up revealed 5/13 amyloid-positive patients, but 0/10 amyloid-negative patients, converted to clinical AD. Further, 3/10 amyloid-negative patients “reverted to normal” on follow-up. Interpretation These data support the notion that amyloid-positive patients are likely to have early AD and that the use of amyloid imaging may have an important role in determining which patients are likely to benefit from disease-specific therapies. In addition, our data is consistent with longitudinal studies suggesting that a significant percentage of all MCI subtypes will develop clinical AD. PMID:19475670

  18. 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 Aβ42 peptide, the Aβ42 /Aβ40 ratio, and the levels of Aβ oligomers such as trimers and tetramers. Moreover, we show that activating Wnt signaling reduces the levels of Aβ42 and its aggregates, increases Aβ40 levels, and reduces the Aβ42 /Aβ40 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.

  19. Beyond Amyloid: Getting Real about Non-Amyloid Targets in Alzheimer’s Disease

    PubMed Central

    Herrup, Karl; Carrillo, Maria; Schenk, Dale; Cacace, Angela; DeSanti, Susan; Fremeau, Robert; Bhat, Ratan; Glicksman, Marcie; May, Patrick; Swerdlow, Russell; van Eldik, Linda; Bain, Lisa J.; Budd, Samantha

    2014-01-01

    For decades, researchers have focused primarily on a pathway initiated by beta-amyloid (Aβ) aggregation, amyloid deposition, and accumulation in the brain as the key mechanism underlying the disease and the most important treatment target. However, evidence increasingly suggests that amyloid is deposited early in the course of disease, even prior to the onset of clinical symptoms; thus, targeting amyloid in mild-to-moderate patients, as past failed clinical trials have done, may be insufficient to halt further disease progression. Scientists are investigating other molecular and cellular pathways and processes that contribute to AD pathogenesis. Thus, the Alzheimer’s Association’s Research Roundtable convened a meeting in April 2012 to move beyond amyloid and explore AD as a complex multi-factorial disease, with the goal of using a more inclusive perspective to identify novel treatment strategies. PMID:23809366

  20. Carnosine's Effect on Amyloid Fibril Formation and Induced Cytotoxicity of Lysozyme

    PubMed Central

    Wu, Josephine W.; Liu, Kuan-Nan; How, Su-Chun; Chen, Wei-An; Lai, Chia-Min; Liu, Hwai-Shen; Hu, Chaur-Jong; Wang, Steven S. -S.

    2013-01-01

    Carnosine, a common dipeptide in mammals, has previously been shown to dissemble alpha-crystallin amyloid fibrils. To date, the dipeptide's anti-fibrillogensis effect has not been thoroughly characterized in other proteins. For a more complete understanding of carnosine's mechanism of action in amyloid fibril inhibition, we have investigated the effect of the dipeptide on lysozyme fibril formation and induced cytotoxicity in human neuroblastoma SH-SY5Y cells. Our study demonstrates a positive correlation between the concentration and inhibitory effect of carnosine against lysozyme fibril formation. Molecular docking results show carnosine's mechanism of fibrillogenesis inhibition may be initiated by binding with the aggregation-prone region of the protein. The dipeptide attenuates the amyloid fibril-induced cytotoxicity of human neuronal cells by reducing both apoptotic and necrotic cell deaths. Our study provides solid support for carnosine's amyloid fibril inhibitory property and its effect against fibril-induced cytotoxicity in SH-SY5Y cells. The additional insights gained herein may pave way to the discovery of other small molecules that may exert similar effects against amyloid fibril formation and its associated neurodegenerative diseases. PMID:24349167

  1. Identifying structural features of fibrillar islet amyloid polypeptide using site-directed spin labeling.

    PubMed

    Jayasinghe, Sajith A; Langen, Ralf

    2004-11-12

    Pancreatic amyloid deposits, composed primarily of the 37-residue islet amyloid polypeptide (IAPP), are a characteristic feature found in more than 90% of patients with type II diabetes. Although IAPP amyloid deposits are associated with areas of pancreatic islet beta-cell dysfunction and depletion and are thought to play a role in disease, their structure is unknown. We used electron paramagnetic resonance spectroscopy to analyze eight spin-labeled derivatives of IAPP in an effort to determine structural features of the peptide. In solution, all eight derivatives gave rise to electron paramagnetic resonance spectra with sharp lines indicative of rapid motion on the sub-nanosecond time scale. These spectra are consistent with a rapidly tumbling and highly dynamic peptide. In contrast, spectra for the fibrillar form exhibit reduced mobility and the presence of strong intermolecular spin-spin interactions. The latter implies that the peptide subunits are ordered and that the same residues from neighboring peptides are in close proximity to one another. Our data are consistent with a parallel arrangement of IAPP peptides within the amyloid fibril. Analysis of spin label mobility indicates a high degree of order throughout the peptide, although the N-terminal region is slightly less ordered. Possible similarities with respect to the domain organization and parallelism of Alzheimer's amyloid beta peptide fibrils are discussed.

  2. Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease.

    PubMed

    Pistollato, Francesca; Sumalla Cano, Sandra; Elio, Iñaki; Masias Vergara, Manuel; Giampieri, Francesca; Battino, Maurizio

    2016-10-01

    It has been hypothesized that alterations in the composition of the gut microbiota might be associated with the onset of certain human pathologies, such as Alzheimer disease, a neurodegenerative syndrome associated with cerebral accumulation of amyloid-β fibrils. It has been shown that bacteria populating the gut microbiota can release significant amounts of amyloids and lipopolysaccharides, which might play a role in the modulation of signaling pathways and the production of proinflammatory cytokines related to the pathogenesis of Alzheimer disease. Additionally, nutrients have been shown to affect the composition of the gut microbiota as well as the formation and aggregation of cerebral amyloid-β. This suggests that modulating the gut microbiome and amyloidogenesis through specific nutritional interventions might prove to be an effective strategy to prevent or reduce the risk of Alzheimer disease. This review examines the possible role of the gut in the dissemination of amyloids, the role of the gut microbiota in the regulation of the gut-brain axis, the potential amyloidogenic properties of gut bacteria, and the possible impact of nutrients on modulation of microbiota composition and amyloid formation in relation to the pathogenesis of Alzheimer disease.

  3. Review of the advances in treatment for Alzheimer disease: Strategies for combating β-amyloid protein.

    PubMed

    Folch, J; Ettcheto, M; Petrov, D; Abad, S; Pedrós, I; Marin, M; Olloquequi, J; Camins, A

    2015-05-11

    Alzheimer disease (AD) is a major neurodegenerative disorder which eventually results in total intellectual disability. The high global prevalence and the socioeconomic burden associated with the disease pose major challenges for public health in the 21st century. In this review we focus on both existing treatments and the therapies being developed, which principally target the β-amyloid protein. The amyloidogenic hypothesis proposes that β-amyloid plays a key role in AD. Several pharmacological approaches aim to reduce the formation of β-amyloid peptides by inhibiting the β-secretase and γ-secretase enzymes. In addition, both passive and active immunotherapies have been developed for the purpose of inhibiting β-amyloid peptide aggregation. Progress in identifying the molecular basis of AD may provide better models for understanding the causes of this neurodegenerative disease. The lack of efficacy of solanezumab (a humanised monoclonal antibody that promotes β-amyloid clearance in the brain), demonstrated by 2 recent Phase III clinical trials in patients with mild AD, suggests that the amyloidogenic hypothesis needs to be revised. Copyright © 2015 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

  4. Cupric-amyloid beta peptide complex stimulates oxidation of ascorbate and generation of hydroxyl radical.

    PubMed

    Dikalov, Sergey I; Vitek, Michael P; Mason, Ronald P

    2004-02-01

    A growing body of evidence supports an important role for oxidative stress in the pathogenesis of Alzheimer's disease. Recently, a number of papers have shown a synergistic neurotoxicity of amyloid beta peptide and cupric ions. We hypothesized that complexes of cupric ions with neurotoxic amyloid beta peptides (Abeta) can stimulate copper-mediated free radical formation. We found that neurotoxic Abeta (1-42), Abeta (1-40), and Abeta (25-35) stimulated copper-mediated oxidation of ascorbate, whereas nontoxic Abeta (40-1) did not. Formation of ascorbate free radical was significantly increased by Abeta (1-42) in the presence of ceruloplasmin. Once cupric ion is reduced to cuprous ion, it can be oxidized by oxygen to generate superoxide radical or it can react with hydrogen peroxide to form hydroxyl radical. Hydrogen peroxide greatly increased the oxidation of cyclic hydroxylamines and ascorbate by cupric-amyloid beta peptide complexes, implying redox cycling of copper ions. Using the spin-trapping technique, we have shown that toxic amyloid beta peptides led to a 4-fold increase in copper-mediated hydroxyl radical formation. We conclude that toxic Abeta peptides do indeed stimulate copper-mediated oxidation of ascorbate and generation of hydroxyl radicals. Therefore, cupric-amyloid beta peptide-stimulated free radical generation may be involved in the pathogenesis of Alzheimer's disease.

  5. Carnosine's effect on amyloid fibril formation and induced cytotoxicity of lysozyme.

    PubMed

    Wu, Josephine W; Liu, Kuan-Nan; How, Su-Chun; Chen, Wei-An; Lai, Chia-Min; Liu, Hwai-Shen; Hu, Chaur-Jong; Wang, Steven S-S

    2013-01-01

    Carnosine, a common dipeptide in mammals, has previously been shown to dissemble alpha-crystallin amyloid fibrils. To date, the dipeptide's anti-fibrillogensis effect has not been thoroughly characterized in other proteins. For a more complete understanding of carnosine's mechanism of action in amyloid fibril inhibition, we have investigated the effect of the dipeptide on lysozyme fibril formation and induced cytotoxicity in human neuroblastoma SH-SY5Y cells. Our study demonstrates a positive correlation between the concentration and inhibitory effect of carnosine against lysozyme fibril formation. Molecular docking results show carnosine's mechanism of fibrillogenesis inhibition may be initiated by binding with the aggregation-prone region of the protein. The dipeptide attenuates the amyloid fibril-induced cytotoxicity of human neuronal cells by reducing both apoptotic and necrotic cell deaths. Our study provides solid support for carnosine's amyloid fibril inhibitory property and its effect against fibril-induced cytotoxicity in SH-SY5Y cells. The additional insights gained herein may pave way to the discovery of other small molecules that may exert similar effects against amyloid fibril formation and its associated neurodegenerative diseases.

  6. Alzheimer disease therapy--moving from amyloid-β to tau.

    PubMed

    Giacobini, Ezio; Gold, Gabriel

    2013-12-01

    Disease-modifying treatments for Alzheimer disease (AD) have focused mainly on reducing levels of amyloid-β (Aβ) in the brain. Some compounds have achieved this goal, but none has produced clinically meaningful results. Several methodological issues relating to clinical trials of these agents might explain this failure; an additional consideration is that the amyloid cascade hypothesis--which places amyloid plaques at the heart of AD pathogenesis--does not fully integrate a large body of data relevant to the emergence of clinical AD. Importantly, amyloid deposition is not strongly correlated with cognition in multivariate analyses, unlike hyperphosphorylated tau, neurofibrillary tangles, and synaptic and neuronal loss, which are closely associated with memory deficits. Targeting tau pathology, therefore, might be more clinically effective than Aβ-directed therapies. Furthermore, numerous immunization studies in animal models indicate that reduction of intracellular levels of tau and phosphorylated tau is possible, and is associated with improved cognitive performance. Several tau-related vaccines are in advanced preclinical stages and will soon enter clinical trials. In this article, we present a critical analysis of the failure of Aβ-directed therapies, discuss limitations of the amyloid cascade hypothesis, and suggest the potential value of tau-targeted therapy for AD.

  7. Investigating the effects of erythrosine B on amyloid fibril formation derived from lysozyme.

    PubMed

    Kuo, Chun-Tien; Chen, Yi-Lin; Hsu, Wei-Tse; How, Su-Chun; Cheng, Yu-Hong; Hsueh, Shu-Shun; Liu, Hwai-Shen; Lin, Ta-Hsien; Wu, Josephine W; Wang, Steven S-S

    2017-05-01

    Formation of amyloid fibrils has been associated with at least 30 different protein aggregation diseases. The 129-residue polypeptide hen lysozyme, which is structurally homologous to human lysozyme, has been demonstrated to exhibit amyloid fibril-forming propensity in vitro. This study is aimed at exploring the influence of erythrosine B on the in vitro amyloid fibril formation of hen lysozyme at pH 2.0 and 55°C using ThT binding assay, transmission electron microscopy, far-UV circular dichroism absorption spectroscopy, 1-anilinonaphthalene-8-sulfonic acid fluorescence spectroscopy, and synchronous fluorescence study. We found that lysozyme fibrillogenesis was dose-dependently suppressed by erythrosine B. In addition, our far-UV CD and ANS fluorescence data showed that, as compared with the untreated lysozyme control, the α-to-ß transition and exposure of hydrophobic clusters in lysozyme were reduced upon treatment with erythrosine B. Moreover, it could be inferred that the binding of erythrosine B occurred in the vicinity of the tryptophan residues. Finally, molecular docking and molecular dynamics simulations were further employed to gain some insights into the possible binding site(s) and interactions between lysozyme and erythrosine B. We believe the results obtained here may contribute to the development of potential strategies/approaches for the suppression of amyloid fibrillogenesis, which is implicated in amyloid pathology.

  8. Anxiety symptoms, cerebral amyloid burden and memory decline in healthy older adults without dementia: 3-year prospective cohort study.

    PubMed

    Pietrzak, Robert H; Scott, J Cobb; Neumeister, Alexander; Lim, Yen Ying; Ames, David; Ellis, Kathryn A; Harrington, Karra; Lautenschlager, Nicola T; Szoeke, Cassandra; Martins, Ralph N; Masters, Colin L; Villemagne, Victor L; Rowe, Christopher C; Maruff, Paul

    2014-01-01

    Although beta-amyloid, anxiety and depression have linked cross-sectionally to reduced memory function in healthy older adults without dementia, prospective data evaluating these associations are lacking. Using data an observational cohort study of 178 healthy older adults without dementia followed for 3 years, we found that anxiety symptoms significantly moderated the relationship between beta-amyloid level and decline in verbal (Cohen's d = 0.65) and episodic (Cohen's d = 0.38) memory. Anxiety symptoms were additionally linked to greater decline in executive function, irrespective of beta-amyloid and other risk factors. These findings suggest that interventions to mitigate anxiety symptoms may help delay memory decline in otherwise healthy older adults with elevated beta-amyloid.

  9. Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease

    PubMed Central

    DeMattos, Ronald B.; O'dell, Mark A.; Parsadanian, Maia; Taylor, Jennie W.; Harmony, Judith A. K.; Bales, Kelly R.; Paul, Steven M.; Aronow, Bruce J.; Holtzman, David M.

    2002-01-01

    Studies have shown that clusterin (also called apolipoprotein J) can influence the structure and toxicity of amyloid-β (Aβ) in vitro. To determine whether endogenous clusterin plays a role in influencing Aβ deposition, structure, and toxicity in vivo, we bred PDAPP mice, a transgenic mouse model of Alzheimer's disease, to clusterin−/− mice. By 12 months of age, PDAPP, clusterin−/− mice had similar levels of brain Aβ deposition as did PDAPP, clusterin+/+ mice. Although Aβ deposition was similar, PDAPP, clusterin−/− mice had significantly fewer fibrillar Aβ (amyloid) deposits than PDAPP mice expressing clusterin. In the absence of clusterin, neuritic dystrophy associated with the deposited amyloid was markedly reduced, resulting in a dissociation between fibrillar amyloid formation and neuritic dystrophy. These findings demonstrate that clusterin markedly influences Aβ structure and neuritic toxicity in vivo and is likely to play an important role in Alzheimer's disease pathogenesis. PMID:12145324

  10. [Conservative and surgical treatment of convergence excess].

    PubMed

    Ehrt, O

    2016-07-01

    Convergence excess is a common finding especially in pediatric strabismus. A detailed diagnostic approach has to start after full correction of any hyperopia measured in cycloplegia. It includes measurements of manifest and latent deviation at near and distance fixation, near deviation after relaxation of accommodation with addition of +3 dpt, assessment of binocular function with and without +3 dpt as well as the accommodation range. This diagnostic approach is important for the classification into three types of convergence excess, which require different therapeutic approaches: 1) hypo-accommodative convergence excess is treated with permanent bifocal glasses, 2) norm-accommodative patients should be treated with bifocals which can be weaned over years, especially in patients with good stereopsis and 3) non-accommodative convergence excess and patients with large distance deviations need a surgical approach. The most effective operations include those which reduce the muscle torque, e. g. bimedial Faden operations or Y‑splitting of the medial rectus muscles.

  11. Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice.

    PubMed

    Pan, Xiaoli; Gong, Neng; Zhao, Jing; Yu, Zhe; Gu, Fenghua; Chen, Jia; Sun, Xiaojing; Zhao, Lei; Yu, Meijing; Xu, Zhiru; Dong, Wenxin; Qin, Yan; Fei, Guoqiang; Zhong, Chunjiu; Xu, Tian-Le

    2010-05-01

    Reduction of glucose metabolism in brain is one of the main features of Alzheimer's disease. Thiamine (vitamin B1)-dependent processes are critical in glucose metabolism and have been found to be impaired in brains from patients with Alzheimer's disease. However, thiamine treatment exerts little beneficial effect in these patients. Here, we tested the effect of benfotiamine, a thiamine derivative with better bioavailability than thiamine, on cognitive impairment and pathology alterations in a mouse model of Alzheimer's disease, the amyloid precursor protein/presenilin-1 transgenic mouse. We show that after a chronic 8 week treatment, benfotiamine dose-dependently enhanced the spatial memory of amyloid precursor protein/presenilin-1 mice in the Morris water maze test. Furthermore, benfotiamine effectively reduced both amyloid plaque numbers and phosphorylated tau levels in cortical areas of the transgenic mice brains. Unexpectedly, these effects were not mimicked by another lipophilic thiamine derivative, fursultiamine, although both benfotiamine and fursultiamine were effective in increasing the levels of free thiamine in the brain. Most notably, benfotiamine, but not fursultiamine, significantly elevated the phosphorylation level of glycogen synthase kinase-3alpha and -3beta, and reduced their enzymatic activities in the amyloid precursor protein/presenilin-1 transgenic brain. Therefore, in the animal Alzheimer's disease model, benfotiamine appears to improve the cognitive function and reduce amyloid deposition via thiamine-independent mechanisms, which are likely to include the suppression of glycogen synthase kinase-3 activities. These results suggest that, unlike many other thiamine-related drugs, benfotiamine may be beneficial for clinical Alzheimer's disease treatment.

  12. Consequences of Excessive Educational Planning

    ERIC Educational Resources Information Center

    Benveniste, Guy

    1974-01-01

    Discusses three issues that raise serious questions about the behavioral norms and moral obligations of educational planners. From a cost-benefit point of view, excessive planning is reached when overall societal costs exceed overall societal benefits. (Author/WM)

  13. Cyclic N-terminal loop of amylin forms non amyloid fibers.

    PubMed

    Cope, Stephanie M; Shinde, Sandip; Best, Robert B; Ghirlanda, Giovanna; Vaiana, Sara M

    2013-10-01

    We report for the first time, to our knowledge, that the N-terminal loop (N_loop) of amylin (islet amyloid polypeptide (IAPP) residues 1-8) forms extremely long and stable non-β-sheet fibers in solution under the same conditions in which human amylin (hIAPP) forms amyloid fibers. This observation applies to the cyclic, oxidized form of the N_loop but not to the linear, reduced form, which does not form fibers. Our findings indicate a potential role of direct N_loop-N_loop interactions in hIAPP aggregation, which has not been previously explored, with important implications for the mechanism of hIAPP amyloid fiber formation, the inhibitory action of IAPP variants, and the competition between ordered and disordered aggregation in peptides of the calcitonin peptide family.

  14. Cyclic N-Terminal Loop of Amylin Forms Non Amyloid Fibers

    PubMed Central

    Cope, Stephanie M.; Shinde, Sandip; Best, Robert B.; Ghirlanda, Giovanna; Vaiana, Sara M.

    2013-01-01

    We report for the first time, to our knowledge, that the N-terminal loop (N_loop) of amylin (islet amyloid polypeptide (IAPP) residues 1–8) forms extremely long and stable non-β-sheet fibers in solution under the same conditions in which human amylin (hIAPP) forms amyloid fibers. This observation applies to the cyclic, oxidized form of the N_loop but not to the linear, reduced form, which does not form fibers. Our findings indicate a potential role of direct N_loop-N_loop interactions in hIAPP aggregation, which has not been previously explored, with important implications for the mechanism of hIAPP amyloid fiber formation, the inhibitory action of IAPP variants, and the competition between ordered and disordered aggregation in peptides of the calcitonin peptide family. PMID:24094407

  15. Inhibition of Amyloid-like Fibril Formation of Trypsin by Red Wines.

    PubMed

    Kotormán, Márta; Kasi, Phanindra Babu; Halász, László; Borics, Attila

    2017-02-14

    The aim of the present study was to examine the potential role and applicability