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Sample records for alzheimer-like amyloid pathology

  1. Cnga2 Knockout Mice Display Alzheimer's-Like Behavior Abnormities and Pathological Changes.

    PubMed

    Xie, Ao-Ji; Liu, En-Jie; Huang, He-Zhou; Hu, Yu; Li, Ke; Lu, Youming; Wang, Jian-Zhi; Zhu, Ling-Qiang

    2016-09-01

    Olfactory dysfunction is recognized as a potential risk factor for Alzheimer's disease (AD). We have reported previously that olfactory deprivation by olfactory bulbectomy (OBX) induced Alzheimer's-like pathological changes and behavioral abnormalities. However, the acute OBX model undergoes surgical-induced brain parenchyma loss and unexpected massive hemorrhage so that it cannot fully mimic the progressive olfactory loss and neurodegeneration in AD. Here, we employed the mice loss of cyclic nucleotide-gated channel alpha 2 (Cnga2) which is critical for olfactory sensory transduction, to investigate the role of olfactory dysfunction in AD pathological process. We found that impaired learning and memory abilities, loss of dendrite spines, as well as decrement of synaptic proteins were displayed in Cnga2 knockout mice. Moreover, Aβ overproduction, tau hyperphosphorylation, and somatodendritic translocation were also found in Cnga2 knockout mice. Our findings suggest that progressive olfactory loss leads to Alzheimer's-like behavior abnormities and pathological changes. PMID:26377105

  2. Lipolysaccharide-Induced Neuroinflammation Is Associated with Alzheimer-Like Amyloidogenic Axonal Pathology and Dendritic Degeneration in Rats

    PubMed Central

    Deng, Xiaohua; Li, Meili; Ai, Weiming; He, Lixin; Lu, Dahua; Patrylo, Peter R.; Cai, Huaibin; Luo, Xuegang; Li, Zhiyuan; Yan, Xiaoxin

    2014-01-01

    Chronic neuroinflammation is thought to play an etiological role in Alzheimer’s disease (AD), which is characterized pathologically by amyloid and tau formation, as well as neuritic dystrophy and synaptic degeneration. The causal relationship between these pathological events is a topic of ongoing research and discussion. Recent data from transgenic AD models point to a tight spatiotemporal link between neuritic and amyloid pathology, with the obligatory enzyme for β-amyloid (Aβ) production, namely β-secretase-1 (BACE1), is overexpressed in axon terminals undergoing dystrophic change. However, the axonal pathology inherent with BACE1 elevation seen in transgenic AD mice may be secondary to increased soluble Aβ in these genetically modified animals. Here we explored the occurrence of the AD-like axonal and dendritic pathology in adult rat brain affected by LPS-induced chronic neuroinflammation. Unilateral intracerebral LPS injection induced prominent inflammatory response in glial cells in the ipsilateral cortex and hippocampal formation. BACE1 protein levels were elevated the ipsilateral hippocampal lysates in the LPS treated animals relative to controls. BACE1 immunoreactive dystrophic axons appeared in the LPS-treated ipsilateral cortex and hippocampal formation, colocalizing with increased β-amyloid precursor protein and Aβ antibody (4G8) immunolabeling. Quantitative Golgi studies revealed reduction of dendritic branching points and spine density on cortical layer III and hippocampal CA3 pyramidal neurons in the LPS-treated ipsilateral cerebrum. These findings suggest that Alzheimer-like amyloidogenic axonal pathology and dendritic degeneration occur in wildtype mammalian brain in partnership with neuroinflammation following LPS injection. PMID:25360394

  3. Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits.

    PubMed

    Kim, Hye Yun; Lee, Dongkeun K; Chung, Bo-Ryehn; Kim, Hyunjin V; Kim, YoungSoo

    2016-01-01

    Amyloid-β (Aβ) is a major pathological mediator of both familial and sporadic Alzheimer's disease (AD). In the brains of AD patients, progressive accumulation of Aβ oligomers and plaques is observed. Such Aβ abnormalities are believed to block long-term potentiation, impair synaptic function, and induce cognitive deficits. Clinical and experimental evidences have revealed that the acute increase of Aβ levels in the brain allows development of Alzheimer-like phenotypes. Hence, a detailed protocol describing how to acutely generate an AD mouse model via the intracerebroventricular (ICV) injection of Aβ is necessary in many cases. In this protocol, the steps of the experiment with an Aβ-injected mouse are included, from the preparation of peptides to the testing of behavioral abnormalities. The process of preparing the tools and animal subjects before the injection, of injecting the Aβ into the mouse brain via ICV injection, and of assessing the degree of cognitive impairment are easily explained throughout the protocol, with an emphasis on tips for effective ICV injection of Aβ. By mimicking certain aspects of AD with a designated injection of Aβ, researchers can bypass the aging process and focus on the downstream pathology of Aβ abnormalities. PMID:27023127

  4. Cdk5 is a New Rapid Synaptic Homeostasis Regulator Capable of Initiating the Early Alzheimer-Like Pathology.

    PubMed

    Sheng, Yanghui; Zhang, Lei; Su, Susan C; Tsai, Li-Huei; Julius Zhu, J

    2016-07-01

    Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase implicated in synaptic plasticity, behavior, and cognition, yet its synaptic function remains poorly understood. Here, we report that physiological Cdk5 signaling in rat hippocampal CA1 neurons regulates homeostatic synaptic transmission using an unexpectedly rapid mechanism that is different from all known slow homeostatic regulators, such as beta amyloid (Aβ) and activity-regulated cytoskeleton-associated protein (Arc, aka Arg3.1). Interestingly, overproduction of the potent Cdk5 activator p25 reduces synapse density, and dynamically regulates synaptic size by suppressing or enhancing Aβ/Arc production. Moreover, chronic overproduction of p25, seen in Alzheimer's patients, induces initially concurrent reduction in synapse density and increase in synaptic size characteristic of the early Alzheimer-like pathology, and later persistent synapse elimination in intact brains. These results identify Cdk5 as the regulator of a novel rapid form of homeostasis at central synapses and p25 as the first molecule capable of initiating the early Alzheimer's synaptic pathology. PMID:26088971

  5. Experimental induction of type 2 diabetes in aging-accelerated mice triggered Alzheimer-like pathology and memory deficits.

    PubMed

    Mehla, Jogender; Chauhan, Balwantsinh C; Chauhan, Neelima B

    2014-01-01

    Alzheimer's disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type 2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-β, dysregulated tau-phosphorylating glycogen synthase kinase 3β, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD. PMID:24121970

  6. Experimental Induction of Type 2 Diabetes in Aging-Accelerated Mice Triggered Alzheimer-Like Pathology and Memory Deficits

    PubMed Central

    Mehla, Jogender; Chauhan, Balwantsinh C.; Chauhan, Neelima B.

    2014-01-01

    Alzheimer’s disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type 2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-β, dysregulated tau-phosphorylating glycogen synthase kinase 3β, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD. PMID:24121970

  7. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology.

    PubMed

    Olmos-Alonso, Adrian; Schetters, Sjoerd T T; Sri, Sarmi; Askew, Katharine; Mancuso, Renzo; Vargas-Caballero, Mariana; Holscher, Christian; Perry, V Hugh; Gomez-Nicola, Diego

    2016-03-01

    The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer's disease. However, the study of microglial proliferation in Alzheimer's disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer's disease, in line with an increased upregulation of the CSF1R-dependent pro-mitogenic cascade, correlating with disease severity. Using a transgenic model of Alzheimer's-like pathology (APPswe, PSEN1dE9; APP/PS1 mice) we define a CSF1R-dependent progressive increase in microglial proliferation, in the proximity of amyloid-β plaques. Prolonged inhibition of CSF1R in APP/PS1 mice by an orally available tyrosine kinase inhibitor (GW2580) resulted in the blockade of microglial proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype. Pharmacological targeting of CSF1R in APP/PS1 mice resulted in an improved performance in memory and behavioural tasks and a prevention of synaptic degeneration, although these changes were not correlated with a change in the number of amyloid-β plaques. Our results provide the first proof of the efficacy of CSF1R inhibition in models of Alzheimer's disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer's disease. PMID:26747862

  8. Regulatory T cells delay disease progression in Alzheimer-like pathology.

    PubMed

    Dansokho, Cira; Ait Ahmed, Dylla; Aid, Saba; Toly-Ndour, Cécile; Chaigneau, Thomas; Calle, Vanessa; Cagnard, Nicolas; Holzenberger, Martin; Piaggio, Eliane; Aucouturier, Pierre; Dorothée, Guillaume

    2016-04-01

    Recent studies highlight the implication of innate and adaptive immunity in the pathophysiology of Alzheimer's disease, and foster immunotherapy as a promising strategy for its treatment. Vaccines targeting amyloid-β peptide provided encouraging results in mouse models, but severe side effects attributed to T cell responses in the first clinical trial AN1792 underlined the need for better understanding adaptive immunity in Alzheimer's disease. We previously showed that regulatory T cells critically control amyloid-β-specific CD4(+) T cell responses in both physiological and pathological settings. Here, we analysed the impact of regulatory T cells on spontaneous disease progression in a murine model of Alzheimer's disease. Early transient depletion of regulatory T cells accelerated the onset of cognitive deficits in APPPS1 mice, without altering amyloid-β deposition. Earlier cognitive impairment correlated with reduced recruitment of microglia towards amyloid deposits and altered disease-related gene expression profile. Conversely, amplification of regulatory T cells through peripheral low-dose IL-2 treatment increased numbers of plaque-associated microglia, and restored cognitive functions in APPPS1 mice. These data suggest that regulatory T cells play a beneficial role in the pathophysiology of Alzheimer's disease, by slowing disease progression and modulating microglial response to amyloid-β deposition. Our study highlights the therapeutic potential of repurposed IL-2 for innovative immunotherapy based on modulation of regulatory T cells in Alzheimer's disease. PMID:26912648

  9. Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like Tau pathology.

    PubMed

    Burlot, Marie-Anne; Braudeau, Jérôme; Michaelsen-Preusse, Kristin; Potier, Brigitte; Ayciriex, Sophie; Varin, Jennifer; Gautier, Benoit; Djelti, Fathia; Audrain, Mickael; Dauphinot, Luce; Fernandez-Gomez, Francisco-Jose; Caillierez, Raphaëlle; Laprévote, Olivier; Bièche, Ivan; Auzeil, Nicolas; Potier, Marie-Claude; Dutar, Patrick; Korte, Martin; Buée, Luc; Blum, David; Cartier, Nathalie

    2015-11-01

    Alzheimer's disease (AD) is characterized by both amyloid and Tau pathologies. The amyloid component and altered cholesterol metabolism are closely linked, but the relationship between Tau pathology and cholesterol is currently unclear. Brain cholesterol is synthesized in situ and cannot cross the blood-brain barrier: to be exported from the central nervous system into the blood circuit, excess cholesterol must be converted to 24S-hydroxycholesterol by the cholesterol 24-hydroxylase encoded by the CYP46A1 gene. In AD patients, the concentration of 24S-hydroxycholesterol in the plasma and the cerebrospinal fluid are lower than in healthy controls. The THY-Tau22 mouse is a model of AD-like Tau pathology without amyloid pathology. We used this model to investigate the potential association between Tau pathology and CYP46A1 modulation. The amounts of CYP46A1 and 24S-hydroxycholesterol in the hippocampus were lower in THY-Tau22 than control mice. We used an adeno-associated virus (AAV) gene transfer strategy to increase CYP46A1 expression in order to investigate the consequences on THY-Tau22 mouse phenotype. Injection of the AAV-CYP46A1 vector into the hippocampus of THY-Tau22 mice led to CYP46A1 and 24S-hydroxycholesterol content normalization. The cognitive deficits, impaired long-term depression and spine defects that characterize the THY-Tau22 model were completely rescued, whereas Tau hyperphosphorylation and associated gliosis were unaffected. These results argue for a causal link between CYP46A1 protein content and memory impairments that result from Tau pathology. Therefore, CYP46A1 may be a relevant therapeutic target for Tauopathies and especially for AD. PMID:26358780

  10. 7,8-dihydroxyflavone ameliorates scopolamine-induced Alzheimer-like pathologic dysfunction.

    PubMed

    Chen, Chong; Li, Xiao-Hong; Zhang, Sai; Tu, Yue; Wang, Yan-Min; Sun, Hong-Tao

    2014-06-01

    Scopolamine (Sco) can induce amyloid β (Aβ) deposition, oxidative stress, synaptic dysfunction, and learning/memory impairment as observed in Alzheimer's disease (AD), the most common form of dementia affecting more than 25 million elderly people worldwide. Herein we explored the protective effect of 7,8-dihydroxyflavone (7,8-DHF) on Sco-induced Aβ deposition, oxidative stress, synaptic dysfunction, and learning/memory defects. Rats were randomly divided into four groups (n=12 for each group). The control group received normal saline (NS); the Sco group received Sco (1 mg/kg per day) intraperitoneally (i.p.) for 2 weeks. Mice in the Sco+7,8-DHF group received 1 mg/kg per day 7,8-DHF i.p. for 2 weeks, followed by Sco (1 mg/kg per day)+1 mg/kg per day 7,8-DHF (i.p.) for another 2 weeks. The 7,8-DHF group received 1 mg/kg per day 7,8-DHF (i.p.) for 4 weeks. Results showed that the supplement of 7,8-DHF significantly reversed Aβ deposition, oxidative stress, synaptic dysfunction, and cognitive defects. Our data suggest that 7,8-DHF might serve as a promising therapeutic candidate for attenuating Sco-induced AD-like pathological dysfuntion. PMID:24325271

  11. Uptake of silica nanoparticles: neurotoxicity and Alzheimer-like pathology in human SK-N-SH and mouse neuro2a neuroblastoma cells.

    PubMed

    Yang, Xifei; He, Chun'e; Li, Jie; Chen, Hongbin; Ma, Quan; Sui, Xiaojing; Tian, Shengli; Ying, Ming; Zhang, Qian; Luo, Yougen; Zhuang, Zhixiong; Liu, Jianjun

    2014-08-17

    Growing concern has been raised over the potential adverse effects of engineered nanoparticles on human health due to their increasing use in commercial and medical applications. Silica nanoparticles (SiNPs) are one of the most widely used nanoparticles in industry and have been formulated for cellular and non-viral gene delivery in the central nerve system. However, the potential neurotoxicity of SiNPs remains largely unclear. In this study, we investigated the cellular uptake of SiNPs in human SK-N-SH and mouse neuro2a (N2a) neuroblastoma cells treated with 10.0 μg/ml of 15-nm SiNPs for 24 h by transmission electron microscopy. We found that SiNPs were mainly localized in the cytoplasm of the treated cells. The treatment of SiNPs at various concentrations impaired the morphology of SK-N-SH and N2a cells, characterized by increased number of round cells, diminishing of dendrite-like processes and decreased cell density. SiNPs significantly decreased the cell viability, induced cellular apoptosis, and elevated the levels of intracellular reactive oxygen species (ROS) in a dose-dependent manner in both cell lines. Additionally, increased deposit of intracellular β-amyloid 1-42 (Aβ(1-42)) and enhanced phosphorylation of tau at Ser262 and Ser396, two specific pathological hallmarks of Alzheimer's disease (AD), were observed in both cell lines with SiNPs treatment. Concomitantly, the expression of amyloid precursor protein (APP) was up-regulated, while amyloid-β-degrading enzyme neprilysin was down-regulated in SiNP-treated cells. Finally, activity-dependent phosphorylation of glycogen syntheses kinase (GSK)-3β at Ser9 (inactive form) was significantly decreased in SiNP-treated SK-N-SH cells. Taken together, these data demonstrated that exposure to SiNPs induced neurotoxicity and pathological signs of AD. The pre-Alzheimer-like pathology induced by SiNPs might result from the dys-regulated expression of APP/neprilysin and activation of GSK-3β. This is the first

  12. Bone Marrow-Derived Endothelial Progenitor Cells Protect Against Scopolamine-Induced Alzheimer-Like Pathological Aberrations.

    PubMed

    Safar, Marwa M; Arab, Hany H; Rizk, Sherine M; El-Maraghy, Shohda A

    2016-04-01

    Vascular endothelial dysfunction plays a key role in the pathogenesis of Alzheimer's disease (AD). Patients with AD have displayed decreased circulating endothelial progenitor cells (EPCs) which repair and maintain the endothelial function. Transplantation of EPCs has emerged as a promising approach for the management of cerebrovascular diseases including ischemic stroke, however, its impact on AD has been poorly described. Thus, the current study aimed at investigating the effects of bone marrow-derived (BM) EPCs transplantation in repeated scopolamine-induced cognitive impairment, an experimental model that replicates biomarkers of AD. Intravenously transplanted BM-EPCs migrated into the brain of rats and improved the learning and memory deficits. Meanwhile, they mitigated the deposition of amyloid plaques and associated histopathological alterations. At the molecular levels, BM-EPCs blunted the increase of hippocampal amyloid beta protein (Aβ), amyloid precursor protein (APP) and reinstated the Aβ-degrading neprilysin together with downregulation of p-tau and its upstream glycogen synthase kinase-3β (GSK-3β). They also corrected the perturbations of neurotransmitter levels including restoration of acetylcholine and associated esterase along with dopamine, GABA, and the neuroexitatory glutamate. Furthermore, BM-EPCs induced behavioral recovery via boosting of vascular endothelial growth factor (VEGF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and its upstream cAMP response element binding (CREB), suppression of the proinflammatory tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and upregulation of interleukin-10 (IL-10). BM-EPCs also augmented Nrf2 and seladin-1. Generally, these actions were analogous to those exerted by adipose tissue-derived mesenchymal stem cells (AT-MSCs) and the reference anti-Alzheimer donepezil. For the first time, these findings highlight the beneficial actions of BM-EPCs against the memory

  13. Sulforaphane ameliorates neurobehavioral deficits and protects the brain from amyloid β deposits and peroxidation in mice with Alzheimer-like lesions.

    PubMed

    Zhang, Rui; Miao, Qian-Wei; Zhu, Chun-Xiao; Zhao, Yue; Liu, Li; Yang, Jun; An, Li

    2015-03-01

    Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly individuals and its effective therapies are still unavailable. This study was designed to investigate the neuroprotection of sulforaphane (SFN) in AD-lesion mice induced by combined administration of d-galactose and aluminium. Results showed that SFN ameliorated spatial cognitive impairment and locomotor activity decrease in Morris water maze and open field test, respectively. And attenuated numbers of amyloid β (Aβ) plaques in both hippocampus and cerebral cortex of AD-lesion mice were detected by immunohistochemistry. According to spectrophotometry and quantitative reverse-transcriptase polymerase chain reaction results, a significant increase in carbonyl group level and obvious decreases in both activity and messenger RNA expression of glutathione peroxidase were found in brain of AD-lesion mice compared with control, but not in SFN-treated AD-lesion mice. In conclusion, SFN ameliorates neurobehavioral deficits and protects the brain from Aβ deposits and peroxidation in mice with Alzheimer-like lesions, suggesting SFN is likely a potential phytochemical to be used in AD therapeutics. PMID:25024455

  14. Beneficial effect of antibodies against β- secretase cleavage site of APP on Alzheimer's-like pathology in triple-transgenic mice.

    PubMed

    Rabinovich-Nikitin, Inna; Rakover, Idan S; Becker, Maria; Solomon, Beka

    2012-01-01

    The toxicity of amyloid β and tau, the two hallmark proteins in Alzheimer's disease (AD), has been extensively studied individually. Recently new data suggest their possible interactions and synergistic effects in the disease. In this study, we investigate the ability of antibodies against the β secretase cleavage site on APP, named BBS1, to affect tau pathology, besides their well established effect on intracellular Aβ and amyloid load. For this purpose we treated the triple transgenic mice model of AD (3x Tg-AD) with mAb BBS1 intracerebroventricularly, using mini osmotic pumps for one month. The experimental data demonstrated reduction in total and phosphorylated tau levels, explained by significant reduction in GSK3β which phosphorylates tau on sites recognized by antibodies against PHF1 and AT-8. The treatment increased the cognitive capabilities and reduced the brain inflammation levels which accompany AD pathology. The data showing that tau pathology was significantly reduced by BBS1 antibodies suggest a close interaction between tau and Aβ in the development of AD, and may serve as an efficient novel immunotherapy against both hallmarks of this disease. PMID:23071606

  15. Prevalence of Cerebral Amyloid Pathology in Persons Without Dementia

    PubMed Central

    Jansen, Willemijn J.; Ossenkoppele, Rik; Knol, Dirk L.; Tijms, Betty M.; Scheltens, Philip; Verhey, Frans R. J.; Visser, Pieter Jelle

    2015-01-01

    IMPORTANCE Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. STUDY SELECTION Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION AND SYNTHESIS Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOEε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and

  16. The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits and Alzheimer-like pathology in an interventional study with aged tau transgenic mice

    PubMed Central

    Zhang, Bin; Carroll, Jenna; Trojanowski, John Q.; Yao, Yuemang; Iba, Michiyo; Potuzak, Justin S.; Hogan, Anne-Marie L.; Xie, Sharon X.; Ballatore, Carlo; Smith, Amos B.; Lee, Virginia M-Y.; Brunden, Kurt R.

    2012-01-01

    Neurodegenerative tauopathies, such as Alzheimer’s disease (AD), are characterized by insoluble deposits of hyperphosphorylated tau protein within brain neurons. Increased phosphorylation and decreased solubility has been proposed to diminish normal tau stabilization of microtubules (MTs), thereby leading to neuronal dysfunction. Earlier studies have provided evidence that small molecule MT-stabilizing drugs that are used in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been established whether treatment with a small molecule MT-stabilizing compound will provide benefit in a Tg model with pre-existing tau pathology, as would be seen in human patients with clinical symptoms. Accordingly, we describe here an interventional study of the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), in aged PS19 mice with existing tau pathology and related behavioral deficits. EpoD treatment reduced axonal dystrophy and increased axonal MT density in the aged PS19 mice, which led to improved fast axonal transport and cognitive performance. Moreover, the EpoD-treated PS19 mice had less forebrain tau pathology and increased hippocampal neuronal integrity, with no dose-limiting side effects. These data reveal that brain-penetrant MT-stabilizing drugs hold promise for the treatment of AD and related tauopathies, and that EpoD could be a candidate for clinical testing. PMID:22423084

  17. Genetic deletion of TNFRII gene enhances the Alzheimer-like pathology in an APP transgenic mouse model via reduction of phosphorylated IκBα.

    PubMed

    Jiang, Hong; He, Ping; Xie, Junxia; Staufenbiel, Matthias; Li, Rena; Shen, Yong

    2014-09-15

    Tumor necrosis factor receptor II (TNFRII) is one of the TNF receptor superfamily members and our recent pathological studies show that TNFRII is deficient in the brains of Alzheimer's disease (AD). However, the mechanisms of TNFRII in AD pathogenesis remain unclear. In the present study, by using the gene-targeting approach to delete TNFRII in AD transgenic mouse model, we found that, in the brain of APP23 mice with TNFRII deletion (APP23/TNFRII(-/-)), AD-like pathology, i.e. plaque formation and microglial activation, occurs as early as 6 months of age. To test whether the increased levels of Aβ plaques was due to elevated Aβ, we measured Aβ and found that Aβ levels indeed were significantly increased at this age. Because β-secretase, BACE1, is critical enzyme for Aβ production, we have examined BACE1 and found that BACE1 is increased in both protein levels and enzymatic activity as early as 6 months of age; Having shown that BACE1 promoter region contains NF-κB binding sites, we found that cytoplasmic NF-κB was elevated and SUMO1 binding to IκBα was decreased. To further verify these findings, we have overexpressed TNFRII and identified that overexpressing TNFRII can reverse the findings from APP23/TNFRII(-/-) mice. Altogether, our results demonstrate novel roles of TNFRII in the regulation of Aβ production, suggesting a potential therapeutic strategy for AD by up-regulating TNFRII levels and elevating phosphorylated IκBα by SUMOylation. PMID:24824215

  18. Experimental manipulations of microglia in mouse models of Alzheimer’s pathology. Activation reduces amyloid but hastens tau pathology

    PubMed Central

    Lee, Daniel C.; Rizer, Justin; Hunt, Jerry B.; Selenica, Maj-Linda B.; Gordon, Marcia N.; Morgan, Dave

    2015-01-01

    The inflammation hypothesis of Alzheimer’s pathogenesis has directed much scientific effort towards ameliorating this disease. The development of mouse models of amyloid deposition permitted direct tests of the proposal that amyloid-activated microglia could cause neurodegeneration in vivo. Many approaches to manipulating microglial activation have been applied to these mouse models, and are the subject of this review. In general, these results do not support a direct neuricidal action of microglia in mouse amyloid models under any activation state. Some of the manipulations cause both a reduction in pathology, and a reduction in microglial activation. However, at least for agents like ibuprofen, this outcome may result from a direct action on amyloid production, and a reduction in the microglial provoking amyloid deposits, rather than from reduced microglial activation leading to a decline in amyloid deposition. Instead, a surprising number of the experimental manipulations which increase microglial activation lead to enhanced clearance of the amyloid deposits. Both the literature and new data presented here suggest that either classical or alternative activation of microglia can lead to enhanced amyloid clearance. However, a limited number of studies comparing the same treatments in amyloid-depositing vs tau-depositing mice find the opposite effects. Treatments that benefit amyloid pathology accelerate tau pathology. This observation argues strongly that potential treatments be tested for impact on both amyloid and tau pathology before consideration of testing in humans. PMID:23171029

  19. Evidence for human transmission of amyloidpathology and cerebral amyloid angiopathy.

    PubMed

    Jaunmuktane, Zane; Mead, Simon; Ellis, Matthew; Wadsworth, Jonathan D F; Nicoll, Andrew J; Kenny, Joanna; Launchbury, Francesca; Linehan, Jacqueline; Richard-Loendt, Angela; Walker, A Sarah; Rudge, Peter; Collinge, John; Brandner, Sebastian

    2015-09-10

    More than two hundred individuals developed Creutzfeldt-Jakob disease (CJD) worldwide as a result of treatment, typically in childhood, with human cadaveric pituitary-derived growth hormone contaminated with prions. Although such treatment ceased in 1985, iatrogenic CJD (iCJD) continues to emerge because of the prolonged incubation periods seen in human prion infections. Unexpectedly, in an autopsy study of eight individuals with iCJD, aged 36-51 years, in four we found moderate to severe grey matter and vascular amyloid-β (Aβ) pathology. The Aβ deposition in the grey matter was typical of that seen in Alzheimer's disease and Aβ in the blood vessel walls was characteristic of cerebral amyloid angiopathy and did not co-localize with prion protein deposition. None of these patients had pathogenic mutations, APOE ε4 or other high-risk alleles associated with early-onset Alzheimer's disease. Examination of a series of 116 patients with other prion diseases from a prospective observational cohort study showed minimal or no Aβ pathology in cases of similar age range, or a decade older, without APOE ε4 risk alleles. We also analysed pituitary glands from individuals with Aβ pathology and found marked Aβ deposition in multiple cases. Experimental seeding of Aβ pathology has been previously demonstrated in primates and transgenic mice by central nervous system or peripheral inoculation with Alzheimer's disease brain homogenate. The marked deposition of parenchymal and vascular Aβ in these relatively young patients with iCJD, in contrast with other prion disease patients and population controls, is consistent with iatrogenic transmission of Aβ pathology in addition to CJD and suggests that healthy exposed individuals may also be at risk of iatrogenic Alzheimer's disease and cerebral amyloid angiopathy. These findings should also prompt investigation of whether other known iatrogenic routes of prion transmission may also be relevant to Aβ and other proteopathic

  20. A subcutaneous cellular implant for passive immunization against amyloid-β reduces 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. PMID:26956423

  1. Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly

    PubMed Central

    Lesnick, Timothy G.; Przybelski, Scott A.; Knopman, David S.; Preboske, Greg M.; Kantarci, Kejal; Raman, Mekala R.; Machulda, Mary M.; Mielke, Michelle M.; Lowe, Val J.; Senjem, Matthew L.; Gunter, Jeffrey L.; Rocca, Walter A.; Roberts, Rosebud O.; Petersen, Ronald C.; Jack, Clifford R.

    2015-01-01

    Our primary objective was to investigate a biomarker driven model for the interrelationships between vascular disease pathology, amyloid pathology, and longitudinal cognitive decline in cognitively normal elderly subjects between 70 and 90 years of age. Our secondary objective was to investigate the beneficial effect of cognitive reserve on these interrelationships. We used brain amyloid-β load measured using Pittsburgh compound B positron emission tomography as a marker for amyloid pathology. White matter hyperintensities and brain infarcts were measured using fluid-attenuated inversion recovery magnetic resonance imaging as a marker for vascular pathology. We studied 393 cognitively normal elderly participants in the population-based Mayo Clinic Study of Aging who had a baseline 3 T fluid-attenuated inversion recovery magnetic resonance imaging assessment, Pittsburgh compound B positron emission tomography scan, baseline cognitive assessment, lifestyle measures, and at least one additional clinical follow-up. We classified subjects as being on the amyloid pathway if they had a global cortical amyloid-β load of ≥1.5 standard uptake value ratio and those on the vascular pathway if they had a brain infarct and/or white matter hyperintensities load ≥1.11% of total intracranial volume (which corresponds to the top 25% of white matter hyperintensities in an independent non-demented sample). We used a global cognitive z-score as a measure of cognition. We found no evidence that the presence or absence of vascular pathology influenced the presence or absence of amyloid pathology and vice versa, suggesting that the two processes seem to be independent. Baseline cognitive performance was lower in older individuals, in males, those with lower education/occupation, and those on the amyloid pathway. The rate of cognitive decline was higher in older individuals (P < 0.001) and those with amyloid (P = 0.0003) or vascular (P = 0.0037) pathologies. In those subjects with

  2. Imaging linear birefringence and dichroism in cerebral amyloid pathologies

    PubMed Central

    Jin, Lee-Way; Claborn, Kacey A.; Kurimoto, Miki; Geday, Morten A.; Maezawa, Izumi; Sohraby, Faranak; Estrada, Marcus; Kaminksy, Werner; Kahr, Bart

    2003-01-01

    New advances in polarized light microscopy were used to image Congo red-stained cerebral amyloidosis in sharp relief. The rotating-polarizer method was used to separate the optical effects of transmission, linear birefringence, extinction, linear dichroism, and orientation of the electric dipole transition moments and to display them as false-color maps. These effects are typically convolved in an ordinary polarized light microscope. In this way, we show that the amyloid deposits in Alzheimer's disease plaques contain structurally disordered centers, providing clues to mechanisms of crystallization of amyloid in vivo. Comparisons are made with plaques from tissues of subjects having Down's syndrome and a prion disease. In plaques characteristic of each disease, the Congo red molecules are oriented radially. The optical orientation in amyloid deposited in blood vessels from subjects having cerebral amyloid angiopathy was 90° out of phase from that in the plaques, suggesting that the fibrils run tangentially with respect to the circumference of the blood vessels. Our result supports an early model in which Congo red molecules are aligned along the long fiber axis and is in contrast to the most recent binding models that are based on computation. This investigation illustrates that the latest methods for the optical analysis of heterogeneous substances are useful for in situ study of amyloid. PMID:14668440

  3. Alzheimer's Disease Amyloid-β Links Lens and Brain Pathology in Down Syndrome

    PubMed Central

    Lu, Suqian; Burton, Mark A.; Ghosh, Joy G.; Ericsson, Maria; Soscia, Stephanie J.; Mocofanescu, Anca; Folkerth, Rebecca D.; Robb, Richard M.; Kuszak, Jer R.; Clark, John I.; Tanzi, Rudolph E.; Hunter, David G.; Goldstein, Lee E.

    2010-01-01

    Down syndrome (DS, trisomy 21) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. In DS, triplication of chromosome 21 invariably includes the APP gene (21q21) encoding the Alzheimer's disease (AD) amyloid precursor protein (APP). Triplication of the APP gene accelerates APP expression leading to cerebral accumulation of APP-derived amyloid-β peptides (Aβ), early-onset AD neuropathology, and age-dependent cognitive sequelae. The DS phenotype complex also includes distinctive early-onset cerulean cataracts of unknown etiology. Previously, we reported increased Aβ accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the ocular lenses of subjects with AD. Here, we investigate the hypothesis that related AD-linked Aβ pathology underlies the distinctive lens phenotype associated with DS. Ophthalmological examinations of DS subjects were correlated with phenotypic, histochemical, and biochemical analyses of lenses obtained from DS, AD, and normal control subjects. Evaluation of DS lenses revealed a characteristic pattern of supranuclear opacification accompanied by accelerated supranuclear Aβ accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic Aβ aggregates (∼5 to 50 nm) identical to the lens pathology identified in AD. Peptide sequencing, immunoblot analysis, and ELISA confirmed the identity and increased accumulation of Aβ in DS lenses. Incubation of synthetic Aβ with human lens protein promoted protein aggregation, amyloid formation, and light scattering that recapitulated the molecular pathology and clinical features observed in DS lenses. These results establish the genetic etiology of the distinctive lens phenotype in DS and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Moreover, these findings confirm increased Aβ accumulation as a key pathogenic

  4. Is pathological aging a successful resistance against amyloid-beta or preclinical Alzheimer's disease?

    PubMed

    Murray, Melissa E; Dickson, Dennis W

    2014-01-01

    Individuals with pathological aging, a form of cerebral amyloidosis in older people, have widespread extracellular amyloid-beta (Aβ) senile plaque deposits in the setting of limited neurofibrillary tau pathology. Unlike the characteristic finding of antemortem cognitive impairment in Alzheimer's disease patients, individuals with pathological aging usually lack cognitive impairment despite similar Aβ senile plaque burdens. It has been hypothesized that protective or resistance factors may underlie pathological aging, thus minimizing or preventing deleterious effects on cognition. Despite increasing interest and recognition, a review of the literature remains challenging given the range of terms used to describe pathological aging. This debate briefly reviews neuropathologic and biochemical evidence that pathological aging individuals have resistance factors to Aβ plaque pathology. Additionally, we will discuss evidence of pathological aging as an intermediate between normal individuals and Alzheimer's disease patients, and discuss protective or resistance factors against vascular disease and neurofibrillary pathology. Lastly, we will emphasize the need for longitudinal biomarker evidence using amyloid positron emission tomography, which will provide a better understanding of the kinetics of Aβ deposition in pathological aging. PMID:25031637

  5. EFhd2 is a novel amyloid protein associated with pathological tau in Alzheimer's disease.

    PubMed

    Ferrer-Acosta, Yancy; Rodríguez-Cruz, Eva N; Orange, François; De Jesús-Cortés, Hector; Madera, Bismark; Vaquer-Alicea, Jaime; Ballester, Juan; Guinel, Maxime J-F; Bloom, George S; Vega, Irving E

    2013-06-01

    EFhd2 is a conserved calcium-binding protein, abundant within the central nervous system. Previous studies identified EFhd2 associated with pathological forms of tau proteins in the tauopathy mouse model JNPL3, which expresses the human tau(P301L) mutant. This association was validated in human tauopathies, such as Alzheimer's disease (AD). However, the role that EFhd2 may play in tauopathies is still unknown. Here, we show that EFhd2 formed amyloid structures in vitro, a capability that is reduced by calcium ions. Electron microscopy (EM) analyses demonstrated that recombinant EFhd2 formed filamentous structures. EM analyses of sarkosyl-insoluble fractions derived from human AD brains also indicated that EFhd2 co-localizes with aggregated tau proteins and formed granular structures. Immunohistological analyses of brain slices demonstrated that EFhd2 co-localizes with pathological tau proteins in AD brains, confirming the co-aggregation of EFhd2 and pathological tau. Furthermore, EFhd2's coiled-coil domain mediated its self-oligomerization in vitro and its association with tau proteins in JNPL3 mouse brain extracts. The results demonstrate that EFhd2 is a novel amyloid protein associated with pathological tau proteins in AD brain and that calcium binding may regulate the formation of EFhd2's amyloid structures. Hence, EFhd2 may play an important role in the pathobiology of tau-mediated neurodegeneration. PMID:23331044

  6. Beta-amyloid fibrils of Alzheimer's disease: pathologically altered, basement membrane-associated microfibrils?

    PubMed

    Inoue, S; Kisilevsky, R

    2001-01-01

    Beta amyloid fibrils were examined in situ in the cerebral cortex of brains from patients with Alzheimer's disease using high resolution ultrastructural and immunohistochemical techniques. The main body of the fibril was identical with that of microfibrils and was made up of a core containing amyloid P component (AP), and a surface layer. Beta amyloid protein (Abeta) in the form of 1 nm wide flexible filaments was associated with the external surface of the microfibril. In cerebrovascular amyloid angiopathy the fibrils were formed at the outer surface of the vascular basement membrane. Overproduction of microfibrils has been reported at the basement membrane of "leaky" capillaries including the glomerular capillary in disease or leaky alveolar-capillary walls of normal lungs. Similarly, in Alzheimer's disease overproduction of microfibril-like beta amyloid fibrils in amyloid angiopathy coincided with breakdown of the blood-brain barrier of the cerebromicrovasculature. Thus, in the above three locations, the presence of abundant microfibrils, or microfibril-like structures, may be related to plasma which leaks out of the circulation into the adjoining vascular basement membrane. AP is an essential constituent of microfibrils and since the only site where AP is available in the cerebral cortex is in leaky microvasculature, a chronic, steady supply of AP into perivascular areas may be the cause of overproduction of microfibrils. Brain "microfibrils" may further be altered pathologically into beta amyloid fibrils by the addition of Abeta. The origin of the fibrils in senile plaques may also be the microvasculature since in the area of the plaques no source of AP is apparent. PMID:11730002

  7. Amyloid pathology and axonal injury after brain trauma

    PubMed Central

    Scott, Gregory; Ramlackhansingh, Anil F.; Edison, Paul; Hellyer, Peter; Cole, James; Veronese, Mattia; Leech, Rob; Greenwood, Richard J.; Turkheimer, Federico E.; Gentleman, Steve M.; Heckemann, Rolf A.; Matthews, Paul M.; Brooks, David J.

    2016-01-01

    Objective: To image β-amyloid (Aβ) plaque burden in long-term survivors of traumatic brain injury (TBI), test whether traumatic axonal injury and Aβ are correlated, and compare the spatial distribution of Aβ to Alzheimer disease (AD). Methods: Patients 11 months to 17 years after moderate–severe TBI underwent 11C-Pittsburgh compound B (11C-PiB)-PET, structural and diffusion MRI, and neuropsychological examination. Healthy aged controls and patients with AD underwent PET and structural MRI. Binding potential (BPND) images of 11C-PiB, which index Aβ plaque density, were computed using an automatic reference region extraction procedure. Voxelwise and regional differences in BPND were assessed. In TBI, a measure of white matter integrity, fractional anisotropy, was estimated and correlated with 11C-PiB BPND. Results: Twenty-eight participants (9 with TBI, 9 controls, 10 with AD) were assessed. Increased 11C-PiB BPND was found in TBI vs controls in the posterior cingulate cortex and cerebellum. Binding in the posterior cingulate cortex increased with decreasing fractional anisotropy of associated white matter tracts and increased with time since injury. Compared to AD, binding after TBI was lower in neocortical regions but increased in the cerebellum. Conclusions: Increased Aβ burden was observed in TBI. The distribution overlaps with, but is distinct from, that of AD. This suggests a mechanistic link between TBI and the development of neuropathologic features of dementia, which may relate to axonal damage produced by the injury. PMID:26843562

  8. Amyloid accumulation is a late event in sporadic Alzheimer's disease-like pathology in nontransgenic rats

    PubMed Central

    Stefanova, Natalia A.; Muraleva, Natalia A.; Korbolina, Elena E.; Kiseleva, Elena; Maksimova, Kseniya Yi.; Kolosova, Nataliya G.

    2015-01-01

    The amyloid cascade hypothesis posits that deposition of the amyloid β (Aβ) peptide in the brain is a key event in the initiation of Alzheimer's disease (AD). Nonetheless, it now seems increasingly unlikely that amyloid toxicity is the cause of sporadic AD, which leads to cognitive decline. Here, using accelerated-senescence nontransgenic OXYS rats, we confirmed that aggregation of Aβ is a later event in AD-like pathology. We showed that an age-dependent increase in the levels of Aβ1–42 and extracellular Aβ deposits in the brain of OXYS rats occur later than do synaptic losses, neuronal cell death, mitochondrial structural abnormalities, and hyperphosphorylation of the tau protein. We identified the variants of the genes that are strongly associated with the risk of either late-onset or early-onset AD, including App, Apoe4, Bace1, Psen1, Psen2, and Picalm. We found that in OXYS rats nonsynonymous SNPs were located only in the genes Casp3 and Sorl1. Thus, we present proof that OXYS rats may be a model of sporadic AD. It is possible that multiple age-associated pathological processes may precede the toxic amyloid accumulation, which in turn triggers the final stage of the sporadic form of AD and becomes a hallmark event of the disease. PMID:25595891

  9. Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloidpathology.

    PubMed

    Spangenberg, Elizabeth E; Lee, Rafael J; Najafi, Allison R; Rice, Rachel A; Elmore, Monica R P; Blurton-Jones, Mathew; West, Brian L; Green, Kim N

    2016-04-01

    In addition to amyloid-β plaque and tau neurofibrillary tangle deposition, neuroinflammation is considered a key feature of Alzheimer's disease pathology. Inflammation in Alzheimer's disease is characterized by the presence of reactive astrocytes and activated microglia surrounding amyloid plaques, implicating their role in disease pathogenesis. Microglia in the healthy adult mouse depend on colony-stimulating factor 1 receptor (CSF1R) signalling for survival, and pharmacological inhibition of this receptor results in rapid elimination of nearly all of the microglia in the central nervous system. In this study, we set out to determine if chronically activated microglia in the Alzheimer's disease brain are also dependent on CSF1R signalling, and if so, how these cells contribute to disease pathogenesis. Ten-month-old 5xfAD mice were treated with a selective CSF1R inhibitor for 1 month, resulting in the elimination of ∼80% of microglia. Chronic microglial elimination does not alter amyloid-β levels or plaque load; however, it does rescue dendritic spine loss and prevent neuronal loss in 5xfAD mice, as well as reduce overall neuroinflammation. Importantly, behavioural testing revealed improvements in contextual memory. Collectively, these results demonstrate that microglia contribute to neuronal loss, as well as memory impairments in 5xfAD mice, but do not mediate or protect from amyloid pathology. PMID:26921617

  10. Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease

    PubMed Central

    Sundgren, Pia C.; Strandberg, Olof; Zetterberg, Henrik; Minthon, Lennart; Blennow, Kaj; Wahlund, Lars-Olof; Westman, Eric

    2016-01-01

    Objective: We aimed to test whether in vivo levels of magnetic resonance spectroscopy (MRS) metabolites myo-inositol (mI), N-acetylaspartate (NAA), and choline are abnormal already during preclinical Alzheimer disease (AD), relating these changes to amyloid or tau pathology, and functional connectivity. Methods: In this cross-sectional multicenter study (a subset of the prospective Swedish BioFINDER study), we included 4 groups, representing the different stages of predementia AD: (1) cognitively healthy elderly with normal CSF β-amyloid 42 (Aβ42), (2) cognitively healthy elderly with abnormal CSF Aβ42, (3) patients with subjective cognitive decline and abnormal CSF Aβ42, (4) patients with mild cognitive decline and abnormal CSF Aβ42 (Ntotal = 352). Spectroscopic markers measured in the posterior cingulate/precuneus were considered alongside known disease biomarkers: CSF Aβ42, phosphorylated tau, total tau, [18F]-flutemetamol PET, f-MRI, and the genetic risk factor APOE. Results: Amyloid-positive cognitively healthy participants showed a significant increase in mI/creatine and mI/NAA levels compared to amyloid-negative healthy elderly (p < 0.05). In amyloid-positive healthy elderly, mI/creatine and mI/NAA correlated with cortical retention of [18F] flutemetamol tracer ( = 0.44, p = 0.02 and = 0.51, p = 0.01, respectively). Healthy elderly APOE ε4 carriers with normal CSF Aβ42 levels had significantly higher mI/creatine levels (p < 0.001) than ε4 noncarriers. Finally, elevated mI/creatine was associated with decreased functional connectivity within the default mode network (rpearson = −0.16, p = 0.02), independently of amyloid pathology. Conclusions: mI levels are elevated already at asymptomatic stages of AD. Moreover, mI/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ42 levels, suggesting that mI levels may reveal regional brain consequences of APOE ε4 before detectable amyloid pathology. PMID:27164711

  11. Humanized Tau Mice with Regionalized Amyloid Exhibit Behavioral Deficits but No Pathological Interaction

    PubMed Central

    Yetman, Michael J.; Fowler, Stephanie W.; Jankowsky, Joanna L.

    2016-01-01

    Alzheimer’s disease (AD) researchers have struggled for decades to draw a causal link between extracellular Aβ aggregation and intraneuronal accumulation of microtubule-associated protein tau. The amyloid cascade hypothesis posits that Aβ deposition promotes tau hyperphosphorylation, tangle formation, cell loss, vascular damage, and dementia. While the genetics of familial AD and the pathological staging of sporadic disease support this sequence of events, attempts to examine the molecular mechanism in transgenic animal models have largely relied on models of other inherited tauopathies as the basis for testing the interaction with Aβ. In an effort to more accurately model the relationship between Aβ and wild-type tau in AD, we intercrossed mice that overproduce human Aβ with a tau substitution model in which all 6 isoforms of the human protein are expressed in animals lacking murine tau. We selected an amyloid model in which pathology was biased towards the entorhinal region so that we could further examine whether the anticipated changes in tau phosphorylation occurred at the site of Aβ deposition or in synaptically connected regions. We found that Aβ and tau had independent effects on locomotion, learning, and memory, but found no behavioral evidence for an interaction between the two transgenes. Moreover, we saw no indication of amyloid-induced changes in the phosphorylation or aggregation of human tau either within the entorhinal area or elsewhere. These findings suggest that robust amyloid pathology within the medial temporal lobe has little effect on the metabolism of wild type human tau in this model. PMID:27070146

  12. Impact of peripheral myeloid cells on amyloidpathology in Alzheimer's disease-like mice.

    PubMed

    Prokop, Stefan; Miller, Kelly R; Drost, Natalia; Handrick, Susann; Mathur, Vidhu; Luo, Jian; Wegner, Anja; Wyss-Coray, Tony; Heppner, Frank L

    2015-10-19

    Although central nervous system-resident microglia are believed to be ineffective at phagocytosing and clearing amyloid-β (Aβ), a major pathological hallmark of Alzheimer's disease (AD), it has been suggested that peripheral myeloid cells constitute a heterogeneous cell population with greater Aβ-clearing capabilities. Here, we demonstrate that the conditional ablation of resident microglia in CD11b-HSVTK (TK) mice is followed by a rapid repopulation of the brain by peripherally derived myeloid cells. We used this system to directly assess the ability of peripheral macrophages to reduce Aβ plaque pathology and therefore depleted and replaced the pool of resident microglia with peripherally derived myeloid cells in Aβ-carrying APPPS1 mice crossed to TK mice (APPPS1;TK). Despite a nearly complete exchange of resident microglia with peripheral myeloid cells, there was no significant change in Aβ burden or APP processing in APPPS1;TK mice. Importantly, however, newly recruited peripheral myeloid cells failed to cluster around Aβ deposits. Even additional anti-Aβ antibody treatment aimed at engaging myeloid cells with amyloid plaques neither directed peripherally derived myeloid cells to amyloid plaques nor altered Aβ burden. These data demonstrate that mere recruitment of peripheral myeloid cells to the brain is insufficient in substantially clearing Aβ burden and suggest that specific additional triggers appear to be required to exploit the full potential of myeloid cell-based therapies for AD. PMID:26458768

  13. The Acyl-Coenzyme A:Cholesterol Acyltransferase Inhibitor CI-1011 Reverses Diffuse Brain Amyloid Pathology in Aged Amyloid Precursor Protein Transgenic Mice

    PubMed Central

    Huttunen, Henri J.; Havas, Daniel; Peach, Camilla; Barren, Cory; Duller, Stephan; Xia, Weiming; Frosch, Matthew P.; Hutter-Paier, Birgit; Windisch, Manfred; Kovacs, Dora M.

    2010-01-01

    Cerebral accumulation of amyloid β-peptide (Aβ) is characteristic of Alzheimer disease and of amyloid precursor protein (APP) transgenic mice. Here, we assessed the efficacy of CI-1011, an inhibitor of acyl-coenzyme A:cholesterol acyltransferase, which is suitable for clinical use, in reducing amyloid pathology in both young (6.5 months old) and aged (16 months old) hAPP transgenic mice. Treatment of young animals with CI-1011 decreased amyloid plaque load in the cortex and hippocampus and reduced the levels of insoluble Aβ40 and Aβ42 and C-terminal fragments of APP in brain extracts. In aged mice, CI-1011 specifically reduced diffuse amyloid plaques with a minor effect on thioflavin S+ dense-core plaques. Reduced diffusible amyloid was accompanied by suppression of astrogliosis and enhanced microglial activation. Collectively, these data suggest that CI-1011 treatment reduces amyloid burden in hAPP mice by limiting generation and increasing clearance of diffusible Aβ. PMID:20613640

  14. Hook Proteins: Association with Alzheimer Pathology and Regulatory Role of Hook3 in Amyloid Beta Generation

    PubMed Central

    Arsalan-Werner, Annika; Hilbrich, Isabel; Jäger, Carsten; Flach, Katharina; Suttkus, Anne; Lachmann, Ingolf; Arendt, Thomas; Holzer, Max

    2015-01-01

    Defects in intracellular transport are implicated in the pathogenesis of Alzheimer’s disease (AD). Hook proteins are a family of cytoplasmic linker proteins that participate in endosomal transport. In this study we show that Hook1 and Hook3 are expressed in neurons while Hook2 is predominantly expressed in astrocytes. Furthermore, Hook proteins are associated with pathological hallmarks in AD; Hook1 and Hook3 are localized to tau aggregates and Hook2 to glial components within amyloid plaques. Additionally, the expression of Hook3 is reduced in AD. Modelling of Hook3 deficiency in cultured cells leads to slowing of endosomal transport and increases β-amyloid production. We propose that Hook3 plays a role in pathogenic events exacerbating AD. PMID:25799409

  15. A comparison of Aβ amyloid pathology staging systems and correlation with clinical diagnosis

    PubMed Central

    Boluda, Susana; Toledo, Jon B.; Irwin, David J.; Raible, Kevin M.; Byrne, Matt D.; Lee, Edward B.; Lee, Virginia M.-Y.

    2015-01-01

    Current neuropathological Alzheimer's disease (AD) criteria from the National Institute on Aging-Alzheimer's Association (NIA-AA) incorporate two staging systems for Aβ pathology, namely the Thal Aβ phase (TAP) and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) methods. The goal of this study was to compare and contrast results obtained with these two different staging systems for Aβ pathology since this is critical for future correlations of Aβ amyloid imaging data with Aβ neuropathology data based on immunohistochemical detection of Aβ deposits. A total of 123 cases, divided into 82 training and 41 validation cases, with a diagnosis of either unremarkable adult brain (normal) or AD and CERAD scores ranging from none to frequent were included. There was no clear and consistent relationship between CERAD and the TAP Aβ scores with the exception of scores for the highest plaque burdens (i.e., CERAD C3 and TAP A3) in the cases studied here. However, we developed an algorithm that relates CERAD scores to TAP scores with high agreement (94 % in training and 98 % in the validation set). In addition, TAP scores were a better predictor of dementia (sensitivity of 94 % specifcity 87.7 %) than CERAD scores (sensitivity of 57 % specifcity 100 %). Yet, further research is needed to define strategies to relate CERAD and TAP Aβ plaque scores to compare their utility and for determining the clinical associations of these different amyloid staging systems with aging and AD. PMID:24916271

  16. ABCA7 Genotypes Confer Alzheimer's Disease Risk by Modulating AmyloidPathology.

    PubMed

    Zhao, Qing-Fei; Wan, Yu; Wang, Hui-Fu; Sun, Fu-Rong; Hao, Xiao-Ke; Tan, Meng-Shan; Tan, Chen-Chen; Zhang, Dao-Qiang; Tan, Lan; Yu, Jin-Tai

    2016-03-21

    ABCA7 gene has been identified as a strong genetic locus for Alzheimer's disease (AD) susceptibility in genome wide association studies (GWAS). However, the possible roles of ABCA7 variants in AD pathology were not specifically assessed. Using tagger methods, we extracted 15 targeted ABCA7 loci to investigate their associations with cerebrospinal fluid (CSF) and neuroimaging markers in Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Finally, although we did not detect any significant associations of previously published GWAS SNPs (rs3764650 and rs78117248) with all the CSF (Aβ1 - 42, T-tau, and P-tau) and neuroimaging markers, three other variants (rs3752242, rs3752240, and rs4147912) at ABCA7 loci were detected to show significant associations with amyloid deposition on AV-45 PET in brain. Moreover, haplotype and subgroup analysis confirmed these significant findings. Furthermore, there were no remarkable correlations between ABCA7 variants and neuronal degeneration biomarkers (elevated CSF tau, brain structure atrophy, and hypometabolism on imaging) in this study. Thus, our study suggested that ABCA7 genotypes contribute to the AD risk through involvement in amyloid-β deposition on in vivo imaging, but not in tau pathology, brain atrophy, or decreased glucose metabolism. PMID:27003212

  17. Centrally Delivered BACE1 Inhibitor Activates Microglia, and Reverses Amyloid Pathology and Cognitive Deficit in Aged Tg2576 Mice.

    PubMed

    Thakker, Deepak R; Sankaranarayanan, Sethu; Weatherspoon, Marcy R; Harrison, Jonathan; Pierdomenico, Maria; Heisel, Jennifer M; Thompson, Lorin A; Haskell, Roy; Grace, James E; Taylor, Sarah J; Albright, Charles F; Shafer, Lisa L

    2015-04-29

    Multiple small-molecule inhibitors of the β-secretase enzyme (BACE1) are under preclinical or clinical investigation for Alzheimer's disease (AD). Prior work has illustrated robust lowering of central amyloid β (Aβ) after acute administration of BACE1 inhibitors. However, very few studies have assessed the overall impact of chronically administered BACE1 inhibitors on brain amyloid burden, neuropathology, and behavioral function in aged preclinical models. We investigated the effects of a potent nonbrain-penetrant BACE1 inhibitor, delivered directly to the brain using intracerebroventricular infusion in an aged transgenic mouse model. Intracerebroventricular infusion of the BACE1 inhibitor (0.3-23.5 μg/d) for 8 weeks, initiated in 17-month-old Tg2576 mice, produced dose-dependent increases in brain inhibitor concentrations (0.2-13 μm). BACE1 inhibition significantly reversed the behavioral deficit in contextual fear conditioning, and reduced brain Aβ levels, plaque burden, and associated pathology (e.g., dystrophic neurites), with maximal effects attained with ∼1 μg/d dose. Strikingly, the BACE1 inhibitor also reversed amyloid pathology below baseline levels (amyloid burden at the start of treatment), without adversely affecting cerebral amyloid angiopathy, microhemorrhages, myelination, or neuromuscular function. Inhibitor-mediated decline in brain amyloid pathology was associated with an increase in microglial ramification. This is the first demonstration of chronically administered BACE1 inhibitor to activate microglia, reverse brain amyloid pathology, and elicit functional improvement in an aged transgenic mouse model. Thus, engagement of novel glial-mediated clearance mechanisms may drive disease-modifying therapeutic benefit with BACE1 inhibition in AD. PMID:25926467

  18. Occurrence of extensive spherical amyloid deposits in a prolactin-secreting pituitary macroadenoma: a radiologic-pathologic correlation.

    PubMed

    Levine, Steven N; Ishaq, Shmaila; Nanda, Anil; Wilson, Jon D; Gonzalez-Toledo, Eduardo

    2013-08-01

    Pituitary adenomas are the most common tumors of the sellar region, but the occurrence of spherical amyloid deposits in a pituitary adenoma is rare. We describe the clinical features, radiologic characteristics, and pathologic findings of 45-year-old man who presented with galactorrhea, hypogonadism, and hyperprolactinemia who had a pituitary adenoma with extensive spherical amyloid deposits. Approximately 30 cases have been reported, almost exclusively in patients with prolactinomas. Treatment with dopaminergic agonists will result in the expected reduction in prolactin levels; however, in most cases, macroadenomas with spherical amyloid deposits fail to decrease in size. The source of the amyloid deposits in prolactinomas is not clearly defined but may be due to abnormal processing of prolactin or its prohormone. These adenomas with spherical amyloid have a characteristic appearance on magnetic resonance imaging with low or heterogeneous intensity on T1 and low intensity on T2-weighted images. Following infusion of gadolinium, there is enhancement of the periphery but not most of the tumor mass. These magnetic resonance imaging characteristics are different than those of typical pituitary adenomas. These differences should alert clinicians to the possibility of extensive spherical amyloid deposits in a prolactin-secreting pituitary adenoma, which may have important clinical implications. In this report, we correlate the radiologic finds with the pathology and compared them with other sellar and parasellar lesions. PMID:23602507

  19. Hemodialysis Induced Amyloid Arthropathy of Hip Presenting as Pathological Fracture-A Case Report and Literature Review

    PubMed Central

    2014-01-01

    Amyloid arthropathy is a recognized complication of chronic renal failure with long term dialysis. The amyloid, a beta 2microglobulin is not filtered by dialysis membrane and remains in the circulation, gets deposited over the synovium, articular bones and cartilage. As a result the large joints like shoulder, hips and knees show cystic bone lesions. The radiological features precede the clinical symptoms. The majority of the patients remain asymptomatic till the advanced stage or may present with pathological fracture. The patient in this case report had a long history of dialysis due to renal failure and presented with pain, limping and difficult to walk after the history of fall in bathroom. The radiological investigations, particularly MRI hip had typical signs of amyloid arthropathy; later on confirmed by biopsy. This case report is presented to call attention of clinicians and radiologists for the early and prompt diagnosis of amyloid arthropathy, avoiding false/delayed diagnosis which can increase morbidity and mortality. PMID:25478427

  20. Injury markers predict time to dementia in subjects with MCI and amyloid pathology

    PubMed Central

    Vos, Stephanie J.B.; Burns, Leah; Knol, Dirk L.; Scheltens, Philip; Soininen, Hilkka; Wahlund, Lars-Olof; Hampel, Harald; Tsolaki, Magda; Minthon, Lennart; L'Italien, Gilbert; van der Flier, Wiesje M.; Teunissen, Charlotte E.; Blennow, Kaj; Barkhof, Frederik; Rueckert, Daniel; Wolz, Robin; Verhey, Frans; Visser, Pieter Jelle

    2012-01-01

    Objectives: Alzheimer disease (AD) can now be diagnosed in subjects with mild cognitive impairment (MCI) using biomarkers. However, little is known about the rate of decline in those subjects. In this cohort study, we aimed to assess the conversion rate to dementia and identify prognostic markers in subjects with MCI and evidence of amyloid pathology. Methods: We pooled subjects from the VU University Medical Center Alzheimer Center and the Development of Screening Guidelines and Criteria for Predementia Alzheimer's Disease (DESCRIPA) study. We included subjects with MCI, an abnormal level of β-amyloid1−42 (Aβ1–42) in the CSF, and at least one diagnostic follow-up visit. We assessed the effect of APOE genotype, CSF total tau (t-tau) and tau phosphorylated at threonine 181 (p-tau) and hippocampal volume on time to AD-type dementia using Cox proportional hazards models and on decline on the Mini-Mental State Examination (MMSE) using linear mixed models. Results: We included 110 subjects with MCI with abnormal CSF Aβ1–42 and a mean MMSE score of 26.3 ± 2.8. During a mean follow-up of 2.2 ± 1.0 (range 0.4–5.0) years, 63 subjects (57%) progressed to AD-type dementia. Abnormal CSF t-tau (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.1–4.6, p = 0.03) and CSF p-tau (HR 3.5, 95% CI 1.3–9.2, p = 0.01) concentration and hippocampal atrophy (HR 2.5, 95% CI 1.1–5.6, p = 0.02) predicted time to dementia. For subjects with both abnormal t-tau concentration and hippocampal atrophy, HR was 7.3 (95% CI 1.0–55.9, p = 0.06). Furthermore, abnormal CSF t-tau and p-tau concentrations and hippocampal atrophy predicted decline in MMSE score. Conclusions: In subjects with MCI and evidence of amyloid pathology, the injury markers CSF t-tau and p-tau and hippocampal atrophy can predict further cognitive decline. PMID:23019259

  1. Intracellular Aβ pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study.

    PubMed

    Iulita, M Florencia; Allard, Simon; Richter, Luise; Munter, Lisa-Marie; Ducatenzeiler, Adriana; Weise, Christoph; Do Carmo, Sonia; Klein, William L; Multhaup, Gerhard; Cuello, A Claudio

    2014-01-01

    Numerous studies have implicated the abnormal accumulation of intraneuronal amyloid-β (Aβ) as an important contributor to Alzheimer's disease (AD) pathology, capable of triggering neuroinflammation, tau hyperphosphorylation and cognitive deficits. However, the occurrence and pathological relevance of intracellular Aβ remain a matter of controversial debate. In this study, we have used a multidimensional approach including high-magnification and super-resolution microscopy, cerebro-spinal fluid (CSF) mass spectrometry analysis and ELISA to investigate the Aβ pathology and its associated cognitive impairments, in a novel transgenic rat model overexpressing human APP. Our microscopy studies with quantitative co-localization analysis revealed the presence of intraneuronal Aβ in transgenic rats, with an immunological signal that was clearly distinguished from that of the amyloid precursor protein (APP) and its C-terminal fragments (CTFs). The early intraneuronal pathology was accompanied by a significant elevation of soluble Aβ42 peptides that paralleled the presence and progression of early cognitive deficits, several months prior to amyloid plaque deposition. Aβ38, Aβ39, Aβ40 and Aβ42 peptides were detected in the rat CSF by MALDI-MS analysis even at the plaque-free stages; suggesting that a combination of intracellular and soluble extracellular Aβ may be responsible for impairing cognition at early time points. Taken together, our results demonstrate that the intraneuronal development of AD-like amyloid pathology includes a mixture of molecular species (Aβ, APP and CTFs) of which a considerable component is Aβ; and that the early presence of these species within neurons has deleterious effects in the CNS, even before the development of full-blown AD-like pathology. PMID:24903713

  2. Zileuton restores memory impairments and reverses amyloid and tau pathology in aged Alzheimer's disease mice.

    PubMed

    Di Meco, Antonio; Lauretti, Elisabetta; Vagnozzi, Alana N; Praticò, Domenico

    2014-11-01

    The enzyme 5-lipoxygenase (5LO) is upregulated in Alzheimer's disease (AD), and its pharmacologic blockade with zileuton slows down the development of the AD-like phenotype in young AD mice. However, its efficacy after the AD pathology is established is unknown. To this end, starting at 12 months of age triple transgenic mice (3xTg) received zileuton, a selective 5LO inhibitor, or placebo for 3 months, and then the effect of this treatment on behavior, amyloid, and tau pathology assessed. Although mice on placebo showed worsening of their memory, treated mice performed even better than at baseline. Compared with placebo, treated mice had significantly less Aβ deposits and tau phosphorylation secondary to reduced γ-secretase and CDK-5 activation, respectively. Our data provide novel insights into the disease-modifying action of pharmacologically inhibiting 5LO as a viable AD therapeutic approach. They represent the successful completion of preclinical studies for the development of this class of drug as clinically applicable therapy for the disease. PMID:24973121

  3. Cortical and Leptomeningeal Cerebrovascular Amyloid and White Matter Pathology in Alzheimer’s Disease

    PubMed Central

    Roher, Alex E; Kuo, Yu-Min; Esh, Chera; Knebel, Carmen; Weiss, Nicole; Kalback, Walter; Luehrs, Dean C; Childress, Jennifer L; Beach, Thomas G; Weller, Roy O; Kokjohn, Tyler A

    2003-01-01

    Alzheimer’s disease (AD) is characterized by neurofibrillary tangles and by the accumulation of β-amyloid (Aβ) peptides in senile plaques and in the walls of cortical and leptomeningeal arteries as cerebral amyloid angiopathy (CAA). There also is a significant increase of interstitial fluid (ISF) in cerebral white matter (WM), the pathological basis of which is largely unknown. We hypothesized that the accumulation of ISF in dilated periarterial spaces of the WM in AD correlates with the severity of CAA, with the total Aβ load in the cortex and with Apo E genotype. A total of 24 AD brains and 17 nondemented age-matched control brains were examined. CAA was seen in vessels isolated from brain by using EDTA-SDS lysis stained by Thioflavin-S. Total Aβ in gray matter and WM was quantified by immunoassay, ApoE genotyping by PCR, and dilatation of perivascular spaces in the WM was assessed by quantitative histology. The study showed that the frequency and severity of dilatation of perivascular spaces in the WM in AD were significantly greater than in controls (P < 0.001) and correlated with Aβ load in the cortex, with the severity of CAA, and with ApoE ɛ4 genotype. The results of this study suggest that dilation of perivascular spaces and failure of drainage of ISF from the WM in AD may be associated with the deposition of Aβ in the perivascular fluid drainage pathways of cortical and leptomeningeal arteries. This failure of fluid drainage has implications for therapeutic strategies to treat Alzheimer’s disease. PMID:12865947

  4. Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy.

    PubMed

    Casarejos, Maria J; Perucho, Juan; Gomez, Ana; Muñoz, Maria P; Fernandez-Estevez, Marian; Sagredo, Onintza; Fernandez Ruiz, Javier; Guzman, Manuel; de Yebenes, Justo Garcia; Mena, Maria A

    2013-01-01

    Cannabinoids are neuroprotective in models of neurodegenerative dementias. Their effects are mostly mediated through CB1 and CB2 receptor-dependent modulation of excitotoxicity, inflammation, oxidative stress, and other processes. We tested the effects of Sativex®, a mixture of Δ9-tetrahydrocannabinol and cannabidiol, acting on both CB1 and CB2 receptors, in parkin-null, human tau overexpressing (PK-/-/TauVLW) mice, a model of complex frontotemporal dementia, parkinsonism, and lower motor neuron disease. The animals received Sativex®, 4.63 mg/kg, ip, daily, for one month, at six months of age, at the onset of the clinical symptoms. We evaluated the effects of Sativex® on behavior, dopamine neurotransmission, glial activation, redox state, mitochondrial activity, and deposition of abnormal proteins. PK-/-/TauVLW mice developed the neurological deficits, but those treated with Sativex® showed less abnormal behaviors related to stress, less auto and hetero-aggression, and less stereotypy. Sativex® significantly reduced the intraneuronal, MAO-related free radicals produced during dopamine metabolism in the limbic system. Sativex® also decreased gliosis in cortex and hippocampus, increased the ratio reduced/oxidized glutathione in the limbic system, reduced the levels of iNOS, and increased those of complex IV in the cerebral cortex. With regard to tau and amyloid pathology, Sativex® reduced the deposition of both in the hippocampus and cerebral cortex of PK-/-/TauVLW mice and increased autophagy. Sativex®, even after a short administration in animals with present behavioral and pathological abnormalities, improves the phenotype, the oxidative stress, and the deposition of proteins in PK-/-/TauVLW mice, a model of complex neurodegenerative disorders. PMID:23478312

  5. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.

    PubMed

    Bard, F; Cannon, C; Barbour, R; Burke, R L; Games, D; Grajeda, H; Guido, T; Hu, K; Huang, J; Johnson-Wood, K; Khan, K; Kholodenko, D; Lee, M; Lieberburg, I; Motter, R; Nguyen, M; Soriano, F; Vasquez, N; Weiss, K; Welch, B; Seubert, P; Schenk, D; Yednock, T

    2000-08-01

    One hallmark of Alzheimer disease is the accumulation of amyloid beta-peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid beta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms of the human amyloid precursor protein, show many of the pathological features of Alzheimer disease, including extensive deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy. Active immunization of PDAPP mice with human amyloid beta-peptide reduces plaque burden and its associated pathologies. Several hypotheses have been proposed regarding the mechanism of this response. Here we report that peripheral administration of antibodies against amyloid beta-peptide, was sufficient to reduce amyloid burden. Despite their relatively modest serum levels, the passively administered antibodies were able to enter the central nervous system, decorate plaques and induce clearance of preexisting amyloid. When examined in an ex vivo assay with sections of PDAPP or Alzheimer disease brain tissue, antibodies against amyloid beta-peptide triggered microglial cells to clear plaques through Fc receptor-mediated phagocytosis and subsequent peptide degradation. These results indicate that antibodies can cross the blood-brain barrier to act directly in the central nervous system and should be considered as a therapeutic approach for the treatment of Alzheimer disease and other neurological disorders. PMID:10932230

  6. SorLA deficiency dissects amyloid pathology from tau and cholinergic neurodegeneration in a mouse model of Alzheimer's disease.

    PubMed

    Capsoni, Simona; Carlo, Anne-Sophie; Vignone, Domenico; Amato, Gianluca; Criscuolo, Chiara; Willnow, Thomas E; Cattaneo, Antonino

    2013-01-01

    Sortilin-related receptor with A-type repeats (SorLA, also known as LR11) has been implicated in Alzheimer's disease (AD). Thus, genetic studies associated SorLA gene variants with the risk of sporadic AD. Also, in vitro and in vivo studies showed that SorLA impairs processing of the amyloid-β protein precursor (AβPP) to amyloid-β. In particular, it has been found that loss of SorLA accelerates senile plaque deposition in mouse models overexpressing mutant forms of human AβPP and presenilin 1. Here we tested the possibility that SorLA deficiency also interferes with behavioral and neuropathological endpoints in an alternative murine AD model, the AD10 anti-nerve growth factor (NGF) mouse, in which amyloid-β accumulation derives from the altered processing of endogenous AβPP. In addition to alterations in AβPP processing, AD10 mice also show cholinergic deficit and tau hyperphosphorylation resulting in behavioral deficits in learning and memory paradigms. We found that the loss of SorLA not only exacerbates early amyloid pathology but, at the same time, protects from cholinergic deficit and from early phospho-tau mislocalization. The results show that in the AD10 anti-NGF mouse model the AβPP processing-related aspects of neurodegeneration can be dissociated from those related to tau posttranslational processing and to cholinergic phenotypic maintenance by modulation of SorLA expression. We suggest that SorLA regulates different aspects of neurodegeneration in a complex way, supporting the hypothesis that SorLA expression might be critical not only for amyloid-related pathology but also for other cellular processes altered in AD. PMID:22986780

  7. The effect of amyloid pathology and glucose metabolism on cortical volume loss over time in Alzheimer’s disease

    PubMed Central

    van Dijk, Koene R. A.; Ossenkoppele, Rik; Reuter, Martin; Tolboom, Nelleke; Zwan, Marissa D.; Yaqub, Maqsood; Boellaard, Ronald; Windhorst, Albert D.; van der Flier, Wiesje M.; Scheltens, Philip; Lammertsma, Adriaan A.; Barkhof, Frederik; van Berckel, Bart N. M.

    2016-01-01

    Purpose The present multimodal neuroimaging study examined whether amyloid pathology and glucose metabolism are related to cortical volume loss over time in Alzheimer’s disease (AD) patients and healthy elderly controls. Methods Structural MRI scans of eleven AD patients and ten controls were available at baseline and follow-up (mean interval 2.5 years). Change in brain structure over time was defined as percent change of cortical volume within seven a-priori defined regions that typically show the strongest structural loss in AD. In addition, two PET scans were performed at baseline: [11C]PIB to assess amyloid-β plaque load and [18F]FDG to assess glucose metabolism. [11C]PIB binding and [18F]FDG uptake were measured in the precuneus, a region in which both amyloid deposition and glucose hypometabolism occur early in the course of AD. Results While amyloid-β plaque load at baseline was not related to cortical volume loss over time in either group, glucose metabolism within the group of AD patients was significantly related to volume loss over time (rho=0.56, p<0.05). Conclusion The present study shows that in a group of AD patients amyloid-β plaque load as measured by [11C]PIB behaves as a trait marker (i.e., all AD patients showed elevated levels of amyloid, not related to subsequent disease course), whilst hypometabolism as measured by [18F]FDG changed over time indicating that it could serve as a state marker that is predictive of neurodegeneration. PMID:24615466

  8. Amyloidpathology is attenuated by tauroursodeoxycholic acid treatment in APP/PS1 mice after disease onset.

    PubMed

    Dionísio, Pedro A; Amaral, Joana D; Ribeiro, Maria F; Lo, Adrian C; D'Hooge, Rudi; Rodrigues, Cecília M P

    2015-01-01

    Alzheimer's disease (AD) is a neurodegenerative disorder hallmarked by the accumulation of extracellular amyloid-β (Aβ) peptide and intraneuronal hyperphosphorylated tau, as well as chronic neuroinflammation. Tauroursodeoxycholic acid (TUDCA) is an endogenous anti-apoptotic bile acid with potent neuroprotective properties in several experimental models of AD. We have previously reported the therapeutic efficacy of TUDCA treatment before amyloid plaque deposition in APP/PS1 double-transgenic mice. In the present study, we evaluated the protective effects of TUDCA when administrated after the onset of amyloid pathology. APP/PS1 transgenic mice with 7 months of age were injected intraperitoneally with TUDCA (500 mg/kg) every 3 days for 3 months. TUDCA treatment significantly attenuated Aβ deposition in the brain, with a concomitant decrease in Aβ₁₋₄₀ and Aβ₁₋₄₂ levels. The amyloidogenic processing of amyloid precursor protein was also reduced, indicating that TUDCA interferes with Aβ production. In addition, TUDCA abrogated GSK3β hyperactivity, which is highly implicated in tau hyperphosphorylation and glial activation. This effect was likely dependent on the specific activation of the upstream kinase, Akt. Finally, TUDCA treatment decreased glial activation and reduced proinflammatory cytokine messenger RNA expression, while partially rescuing synaptic loss. Overall, our results suggest that TUDCA is a promising therapeutic strategy not only for prevention but also for treatment of AD after disease onset. PMID:25443293

  9. Probing amyloidpathology in transgenic Alzheimer's disease (tgArcSwe) mice using MALDI imaging mass spectrometry.

    PubMed

    Carlred, Louise; Michno, Wojciech; Kaya, Ibrahim; Sjövall, Peter; Syvänen, Stina; Hanrieder, Jörg

    2016-08-01

    The pathological mechanisms underlying Alzheimer's disease (AD) are still not understood. The disease pathology is characterized by the accumulation and aggregation of amyloid-β (Aβ) peptides into extracellular plaques, however the factors that promote neurotoxic Aβ aggregation remain elusive. Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate the spatial distribution patterns of lipids, peptides and proteins in biological tissues. In the present study, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS)-based imaging was used to study Aβ deposition in transgenic mouse brain tissue and to elucidate the plaque-associated chemical microenvironment. The imaging experiments were performed in brain sections of transgenic Alzheimer's disease mice carrying the Arctic and Swedish mutation of amyloid-beta precursor protein (tgArcSwe). Multivariate image analysis was used to interrogate the IMS data for identifying pathologically relevant, anatomical features based on their chemical identity. This include cortical and hippocampal Aβ deposits, whose amyloid peptide content was further verified using immunohistochemistry and laser microdissection followed by MALDI MS analysis. Subsequent statistical analysis on spectral data of regions of interest revealed brain region-specific differences in Aβ peptide aggregation. Moreover, other plaque-associated protein species were identified including macrophage migration inhibitory factor suggesting neuroinflammatory processes and glial cell reactivity to be involved in AD pathology. The presented data further highlight the potential of IMS as a powerful approach in neuropathology. Hanrieder et al. described an imaging mass spectrometry based study on comprehensive spatial profiling of C-terminally truncated Aβ species within individual plaques in tgArcSwe mice. Here, brain region-dependent differences in Aβ truncation and other plaque-associated proteins, such as

  10. Characterization of a Novel Mouse Model of Alzheimer’s Disease—Amyloid Pathology and Unique β-Amyloid Oligomer Profile

    PubMed Central

    Liu, Peng; Paulson, Jennifer B.; Forster, Colleen L.; Shapiro, Samantha L.; Ashe, Karen H.; Zahs, Kathleen R.

    2015-01-01

    Amyloid plaques composed of β-amyloid (Aβ) protein are a pathological hallmark of Alzheimer’s disease. We here report the generation and characterization of a novel transgenic mouse model of Aβ toxicity. The rTg9191 mice harbor a transgene encoding the 695 amino-acid isoform of human amyloid precursor protein (APP) with the Swedish and London mutations (APPNLI) linked to familial Alzheimer’s disease, under the control of a tetracycline-response element, as well as a transgene encoding the tetracycline transactivator, under the control of the promoter for calcium-calmodulin kinase IIα. In these mice, APPNLI is expressed at a level four-fold that of endogenous mouse APP and its expression is restricted to forebrain regions. Transgene expression was suppressed by 87% after two months of doxycycline administration. Histologically, we showed that (1) Aβ plaques emerged in cerebral cortex and hippocampus as early as 8 and 10.5-12.5 months of age, respectively; (2) plaque deposition progressed in an age-dependent manner, occupying up to 19% of cortex at ~25 months of age; and (3) neuropathology—such as abnormal neuronal architecture, tau hyperphosphorylation and misfolding, and neuroinflammation—was observed in the vicinity of neuritic plaques. Biochemically, we determined total Aβ production at varied ages of mice, and we showed that mice produced primarily fibrillar Aβ assemblies recognized by conformation-selective OC antibodies, but few non-fibrillar oligomers (e.g., Aβ*56) detectable by A11 antibodies. Finally, we showed that expression of the tetracycline transactivator resulted in reduced brain weight and smaller dentate-gyrus size. Collectively, these data indicate that rTg9191 mice may serve as a model for studying the neurological effects of the fibrillar Aβ assemblies in situ. PMID:25946042

  11. Non-Verbal Episodic Memory Deficits in Primary Progressive Aphasias are Highly Predictive of Underlying Amyloid Pathology.

    PubMed

    Ramanan, Siddharth; Flanagan, Emma; Leyton, Cristian E; Villemagne, Victor L; Rowe, Christopher C; Hodges, John R; Hornberger, Michael

    2016-02-01

    Diagnostic distinction of primary progressive aphasias (PPA) remains challenging, in particular for the logopenic (lvPPA) and nonfluent/agrammatic (naPPA) variants. Recent findings highlight that episodic memory deficits appear to discriminate these PPA variants from each other, as only lvPPA perform poorly on these tasks while having underlying amyloid pathology similar to that seen in amnestic dementias like Alzheimer's disease (AD). Most memory tests are, however, language based and thus potentially confounded by the prevalent language deficits in PPA. The current study investigated this issue across PPA variants by contrasting verbal and non-verbal episodic memory measures while controlling for their performance on a language subtest of a general cognitive screen. A total of 203 participants were included (25 lvPPA; 29 naPPA; 59 AD; 90 controls) and underwent extensive verbal and non-verbal episodic memory testing, with a subset of patients (n = 45) with confirmed amyloid profiles as assessed by Pittsburgh Compound B and PET. The most powerful discriminator between naPPA and lvPPA patients was a non-verbal recall measure (Rey Complex Figure delayed recall), with 81% of PPA patients classified correctly at presentation. Importantly, AD and lvPPA patients performed comparably on this measure, further highlighting the importance of underlying amyloid pathology in episodic memory profiles. The findings demonstrate that non-verbal recall emerges as the best discriminator of lvPPA and naPPA when controlling for language deficits in high load amyloid PPA cases. PMID:26890745

  12. miR-132 loss de-represses ITPKB and aggravates amyloid and TAU pathology in Alzheimer's brain.

    PubMed

    Salta, Evgenia; Sierksma, Annerieke; Vanden Eynden, Elke; De Strooper, Bart

    2016-01-01

    microRNA-132 (miR-132) is involved in prosurvival, anti-inflammatory and memory-promoting functions in the nervous system and has been found consistently downregulated in Alzheimer's disease (AD). Whether and how miR-132 deficiency impacts AD pathology remains, however, unaddressed. We show here that miR-132 loss exacerbates both amyloid and TAU pathology via inositol 1,4,5-trisphosphate 3-kinase B (ITPKB) upregulation in an AD mouse model. This leads to increased ERK1/2 and BACE1 activity and elevated TAU phosphorylation. We confirm downregulation of miR-132 and upregulation of ITPKB in three distinct human AD patient cohorts, indicating the pathological relevance of this pathway in AD. PMID:27485122

  13. Glutamate system, amyloid ß peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology.

    PubMed

    Revett, Timothy J; Baker, Glen B; Jhamandas, Jack; Kar, Satyabrata

    2013-01-01

    Alzheimer disease is the most prevalent form of dementia globally and is characterized premortem by a gradual memory loss and deterioration of higher cognitive functions and postmortem by neuritic plaques containing amyloid ß peptide and neurofibrillary tangles containing phospho-tau protein. Glutamate is the most abundant neurotransmitter in the brain and is essential to memory formation through processes such as long-term potentiation and so might be pivotal to Alzheimer disease progression. This review discusses how the glutamatergic system is impaired in Alzheimer disease and how interactions of amyloid ß and glutamate influence synaptic function, tau phosphorylation and neurodegeneration. Interestingly, glutamate not only influences amyloid ß production, but also amyloid ß can alter the levels of glutamate at the synapse, indicating that small changes in the concentrations of both molecules could influence Alzheimer disease progression. Finally, we describe how the glutamate receptor antagonist, memantine, has been used in the treatment of individuals with Alzheimer disease and discuss its effectiveness. PMID:22894822

  14. Increased Brain Activity May Compensate for Amyloid Pathology in Older Brains

    MedlinePlus

    ... reported the findings online Sept. 14, 2014 in Nature Neuroscience . The work was funded by NIA and ... in older people with brain amyloid-β deposition . Nature Neuroscience . Published online Sept. 14, 2014. doi:10. ...

  15. In Vivo and In Vitro Effects of an Apolipoprotein E Mimetic Peptide on AmyloidPathology

    PubMed Central

    Handattu, Shaila P.; Monroe, Candyce E.; Nayyar, Gaurav; Palgunachari, Mayakonda N.; Kadish, Inga; van Groen, Thomas; Anantharamaiah, G.M.; Garber, David W.

    2014-01-01

    Background Apolipoprotein E (ApoE) is the major apolipoprotein present in the high-density lipoprotein-like particles in the central nervous system (CNS). ApoE is involved in various protective functions in CNS including cholesterol transport, anti-inflammatory, and antioxidant effects. An ApoE peptide would be expected to exert protective effects on neuroinflammation. Objective To determine the effects of an ApoE mimetic peptide Ac-hE18A-NH2 on amyloidpathology. Method Using human APP/PS1ΔE9 transgenic mice and in vitro studies, we have evaluated the effect of an ApoE mimetic peptide, Ac-hE18A-NH2, on amyloid plaque deposition and inflammation. Results Administration of Ac-hE18A-NH2 to APP/PS1ΔE9 mice for 6 weeks (50 μg/mouse, 3 times a week) significantly improved cognition with a concomitant decrease in amyloid plaque deposition and reduced activated microglia and astrocytes, and increased brain ApoE levels. Oligomeric Aβ42 (oAβ42) and oxidized PAPC (ox-PAPC) inhibited secretion of ApoE in U251 cells, a human astrocyte cell line, and this effect was ameliorated in the presence of peptide Ac-hE18A-NH2. The peptide also increased Aβ42 uptake in a cell line of human macrophages. Conclusions Peptide Ac-hE18A-NH2 attenuates the effects of oxidative stress on ApoE secretion, inhibits amyloid plaque deposition, and thus could be beneficial in the treatment of Alzheimer’s disease. PMID:23603398

  16. Systemic administration of fibroblast growth factor-2 (FGF2) reduces BACE1 expression and amyloid pathology in APP23 mice.

    PubMed

    Katsouri, Loukia; Ashraf, Azhaar; Birch, Amy M; Lee, Kevin K L; Mirzaei, Nazanin; Sastre, Magdalena

    2015-02-01

    There is an emerging evidence that growth factors may have a potential beneficial use in the treatment of Alzheimer's disease (AD) because of their neuroprotective properties and effects on neuronal proliferation. Basic fibroblast growth factor or fibroblast growth factor-2 (FGF2) is an anti-inflammatory, angiogenic, and neurotrophic factor that is expressed in many cell types, including neurons and glial cells. Here, we explored whether subcutaneous administration of FGF2 could have therapeutic effects in the APP 23 transgenic mouse, a model of amyloid pathology. FGF2 treatment attenuated spatial memory deficits, reduced amyloid-β (Aβ) and tau pathologies, decreased inducible nitric oxide synthase expression, and increased the number of astrocytes in the dentate gyrus in APP 23 mice compared with the vehicle-treated controls. The decrease in Aβ deposition was associated with a reduction in the expression of BACE1, the main enzyme responsible for Aβ generation. These results were confirmed in a neuroblastoma cell line, which demonstrated that incubation with FGF2 regulates BACE1 transcription. In addition, and in contrast with what has been previously published, the levels of FGF2 were reduced in postmortem brains from AD patients compared with controls. These data, therefore, suggest that systemic administration of FGF2 could have a potential therapeutic application in AD. PMID:25457554

  17. Diarylethene based fluorescent switchable probes for the detection of amyloidpathology in Alzheimer's disease.

    PubMed

    Lv, Guanglei; Cui, Baiping; Lan, Haichuang; Wen, Ying; Sun, Anyang; Yi, Tao

    2015-01-01

    Two fluorescent switchable diarylethene derivatives which exhibit high affinity for amyloid-β aggregates with the increase of fluorescence intensity were reported. Moreover, the probes show excellent photochromic and anti-photobleaching properties both in vitro and in vivo. PMID:25384304

  18. G-protein alpha-subunit levels in hippocampus and entorhinal cortex of brains staged for Alzheimer's disease neurofibrillary and amyloid pathologies.

    PubMed

    García-Jiménez, Angela; Fastbom, Johan; Ohm, Thomas G; Cowburn, Richard F

    2003-08-01

    G-protein alpha-subunits (Galphao, Galphai, Galphas, Galphaq) and adenylyl cyclase (AC) I and II isoforms were quantified in hippocampus and entorhinal cortex from 22 cases staged for Alzheimer's disease (AD) pathologies according to Braak and Braak. Hippocampal Galphai levels declined significantly with neurofibrillary staging, whereas AC I levels in this region increased. Significant amyloid stage-related reductions of Galphai were seen in both the hippocampus and entorhinal cortex. The hippocampus also showed a significant reduction of Galphao with amyloid staging. It is concluded that levels of inhibitory G-protein subunits Galphao, and in particular Galphai, decrease in parallel to the extent of AD pathology. PMID:12960778

  19. Longitudinal Assessment of Amyloid Pathology in Transgenic ArcAβ Mice Using Multi-Parametric Magnetic Resonance Imaging

    PubMed Central

    Klohs, Jan; Politano, Igna Wojtyna; Deistung, Andreas; Grandjean, Joanes; Drewek, Anna; Dominietto, Marco; Keist, Ruth; Schweser, Ferdinand; Reichenbach, Jürgen R.; Nitsch, Roger M.; Knuesel, Irene; Rudin, Markus

    2013-01-01

    Magnetic resonance imaging (MRI) can be used to monitor pathological changes in Alzheimer's disease (AD). The objective of this longitudinal study was to assess the effects of progressive amyloid-related pathology on multiple MRI parameters in transgenic arcAβ mice, a mouse model of cerebral amyloidosis. Diffusion-weighted imaging (DWI), T1-mapping and quantitative susceptibility mapping (QSM), a novel MRI based technique, were applied to monitor structural alterations and changes in tissue composition imposed by the pathology over time. Vascular function and integrity was studied by assessing blood-brain barrier integrity with dynamic contrast-enhanced MRI and cerebral microbleed (CMB) load with susceptibility weighted imaging and QSM. A linear mixed effects model was built for each MRI parameter to incorporate effects within and between groups (i.e. genotype) and to account for changes unrelated to the disease pathology. Linear mixed effects modelling revealed a strong association of all investigated MRI parameters with age. DWI and QSM in addition revealed differences between arcAβ and wt mice over time. CMBs became apparent in arcAβ mice with 9 month of age; and the CMB load reflected disease stage. This study demonstrates the benefits of linear mixed effects modelling of longitudinal imaging data. Moreover, the diagnostic utility of QSM and assessment of CMB load should be exploited further in studies of AD. PMID:23840405

  20. Recapitulating amyloid β and tau pathology in human neural cell culture models: clinical implications

    PubMed Central

    Choi, Se Hoon; Kim, Young Hye; D’Avanzo, Carla; Aronson, Jenna; Tanzi, Rudolph E.; Kim, Doo Yeon

    2015-01-01

    Summary The “amyloid β hypothesis” of Alzheimer’s disease (AD) has been the reigning hypothesis explaining pathogenic mechanisms of AD over the last two decades. However, this hypothesis has not been fully validated in animal models, and several major unresolved issues remain. We recently developed a human neural cell culture model of AD based on a three-dimensional (3D) cell culture system. This unique, cellular model recapitulates key events of the AD pathogenic cascade, including β-amyloid plaques and neurofibrillary tangles. Our 3D human neural cell culture model system provides a premise for a new generation of cellular AD models that can serve as a novel platform for studying pathogenic mechanisms and for high-throughput drug screening in a human brain-like environment. PMID:27019672

  1. Tau pathology-dependent remodelling of cerebral arteries precedes Alzheimer's disease-related microvascular cerebral amyloid angiopathy.

    PubMed

    Merlini, Mario; Wanner, Debora; Nitsch, Roger M

    2016-05-01

    Alzheimer's disease (AD) is characterised by pathologic cerebrovascular remodelling. Whether this occurs already before disease onset, as may be indicated by early Braak tau-related cerebral hypoperfusion and blood-brain barrier (BBB) impairment found in previous studies, remains unknown. Therefore, we systematically quantified Braak tau stage- and cerebral amyloid angiopathy (CAA)-dependent alterations in the alpha-smooth muscle actin (α-SMA), collagen, and elastin content of leptomeningeal arterioles, small arteries, and medium-sized arteries surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP), including the sulci, of 17 clinically and pathologically diagnosed AD subjects (Braak stage IV-VI) and 28 non-demented control subjects (Braak stage I-IV). GFM and HIPP paraffin sections were stained for general collagen and elastin with the Verhoeff-van Gieson stain; α-SMA and CAA/amyloid β (Aβ) were detected using immunohistochemistry. Significant arterial elastin degradation was observed from Braak stage III onward and correlated with Braak tau pathology (ρ = 0.909, 95 % CI 0.370 to 0.990, p < 0.05). This was accompanied by an increase in neutrophil elastase expression by α-SMA-positive cells in the vessel wall. Small and medium-sized arteries exhibited significant CAA-independent α-SMA loss starting between Braak stage I and II-III, along with accumulation of phosphorylated paired helical filament (PHF) tau in the perivascular space of intraparenchymal vessels. α-SMA remained at the decreased level throughout the later Braak stages. In contrast, arterioles exhibited significant α-SMA loss only at Braak stage V and VI/in AD subjects, which was CAA-dependent/correlated with CAA burden (ρ = -0.422, 95 % CI -0.557 to -0.265, p < 0.0001). Collagen content was only significantly changed in small arteries. Our data indicate that vessel wall remodelling of leptomeningeal arteries is an early-onset, Braak tau pathology-dependent process

  2. In Alzheimer's disease, hypometabolism in low-amyloid brain regions may be a functional consequence of pathologies in connected brain regions.

    PubMed

    Klupp, Elisabeth; Förster, Stefan; Grimmer, Timo; Tahmasian, Masoud; Yakushev, Igor; Sorg, Christian; Yousefi, Behrooz H; Drzezga, Alexander

    2014-06-01

    In patients with Alzheimer's disease (AD), prominent hypometabolism has been observed in brain regions with minor amyloid load. These hypometabolism-only (HO) areas cannot be explained merely as a consequence of local amyloid toxicity. The aim of this multimodal imaging study was to explore whether such HO phenomenon may be related to pathologies in functionally connected, remote brain regions. Nineteen AD patients and 15 matched controls underwent examinations with [(11)C]PiB-PET and [(18)F]FDG-PET. Voxel-based statistical group comparisons were performed to obtain maps of significantly elevated amyloid burden and reduced cerebral glucose metabolism, respectively, in patients. An HO area was identified by subtraction of equally thresholded result maps (hypometabolism minus amyloid burden). To identify the network typically functionally connected to this HO area, it was used as a seed region for a functional connectivity analysis in resting-state functional magnetic resonance imaging data of 17 elderly healthy controls. The resulting intrinsic connectivity network (HO-ICN) was retransferred into the brains of AD patients to be able to analyze pathologies within this network in the positron emission tomography (PET) datasets. The most prominent HO area was detected in the left middle frontal gyrus of AD patients. The HO-ICN in healthy controls showed a major overlap with brain areas significantly affected by both amyloid deposition and hypometabolism in patients. This association was substantiated by the results of region-of-interest-based and voxel-wise correlation analyses, which revealed strong correlations between the degree of hypometabolism within the HO region and within the HO-ICN. These results support the notion that hypometabolism in brain regions not strongly affected by locoregional amyloid pathology may be related to ongoing pathologies in remote but functionally connected regions, that is, by reduced neuronal input from these regions. PMID:24870443

  3. Combination of Aβ Secretion and Oxidative Stress in an Alzheimer-Like Cell Line Leads to the Over-Expression of the Nucleotide Excision Repair Proteins DDB2 and XPC.

    PubMed

    Forestier, Anne; Douki, Thierry; De Rosa, Viviana; Béal, David; Rachidi, Walid

    2015-01-01

    Repair of oxidative DNA damage, particularly Base Excision Repair (BER), impairment is often associated with Alzheimer's disease pathology. Here, we aimed at investigating the complete Nucleotide Excision Repair (NER), a DNA repair pathway involved in the removal of bulky DNA adducts, status in an Alzheimer-like cell line. The level of DNA damage was quantified using mass spectrometry, NER gene expression was assessed by qPCR, and the NER protein activity was analysed through a modified version of the COMET assay. Interestingly, we found that in the presence of the Amyloid β peptide (Aβ), NER factors were upregulated at the mRNA level and that NER capacities were also specifically increased following oxidative stress. Surprisingly, NER capacities were not differentially improved following a typical NER-triggering of ultraviolet C (UVC) stress. Oxidative stress generates a differential and specific DNA damage response in the presence of Aβ. We hypothesized that the release of NER components such as DNA damage binding protein 2 (DDB2) and Xeroderma Pigmentosum complementation group C protein (XPC) following oxidative stress might putatively involve their apoptotic role rather than DNA repair function. PMID:26263968

  4. Combination of Aβ Secretion and Oxidative Stress in an Alzheimer-Like Cell Line Leads to the Over-Expression of the Nucleotide Excision Repair Proteins DDB2 and XPC

    PubMed Central

    Forestier, Anne; Douki, Thierry; De Rosa, Viviana; Béal, David; Rachidi, Walid

    2015-01-01

    Repair of oxidative DNA damage, particularly Base Excision Repair (BER), impairment is often associated with Alzheimer’s disease pathology. Here, we aimed at investigating the complete Nucleotide Excision Repair (NER), a DNA repair pathway involved in the removal of bulky DNA adducts, status in an Alzheimer-like cell line. The level of DNA damage was quantified using mass spectrometry, NER gene expression was assessed by qPCR, and the NER protein activity was analysed through a modified version of the COMET assay. Interestingly, we found that in the presence of the Amyloid β peptide (Aβ), NER factors were upregulated at the mRNA level and that NER capacities were also specifically increased following oxidative stress. Surprisingly, NER capacities were not differentially improved following a typical NER-triggering of ultraviolet C (UVC) stress. Oxidative stress generates a differential and specific DNA damage response in the presence of Aβ. We hypothesized that the release of NER components such as DNA damage binding protein 2 (DDB2) and Xeroderma Pigmentosum complementation group C protein (XPC) following oxidative stress might putatively involve their apoptotic role rather than DNA repair function. PMID:26263968

  5. Transgenic Mice Overexpressing Amyloid Precursor Protein Exhibit Early Metabolic Deficits and a Pathologically Low Leptin State Associated with Hypothalamic Dysfunction in Arcuate Neuropeptide Y Neurons

    PubMed Central

    Ishii, Makoto; Wang, Gang; Racchumi, Gianfranco; Dyke, Jonathan P.

    2014-01-01

    Weight loss is a prominent early feature of Alzheimer's disease (AD) that often precedes the cognitive decline and clinical diagnosis. While the exact pathogenesis of AD remains unclear, accumulation of amyloid-β (Aβ) derived from the amyloid precursor protein (APP) in the brain is thought to lead to the neuronal dysfunction and death underlying the dementia. In this study, we examined whether transgenic mice overexpressing the Swedish mutation of APP (Tg2576), recapitulating selected features of AD, have hypothalamic leptin signaling dysfunction leading to early body weight deficits. We found that 3-month-old Tg2576 mice, before amyloid plaque formation, exhibit decreased weight with markedly decreased adiposity, low plasma leptin levels, and increased energy expenditure without alterations in feeding behavior. The expression of the orexigenic neuropeptide Y (NPY) in the hypothalamus to the low leptin state was abnormal at basal and fasting conditions. In addition, arcuate NPY neurons exhibited abnormal electrophysiological responses to leptin in Tg2576 hypothalamic slices or wild-type slices treated with Aβ. Finally, the metabolic deficits worsened as Tg2576 mice aged and amyloid burden increased in the brain. These results indicate that excess Aβ can potentially disrupt hypothalamic arcuate NPY neurons leading to weight loss and a pathologically low leptin state early in the disease process that progressively worsens as the amyloid burden increases. Collectively, these findings suggest that weight loss is an intrinsic pathological feature of Aβ accumulation and identify hypothalamic leptin signaling as a previously unrecognized pathogenic site of action for Aβ. PMID:24990930

  6. LXR agonist treatment ameliorates amyloid pathology and memory deficits caused by high fat diet in APP23 mice

    PubMed Central

    Fitz, Nicholas F.; Cronican, Andrea; Pham, Tam; Fogg, Allison; Fauq, Abdul H.; Chapman, Robert; Lefterov, Iliya; Koldamova, Radosveta

    2010-01-01

    High fat diet and certain dietary patterns are associated with higher incidence of sporadic Alzheimer’s disease (AD) and cognitive decline. However, no specific therapy has been suggested to ameliorate the negative effects of high fat/high cholesterol levels on cognition and amyloid pathology. Here we show that in 9 month old APP23 mice, a high fat/high cholesterol (HF) diet provided for 4 months exacerbates the AD phenotype evaluated by behavioral, morphological and biochemical assays. To examine the therapeutic potential of Liver X Receptor (LXR) ligands, APP23 mice were fed HF diet supplemented with synthetic LXR agonist T0901317 (T0). Our results demonstrate that LXR ligand treatment causes a significant reduction of memory deficits observed during both acquisition and retention phases of the Morris Water Maze. Moreover, the effects of T0 on cognition correlate with AD-like morphological and biochemical parameters. We found a significant decrease in amyloid plaque load, insoluble Aβ and soluble Aβ oligomers. In vitro experiments with primary glia demonstrated that Abca1 is essential for the proper lipidation of ApoE and mediates the effects of T0 on Aβ degradation by microglia. Microdialysis experiments performed on awake freely moving mice showed that T0 decreased Aβ level in the interstitial fluid of the hippocampus, supporting the conclusion that this treatment increases Aβ clearance. The data presented conclusively shows that LXR activation in the context of a metabolic challenge has critical effects on AD phenotype progression by attenuating Aβ deposition and facilitating its clearance. PMID:20484628

  7. LCAT deficiency does not impair amyloid metabolism in APP/PS1 mice.

    PubMed

    Stukas, Sophie; Freeman, Lita; Lee, Michael; Wilkinson, Anna; Ossoli, Alice; Vaisman, Boris; Demosky, Stephen; Chan, Jeniffer; Hirsch-Reinshagen, Veronica; Remaley, Alan T; Wellington, Cheryl L

    2014-08-01

    A key step in plasma HDL maturation from discoidal to spherical particles is the esterification of cholesterol to cholesteryl ester, which is catalyzed by LCAT. HDL-like lipoproteins in cerebrospinal fluid (CSF) are also spherical, whereas nascent lipoprotein particles secreted from astrocytes are discoidal, suggesting that LCAT may play a similar role in the CNS. In plasma, apoA-I is the main LCAT activator, while in the CNS, it is believed to be apoE. apoE is directly involved in the pathological progression of Alzheimer's disease, including facilitating β-amyloid (Aβ) clearance from the brain, a function that requires its lipidation by ABCA1. However, whether apoE particle maturation by LCAT is also required for Aβ clearance is unknown. Here we characterized the impact of LCAT deficiency on CNS lipoprotein metabolism and amyloid pathology. Deletion of LCAT from APP/PS1 mice resulted in a pronounced decrease of apoA-I in plasma that was paralleled by decreased apoA-I levels in CSF and brain tissue, whereas apoE levels were unaffected. Furthermore, LCAT deficiency did not increase Aβ or amyloid in APP/PS1 LCAT(-/-) mice. Finally, LCAT expression and plasma activity were unaffected by age or the onset of Alzheimer's-like pathology in APP/PS1 mice. Taken together, these results suggest that apoE-containing discoidal HDLs do not require LCAT-dependent maturation to mediate efficient Aβ clearance. PMID:24950691

  8. Analyzing and modeling the kinetics of amyloid beta pores associated with Alzheimer’s disease pathology

    DOE PAGESBeta

    Ullah, Ghanim; Demuro, Angelo; Parker, Ian; Pearson, John E.; Xu, Shang -Zhong

    2015-09-08

    Amyloid beta (Aβ) oligomers associated with Alzheimer’s disease (AD) form Ca2+-permeable plasma membrane pores, leading to a disruption of the otherwise well-controlled intracellular calcium (Ca2+) homeostasis. The resultant up-regulation of intracellular Ca2+ concentration has detrimental implications for memory formation and cell survival. The gating kinetics and Ca2+ permeability of Aβ pores are not well understood. We have used computational modeling in conjunction with the ability of optical patch-clamping for massively parallel imaging of Ca2+ flux through thousands of pores in the cell membrane of Xenopus oocytes to elucidate the kinetic properties of Aβ pores. The fluorescence time-series data from individualmore » pores were idealized and used to develop data-driven Markov chain models for the kinetics of the Aβ pore at different stages of its evolution. Our study provides the first demonstration of developing Markov chain models for ion channel gating that are driven by optical-patch clamp data with the advantage of experiments being performed under close to physiological conditions. As a result, we demonstrate the up-regulation of gating of various Ca2+ release channels due to Aβ pores and show that the extent and spatial range of such up-regulation increases as Aβ pores with low open probability and Ca2+ permeability transition into those with high open probability and Ca2+ permeability.« less

  9. Choroid plexus implants rescue Alzheimer's disease-like pathologies by modulating amyloid-β degradation.

    PubMed

    Bolos, Marta; Antequera, Desireé; Aldudo, Jesús; Kristen, Henrike; Bullido, María Jesús; Carro, Eva

    2014-08-01

    The choroid plexuses (CP) release numerous biologically active enzymes and neurotrophic factors, and contain a subpopulation of neural progenitor cells providing the capacity to proliferate and differentiate into other types of cells. These characteristics make CP epithelial cells (CPECs) excellent candidates for cell therapy aiming at restoring brain tissue in neurodegenerative illnesses, including Alzheimer's disease (AD). In the present study, using in vitro approaches, we demonstrated that CP were able to diminish amyloid-β (Aβ) levels in cell cultures, reducing Aβ-induced neurotoxicity. For in vivo studies, CPECs were transplanted into the brain of the APP/PS1 murine model of AD that exhibits advanced Aβ accumulation and memory impairment. Brain examination after cell implantation revealed a significant reduction in brain Aβ deposits, hyperphosphorylation of tau, and astrocytic reactivity. Remarkably, the transplantation of CPECs was accompanied by a total behavioral recovery in APP/PS1 mice, improving spatial and non-spatial memory. These findings reinforce the neuroprotective potential of CPECs and the use of cell therapies as useful tools in AD. PMID:24343520

  10. Analyzing and Modeling the Kinetics of Amyloid Beta Pores Associated with Alzheimer’s Disease Pathology

    PubMed Central

    Ullah, Ghanim; Demuro, Angelo; Parker, Ian; Pearson, John E.

    2015-01-01

    Amyloid beta (Aβ) oligomers associated with Alzheimer’s disease (AD) form Ca2+-permeable plasma membrane pores, leading to a disruption of the otherwise well-controlled intracellular calcium (Ca2+) homeostasis. The resultant up-regulation of intracellular Ca2+ concentration has detrimental implications for memory formation and cell survival. The gating kinetics and Ca2+ permeability of Aβ pores are not well understood. We have used computational modeling in conjunction with the ability of optical patch-clamping for massively parallel imaging of Ca2+ flux through thousands of pores in the cell membrane of Xenopus oocytes to elucidate the kinetic properties of Aβ pores. The fluorescence time-series data from individual pores were idealized and used to develop data-driven Markov chain models for the kinetics of the Aβ pore at different stages of its evolution. Our study provides the first demonstration of developing Markov chain models for ion channel gating that are driven by optical-patch clamp data with the advantage of experiments being performed under close to physiological conditions. Towards the end, we demonstrate the up-regulation of gating of various Ca2+ release channels due to Aβ pores and show that the extent and spatial range of such up-regulation increases as Aβ pores with low open probability and Ca2+ permeability transition into those with high open probability and Ca2+ permeability. PMID:26348728

  11. Smart Soup, a Traditional Chinese Medicine Formula, Ameliorates Amyloid Pathology and Related Cognitive Deficits

    PubMed Central

    Li, Xiaohang; Cui, Jin; Ding, Jianqing; Wang, Ying; Zeng, Xianglu; Ling, Yun; Shen, Xiaoheng; Chen, Shengdi; Huang, Chenggang; Pei, Gang

    2014-01-01

    Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes substantial public health care burdens. Intensive efforts have been made to find effective and safe disease-modifying treatment and symptomatic intervention alternatives against AD. Smart Soup (SS), a Chinese medicine formula composed of Rhizoma Acori Tatarinowii (AT), Poria cum Radix Pini (PRP) and Radix Polygalae (RP), is a typical prescription against memory deficits. Here, we assessed the efficacy of SS against AD. Oral administration of SS ameliorated the cognitive impairment of AD transgenic mice, with reduced Aβ levels, retarded Aβ amyloidosis and reduced Aβ-induced gliosis and neuronal loss in the brains of AD mice. Consistently, SS treatment reduced amyloid-related locomotor dysfunctions and premature death of AD transgenic Drosophila. Mechanistic studies showed that RP reduced Aβ generation, whereas AT and PRP exerted neuroprotective effects against Aβ. Taken together, our study indicates that SS could be effective against AD, providing a practical therapeutic strategy against the disease. PMID:25386946

  12. Anticonvulsants attenuate amyloid beta-peptide neurotoxicity, Ca2+ deregulation, and cytoskeletal pathology.

    PubMed

    Mark, R J; Ashford, J W; Goodman, Y; Mattson, M P

    1995-01-01

    Increasing evidence supports the involvement of amyloid beta-peptide (A beta) and an excitotoxic mechanism of neuronal injury in the pathogenesis of Alzheimer's disease. However, approaches aimed at preventing A beta toxicity and neurofibrillary degeneration are undeveloped. We now report that anticonvulsants (carbamazepine, phenytoin, and valproic acid) can protect cultured rat hippocampal neurons against A beta- and glutamate-induced injury. Each of the anticonvulsants attenuated the elevation of intracellular free calcium levels [(Ca2+)i] elicited by A beta or glutamate suggesting that their neuroprotective mechanism of action involved stabilization of [Ca2+]i. These compounds were effective at clinically relevant concentrations (carbamazepine, 100 nM-10 microM; phenytoin, 100 nM-1 microM; valproic acid, 100 nM-100 microM). The anticonvulsants suppressed glutamate-induced alterations in tau and buiquitin immunoreactivities. Compounds that stabilize [Ca2+]i may afford protection against the kinds of insults believed to underlie neuronal injury in Alzheimer's disease. PMID:7777136

  13. Analyzing and modeling the kinetics of amyloid beta pores associated with Alzheimer’s disease pathology

    SciTech Connect

    Ullah, Ghanim; Demuro, Angelo; Parker, Ian; Pearson, John E.; Xu, Shang -Zhong

    2015-09-08

    Amyloid beta (Aβ) oligomers associated with Alzheimer’s disease (AD) form Ca2+-permeable plasma membrane pores, leading to a disruption of the otherwise well-controlled intracellular calcium (Ca2+) homeostasis. The resultant up-regulation of intracellular Ca2+ concentration has detrimental implications for memory formation and cell survival. The gating kinetics and Ca2+ permeability of Aβ pores are not well understood. We have used computational modeling in conjunction with the ability of optical patch-clamping for massively parallel imaging of Ca2+ flux through thousands of pores in the cell membrane of Xenopus oocytes to elucidate the kinetic properties of Aβ pores. The fluorescence time-series data from individual pores were idealized and used to develop data-driven Markov chain models for the kinetics of the Aβ pore at different stages of its evolution. Our study provides the first demonstration of developing Markov chain models for ion channel gating that are driven by optical-patch clamp data with the advantage of experiments being performed under close to physiological conditions. As a result, we demonstrate the up-regulation of gating of various Ca2+ release channels due to Aβ pores and show that the extent and spatial range of such up-regulation increases as Aβ pores with low open probability and Ca2+ permeability transition into those with high open probability and Ca2+ permeability.

  14. A TREM1 variant alters the accumulation of Alzheimer-related amyloid pathology

    PubMed Central

    Replogle, Joseph M.; Chan, Gail; White, Charles C.; Raj, Towfique; Winn, Phoebe A.; Evans, Denis A.; Sperling, Reisa A.; Chibnik, Lori B.; Bradshaw, Elizabeth M.; Schneider, Julie A.; Bennett, David A.; De Jager, Philip L.

    2015-01-01

    Objective Genome-wide association studies (GWAS) have linked variants in TREM2 and TREML2 with Alzheimer’s disease (AD) and AD endophenotypes. Here, we pursue a targeted analysis of the TREM locus in relation to cognitive decline and pathological features of AD. Methods Clinical, cognitive, and neuropathological phenotypes were collected in three prospective cohorts on aging (n=3421 subjects). Our primary analysis was an association with neuritic plaque pathology. To functionally characterize the associated variants, we used flow cytometry data to measure TREM1 expression on monocytes. Results We provide evidence that an intronic variant, rs6910730G, in Triggering Receptor Expressed on Myeloid cells 1 (TREM1), is associated with an increased burden of neuritic plaques (p=3.7×10−4), diffuse plaques (p=4.1×10−3), and Aβ density (p=2.6×10−3) as well as an increased rate of cognitive decline (p=5.3×10−3). A variant upstream of TREM2, rs7759295C, is independently associated with an increased Tau tangle density (p=4.9×10−4), an increased burden of neurofibrillary tangles (p=9.1×10−3), and an increased rate of cognitive decline (p=2.3×10−3). Finally, a cytometric analysis shows that the TREM1 rs6910730G allele is associated with decreased TREM1 expression on the surface of myeloid cells (p=1.7×10−3). Interpretation We provide evidence that two common variants within the TREM locus are associated with pathological features of AD and aging-related cognitive decline. Our evidence suggests that these variants are likely to be independent of known AD variants and that they may work through an alteration of myeloid cell function. PMID:25545807

  15. Coenzyme Q10 attenuates beta-amyloid pathology in the aged transgenic mice with Alzheimer presenilin 1 mutation.

    PubMed

    Yang, Xifei; Yang, Ying; Li, Geng; Wang, Jianzhi; Yang, Edward S

    2008-02-01

    One of the neuropathological features of Alzheimer's disease (AD) is the deposition of senile plaques containing beta-amyloid (A beta). There is limited evidence for the treatment to arrest A beta pathology of AD. In our present study, we tested the effect of coenzyme Q10 (CoQ10), an endogenous antioxidant and a powerful free radical scavenger, on A beta in the aged transgenic mice overexpressing Alzheimer presenilin 1-L235P (leucine-to-proline mutation at codon 235, 16-17 months old). The treatment by feeding the transgenic mice with CoQ10 for 60 days (1,200 mg kg(-1) day(-1)) partially attenuated A beta overproduction and intracellular A beta deposit in the cortex of the transgenic mice compared with the age-matched untreated transgenic mice. Meanwhile, an increased oxidative stress reaction was detected as evidenced by elevated level of malondialdehyde (MDA) and decreased activity of superoxide dismutase (SOD) in the transgenic mice relative to the wild-type mice, and supplementation of CoQ10 partially decreased MDA level and upregulated the activity of SOD. The results indicate that oxidative stress is enhanced in the brain of the transgenic mice, that this enhancement may further promote A beta 42 overproduction in a vicious formation, and that CoQ10 would be beneficial for the therapy of AD. PMID:18181031

  16. Amyloid fibrils

    PubMed Central

    Rambaran, Roma N

    2008-01-01

    Amyloid refers to the abnormal fibrous, extracellular, proteinaceous deposits found in organs and tissues. Amyloid is insoluble and is structurally dominated by β-sheet structure. Unlike other fibrous proteins it does not commonly have a structural, supportive or motility role but is associated with the pathology seen in a range of diseases known as the amyloidoses. These diseases include Alzheimer's, the spongiform encephalopathies and type II diabetes, all of which are progressive disorders with associated high morbidity and mortality. Not surprisingly, research into the physicochemical properties of amyloid and its formation is currently intensely pursued. In this chapter we will highlight the key scientific findings and discuss how the stability of amyloid fibrils impacts on bionanotechnology. PMID:19158505

  17. Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models.

    PubMed

    Zhao, Lingzhi; Gottesdiener, Andrew J; Parmar, Mayur; Li, Mingjie; Kaminsky, Stephen M; Chiuchiolo, Maria J; Sondhi, Dolan; Sullivan, Patrick M; Holtzman, David M; Crystal, Ronald G; Paul, Steven M

    2016-08-01

    The common apolipoprotein E alleles (ε4, ε3, and ε2) are important genetic risk factors for late-onset Alzheimer's disease, with the ε4 allele increasing risk and reducing the age of onset and the ε2 allele decreasing risk and markedly delaying the age of onset. Preclinical and clinical studies have shown that apolipoprotein E (APOE) genotype also predicts the timing and amount of brain amyloid-β (Aβ) peptide deposition and amyloid burden (ε4 >ε3 >ε2). Using several administration protocols, we now report that direct intracerebral adeno-associated virus (AAV)-mediated delivery of APOE2 markedly reduces brain soluble (including oligomeric) and insoluble Aβ levels as well as amyloid burden in 2 mouse models of brain amyloidosis whose pathology is dependent on either the expression of murine Apoe or more importantly on human APOE4. The efficacy of APOE2 to reduce brain Aβ burden in either model, however, was highly dependent on brain APOE2 levels and the amount of pre-existing Aβ and amyloid deposition. We further demonstrate that a widespread reduction of brain Aβ burden can be achieved through a single injection of vector via intrathalamic delivery of AAV expressing APOE2 gene. Our results demonstrate that AAV gene delivery of APOE2 using an AAV vector rescues the detrimental effects of APOE4 on brain amyloid pathology and may represent a viable therapeutic approach for treating or preventing Alzheimer's disease especially if sufficient brain APOE2 levels can be achieved early in the course of the disease. PMID:27318144

  18. Intravenous Delivery of Targeted Liposomes to AmyloidPathology in APP/PSEN1 Transgenic Mice

    PubMed Central

    Tanifum, Eric A.; Dasgupta, Indrani; Srivastava, Mayank; Bhavane, Rohan C.; Sun, Li; Berridge, John; Pourgarzham, Hoda; Kamath, Rashmi; Espinosa, Gabriela; Cook, Stephen C.; Eriksen, Jason L.; Annapragada, Ananth

    2012-01-01

    Extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles constitute the major neuropathological hallmarks of Alzheimer’s disease (AD). It is now apparent that parenchymal Aβ plaque deposition precedes behavioral signs of disease by several years. The development of agents that can target these plaques may be useful as diagnostic or therapeutic tools. In this study, we synthesized an Aβ-targeted lipid conjugate, incorporated it in stealth liposomal nanoparticles and tested their ability to bind amyloid plaque deposits in an AD mouse model. The results show that the particles maintain binding profiles to synthetic Aβ aggregates comparable to the free ligand, and selectively bind Aβ plaque deposits in brain tissue sections of an AD mouse model (APP/PSEN1 transgenic mice) with high efficiency. When administered intravenously, these long circulating nanoparticles appear to cross the blood-brain barrier and bind to Aβ plaque deposits, labeling parenchymal amyloid deposits and vascular amyloid characteristic of cerebral amyloid angiopathy. PMID:23119043

  19. Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes.

    PubMed

    Plucińska, Kaja; Crouch, Barry; Koss, David; Robinson, Lianne; Siebrecht, Michael; Riedel, Gernot; Platt, Bettina

    2014-08-01

    Key neuropathological hallmarks of Alzheimer's disease (AD) are elevated levels of amyloid β-peptide (Aβ) species generated via amyloid precursor protein (APP) endoproteolysis and cleavage by the rate-limiting β-site enzyme 1 (BACE1). Because rodents do not develop amyloid pathologies, we here investigated whether AD-like endophenotypes can be created in mice by expression of human bace1. To avoid pitfalls of existing models, we introduced hbace1 via knock-in under the control of the CaMKII α promoter into the safe HPRT locus. We report amyloidogenic processing of murine APP in the hBACE1 mice (termed PLB4), resulting in the formation of toxic APP metabolites that accumulate intra- and extraneuronally in hippocampus and cortex. Pronounced accumulation of Aβ*56 and Aβ hexamers in the absence of plaque deposition was detected in brain tissue from symptomatic PLB4 mice. Heightened levels of inflammation (gliosis) also appeared in several AD-related brain regions (dentate gyrus, hippocampal area CA1, piriform and parietal cortices) at 6 and 12 months of age. Behaviorally, deficits in habituation to a novel environment and semantic-like memory (social transmission of food preference) were detected from 3 to 4 months of age. Impairments in spatial learning strategies in long-term reference (water maze) and working memory (Y-maze) tasks presented at 6 months, and were distinct from reductions in locomotor activity and anxiety. Overall, our data indicate for the first time that targeted, subtle forebrain-specific expression through single gene knock-in of hBACE1 is sufficient to generate AD-relevant cognitive impairments amid corresponding histopathologies, confirming human BACE as the key parameter in amyloid pathogenesis. PMID:25100603

  20. In vivo positron emission tomographic imaging of glial responses to amyloid-β and tau pathologies in mouse models of Alzheimer's disease and related disorders

    PubMed Central

    Maeda, Jun; Zhang, Ming-Rong; Okauchi, Takashi; Ji, Bin; Ono, Maiko; Hattori, Satoko; Kumata, Katsushi; Iwata, Nobuhisa; Saido, Takaomi C.; Trojanowski, John Q.; Lee, Virginia M.-Y.; Staufenbiel, Matthias; Tomiyama, Takami; Mori, Hiroshi; Fukumura, Toshimitsu; Suhara, Tetsuya; Higuchi, Makoto

    2011-01-01

    Core pathologies of Alzheimer's disease (AD) are aggregated amyloid-β peptides (Aβ) and tau, and the latter is also characteristic of diverse neurodegenerative tauopathies. These amyloid lesions provoke microglial activation, and recent neuroimaging technologies have enabled visualization of this response in living brains using radioligands for the peripheral benzodiazepine receptor also known as the 18-kDa translocator protein (TSPO). Here we elucidated contributions of Aβ and tau deposits to in vivo TSPO signals in pursuit of mechanistic and diagnostic significance of TSPO imaging in AD and other tauopathies. A new antibody to human TSPO revealed induction of TSPO-positive microgliosis by tau fibrils in tauopathy brains. Emergence of TSPO signals prior to occurrence of brain atrophy and thioflavin-S-positive tau amyloidosis was also demonstrated in living mice transgenic for mutant tau by positron emission tomography (PET) with two classes of TSPO radioligands, [11C]AC-5216 and [18F]fluoroethoxy-DAA1106. Meanwhile, only modest TSPO elevation was observed in aged mice modeling Aβ plaque deposition, despite the notably enhanced in vivo binding of amyloid radiotracer, [11C]Pittsburgh Compound-B, to plaques. In these animals, [11C]AC-5216 yielded better TSPO contrasts than [18F]fluoroethoxy-DAA1106, supporting the possibility of capturing early neurotoxicity with high-performance TSPO probes. Furthermore, an additional line of mice modeling intraneuronal Aβ accumulation displayed elevated TSPO signals following noticeable neuronal loss, unlike TSPO upregulation heralding massive neuronal death in tauopathy model mice. Our data corroborate the utility of TSPO-PET imaging as a biomarker for tau-triggered toxicity, and as a complement to amyloid scans for diagnostic assessment of tauopathies with and without Aβ pathologies. PMID:21430171

  1. MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimer's disease.

    PubMed

    Baranger, Kévin; Marchalant, Yannick; Bonnet, Amandine E; Crouzin, Nadine; Carrete, Alex; Paumier, Jean-Michel; Py, Nathalie A; Bernard, Anne; Bauer, Charlotte; Charrat, Eliane; Moschke, Katrin; Seiki, Mothoharu; Vignes, Michel; Lichtenthaler, Stefan F; Checler, Frédéric; Khrestchatisky, Michel; Rivera, Santiago

    2016-01-01

    Membrane-type 5-matrix metalloproteinase (MT5-MMP) is a proteinase mainly expressed in the nervous system with emerging roles in brain pathophysiology. The implication of MT5-MMP in Alzheimer's disease (AD), notably its interplay with the amyloidogenic process, remains elusive. Accordingly, we crossed the genetically engineered 5xFAD mouse model of AD with MT5-MMP-deficient mice and examined the impact of MT5-MMP deficiency in bigenic 5xFAD/MT5-MMP(-/-) mice. At early stages (4 months) of the pathology, the levels of amyloid beta peptide (Aβ) and its amyloid precursor protein (APP) C-terminal fragment C99 were largely reduced in the cortex and hippocampus of 5xFAD/MT5-MMP(-/-), compared to 5xFAD mice. Reduced amyloidosis in bigenic mice was concomitant with decreased glial reactivity and interleukin-1β (IL-1β) levels, and the preservation of long-term potentiation (LTP) and spatial learning, without changes in the activity of α-, β- and γ-secretases. The positive impact of MT5-MMP deficiency was still noticeable at 16 months of age, as illustrated by reduced amyloid burden and gliosis, and a better preservation of the cortical neuronal network and synaptophysin levels in bigenic mice. MT5-MMP expressed in HEKswe cells colocalized and co-immunoprecipitated with APP and significantly increased the levels of Aβ and C99. MT5-MMP also promoted the release of a soluble APP fragment of 95 kDa (sAPP95) in HEKswe cells. sAPP95 levels were significantly reduced in brain homogenates of 5xFAD/MT5-MMP(-/-) mice, supporting altogether the idea that MT5-MMP influences APP processing. MT5-MMP emerges as a new pro-amyloidogenic regulator of APP metabolism, whose deficiency alleviates amyloid pathology, neuroinflammation and cognitive decline. PMID:26202697

  2. 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. PMID:25434488

  3. Late running is not too late against Alzheimer's pathology.

    PubMed

    Herring, Arne; Münster, Yvonne; Metzdorf, Judith; Bolczek, Bastien; Krüssel, Sarah; Krieter, David; Yavuz, Ilkay; Karim, Fro; Roggendorf, Constanze; Stang, Anthony; Wang, Yachao; Hermann, Dirk M; Teuber-Hanselmann, Sarah; Keyvani, Kathy

    2016-10-01

    In the last decade a vast number of animal studies have produced overwhelming evidence that exercise not only compensates for memory loss by increasing brain plasticity and cognitive reserve but also directly counteracts Alzheimer-like pathology when provided before disease onset or in early disease stages. But so far, there is little knowledge about therapeutic effects of training when started in advanced disease stages. In the present study we show that following seven months of sedentary life style five months of wheel running, started four months after disease onset was still able to mitigate at least some aspects of the full-blown Alzheimer's pathology in TgCRND8 mice. Late running had mild but significant effects on structural plasticity by increasing the dendritic complexity. It further reduced beta-amyloid (Aβ) plaque burden and enhanced Aβ clearance across the blood-brain barrier, along with attenuating microgliosis, inflammation, oxidative stress, and autophagy deficits, resulting in better memory performance and less agitation. However, unlike early exercise, late running did not affect abnormal amyloid precursor protein metabolism, tau pathology, or angiogenesis. These results allow concluding that it is never too late to counteract Alzheimer's disease with physical training but the earlier the intervention starts, the more pronounced is the therapeutic potential. PMID:27312772

  4. Amyloid goes global

    PubMed Central

    Bezprozvanny, Ilya

    2016-01-01

    The brains of Alzheimer’s disease (AD) patients contain abundant amyloid plaques composed of Aβ peptides. It is generally assumed that amyloid plaques and soluble Aβ oligomers induce neuronal pathology in AD. The mechanism of amyloid-mediated pathological effects is not clearly understood. Recent in vivo calcium (Ca2+) imaging studies with AD mouse models provide novel insights into changes in brain function resulting from accumulation of amyloid plaques. The unexpected lesson from these studies is that amyloid plaques result in both localized and global changes in brain function. The amyloid-induced effects include “short-range” changes in neuronal Ca2+ levels, “medium-range” changes in neuronal activity and ‘long-range” changes in astrocytic Ca2+ signaling and induction of intracellular Ca2+ waves spreading via astrocytic network. These results have potential implications for understanding synaptic and neuronal network dysfunction in AD brains. PMID:19318622

  5. Pathologic deposition of non-amyloid immunoglobulin in the brain leading to mass effect and neurological deficits.

    PubMed

    Hersh, David S; Houbova, Petra; Castellani, Rudolph J; Rodriguez, Fausto J; Mehta, Minesh P; Woodworth, Graeme F

    2016-08-01

    We report a 31-year-old man with multiple large, non-enhancing intracerebral lesions exerting significant mass effect. Following debulking, histopathological analysis revealed abundant amorphous non-amyloid eosinophilic material, while liquid chromatography mass spectrometry revealed κ light chains and immunoglobulin A heavy chains, leading to the diagnosis of multiple intracerebral light-and-heavy chain aggregomas. Localized intracranial deposits of non-amyloid immunoglobulin may rarely mimic space-occupying intracranial neoplasms and should be considered in the differential diagnosis. PMID:26954763

  6. Clinical predictors of severe cerebral amyloid angiopathy and influence of APOE genotype in persons with pathologically-verified Alzheimer’s disease

    PubMed Central

    Ringman, John M.; Sachs, Michael C.; Zhou, Yan; Monsell, Sarah E.; Saver, Jeffrey L.; Vinters, Harry V.

    2014-01-01

    Importance Though cerebral amyloid angiopathy (CAA) has important clinical implications, our understanding of it and ability to diagnose it is limited. Objective We sought to determine pathological correlates and clinical factors identifiable during life that predict the presence of severe CAA in persons with pathologically-confirmed Alzheimer’s disease (AD). Design We compared demographic and clinical variables at the earliest visit during life at which subjects were found to have cognitive impairment, and pathological variables between persons ultimately found to have no or severe CAA at autopsy using logistic regression. Analyses were repeated separately for carriers and non-carriers of the APOE ε4 allele. Setting Data were obtained from the Uniform Data Set that comprises longitudinal clinical assessments performed in the Alzheimer’s Disease Centers funded by the National Institute on Aging. Participants 193 persons with severe CAA and 232 persons with no CAA. All subjects had cognitive impairment and met NIA-Reagan neuropathological criteria for AD. Main Outcome Measures Prevalence of demographic characteristics and the APOE ε4 allele and odds ratios of clinical variables for the prediction of severe CAA. Results Persons with severe CAA were more likely to carry an APOE ε4 allele (64.9% vs. 42.8%), to be Hispanic (6.8% vs. 1.3%, p = 0.003), to have had a transient ischemic attack (TIA, 12.5% vs. 6.1%, OR = 2.1, 95% CI = 1 – 4.4), and had lower degrees of diffuse amyloid plaque pathology (mean CERAD scores 1.2 vs. 1.4, p = 0.01) than persons with no CAA. Intracerebral hemorrhage (9.3% vs. 3.5%, p = 0.01), cortical microinfarcts (20.7% vs. 12.9%, p = 0.03), and subcortical leukoencephalopathy (20.5% vs. 12.1%, p = 0.02) were more common in persons with CAA. A higher prevalence of stroke (11.1% vs. 3.9%, OR = 3.8, 95% CI 1.0 – 14.6) and hypercholesterolemia (50% vs. 33.3%, OR = 2.3, CI 1.1 – 4.7) were found in non-carriers of the ε4 allele with

  7. Chronic Noise Exposure Acts Cumulatively to Exacerbate Alzheimer’s Disease-Like AmyloidPathology and Neuroinflammation in the Rat Hippocampus

    PubMed Central

    Cui, Bo; Li, Kang; Gai, Zhihui; She, Xiaojun; Zhang, Na; Xu, Chuanxiang; Chen, Xuewei; An, Gaihong; Ma, Qiang; Wang, Rui

    2015-01-01

    A putative etiological association exists between noise exposure and Alzheimer’s disease (AD). Amyloid-β (Aβ) pathology is thought to be one of the primary initiating factors in AD. It has been further suggested that subsequent dysregulation of Aβ may play a mechanistic role in the AD-like pathophysiology associated with noise exposure. Here, we used ELISA, immunoblotting, cytokine arrays, and RT-PCR, to examine both hippocampal Aβ pathology and neuroinflammation in rats at different time points after noise exposure. We found that chronic noise exposure significantly accelerated the progressive overproduction of Aβ, which persisted for 7 to 14 days after the cessation of exposure. This effect was accompanied by up-regulated expression of amyloid precursor protein (APP) and its cleavage enzymes, β- and γ-secretases. Cytokine analysis revealed that chronic noise exposure increased levels of tumor necrosis factor-α and the receptor for advanced glycation end products, while decreasing the expression of activin A and platelet-derived growth factor- AA. Furthermore, we found persistent elevations of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 expression that closely corresponded to the noise-induced increases in Aβ and neuroinflammation. These studies suggest that lifelong environmental noise exposure may have cumulative effects on the onset and development of AD. PMID:26251361

  8. [Amyloid angiopathy as a clinico-pathological entity to consider in the differential diagnosis of any hemorrhagic cerebrovascular accident].

    PubMed

    Miras Parra, F J; Valverde Romera, M; Gómez Jiménez, F J; de la Higuera Torres-Puchol, J; Cantero Hinojosa, J; Sánchez Parera, R

    1996-06-01

    Intracerebral hemorrhages represent about 10% of the whole of vascular cerebral accidents. According to different authors, the incidence of cerebral amyloid angiopathy varies between 5-10% and up to 20-30% of all primary non-traumatic intracerebral hemorrhages. This incidence was analyzed in our environment. A retrospective study was carried out on 403 patients, 203 of them were analyzed between 1990-91 and the other 200 between 1992-3. Age, arterial tension, relapses and localization were taken as criteria for a diagnosis. For the statistical analysis, Student's T-test was used for quantitative variables, while square Chi with Yates' correction was used for qualitative variables. Ischemic cerebral accidents (90.5% of the total) are more frequent than hemorrhagic cerebral accidents, which represent 5.7%. 3.7% were not registered. Therefore, it was suspected cerebral amyloid angiopathy in 1.4% of all vascular cerebral accidents. This represents 26.1% of the total of hemorrhagic patients. Different variables from groups of hemorrhagic vascular cerebral accidents were compared to those caused by amyloid cerebral angiopathy and significant statistics were found with respect to localization in the cerebral hemispheres (p < 0.01). Neither age, nor arterial tension or relapses were significant. Amyloid cerebral angiopathy as a cause of hemorrhagic cerebrovascular accident is and entity to be considered in the diagnosis of these patients. By using clinical criteria and others of localization through complementary explorations, a diagnosis for guessing such a process can be determined. PMID:8962954

  9. 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,…

  10. The Significance of α-Synuclein, Amyloid-β and Tau Pathologies in Parkinson’s Disease Progression and Related Dementia

    PubMed Central

    Compta, Y.; Parkkinen, L.; Kempster, P.; Selikhova, M.; Lashley, T.; Holton, J.L.; Lees, A.J.; Revesz, T.

    2014-01-01

    Background Dementia is one of the milestones of advanced Parkinson’s disease (PD), with its neuropathological substrate still being a matter of debate, particularly regarding its potential mechanistic implications. Objective The aim of this study was to review the relative importance of Lewy-related α-synuclein and Alzheimer’s tau and amyloid-β (Aβ) pathologies in disease progression and dementia in PD. Methods We reviewed studies conducted at the Queen Square Brain Bank, Institute of Neurology, University College London, using large PD cohorts. Results Cortical Lewy- and Alzheimer-type pathologies are associated with milestones of poorer prognosis and with non-tremor predominance, which have been, in turn, linked to dementia. The combination of these pathologies is the most robust neuropathological substrate of PD-related dementia, with cortical Aβ burden determining a faster progression to dementia. Conclusion The shared relevance of these pathologies in PD progression and dementia is in line with experimental data suggesting synergism between α-synuclein, tau and Aβ and with studies testing these proteins as disease biomarkers, hence favouring the eventual testing of therapeutic strategies targeting these proteins in PD. PMID:24028925

  11. Memantine improves cognition and reduces Alzheimer's-like neuropathology in transgenic mice.

    PubMed

    Martinez-Coria, Hilda; Green, Kim N; Billings, Lauren M; Kitazawa, Masashi; Albrecht, Miriam; Rammes, Gerhard; Parsons, Chris G; Gupta, Sandeep; Banerjee, Pradeep; LaFerla, Frank M

    2010-02-01

    Memantine is an N-methyl-d-aspartate receptor antagonist that is approved for the treatment of moderate to severe Alzheimer's disease (AD). In this study, three groups of triple-transgenic (3xTg-AD) mice with differing levels of AD-like pathology (6, 9, and 15 months of age) were treated for 3 months with doses of memantine equivalent to those used in humans. After the treatment, memantine-treated mice had restored cognition and significantly reduced the levels of insoluble amyloid-beta (Abeta), Abeta dodecamers (Abeta*56), prefibrillar soluble oligomers, and fibrillar oligomers. The effects on pathology were stronger in older, more impaired animals. Memantine treatment also was associated with a decline in the levels of total tau and hyperphosphorylated tau. Finally, memantine pre-incubation prevented Abeta-induced inhibition of long-term potentiation in hippocampal slices of cognitively normal mice. These results suggest that the effects of memantine treatment on AD brain include disease modification and prevention of synaptic dysfunction. PMID:20042680

  12. Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder

    PubMed Central

    Cai, Zhiyou; Yan, Yong; Wang, Yonglong

    2013-01-01

    Background Compelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer’s disease, including increased expression of β-amyloid protein (Aβ) and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder. Method An animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. Results These results showed that minocycline decreased expression of Aβ protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein. Conclusion On the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of Aβ generation, the decreases in Aβ production and tau hyperphosphorylation by minocycline are through inhibiting neuroinflammation, which contributes to Aβ production and tau hyperphosphorylation. Minocycline may also lower the self-perpetuating cycle between neuroinflammation and the pathogenesis of tau and Aβ to act as a neuroprotector. Therefore, the ability of minocycline to modulate inflammatory reactions may be of great importance in the selection of neuroprotective agents, especially in chronic conditions

  13. Decreased AmyloidPathologies by Intracerebral Loading of Glycosphingolipid-enriched Exosomes in Alzheimer Model Mice*

    PubMed Central

    Yuyama, Kohei; Sun, Hui; Sakai, Shota; Mitsutake, Susumu; Okada, Megumi; Tahara, Hidetoshi; Furukawa, Jun-ichi; Fujitani, Naoki; Shinohara, Yasuro; Igarashi, Yasuyuki

    2014-01-01

    Elevated levels of amyloid-β peptide (Aβ) in the human brain are linked to the pathogenesis of Alzheimer disease. Recent in vitro studies have demonstrated that extracellular Aβ can bind to exosomes, which are cell-secreted nanovesicles with lipid membranes that are known to transport their cargos intercellularly. Such findings suggest that the exosomes are involved in Aβ metabolism in brain. Here, we found that neuroblastoma-derived exosomes exogenously injected into mouse brains trapped Aβ and with the associated Aβ were internalized into brain-resident phagocyte microglia. Accordingly, continuous intracerebral administration of the exosomes into amyloid-β precursor protein transgenic mice resulted in marked reductions in Aβ levels, amyloid depositions, and Aβ-mediated synaptotoxicity in the hippocampus. In addition, we determined that glycosphingolipids (GSLs), a group of membrane glycolipids, are highly abundant in the exosomes, and the enriched glycans of the GSLs are essential for Aβ binding and assembly on the exosomes both in vitro and in vivo. Our data demonstrate that intracerebrally administered exosomes can act as potent scavengers for Aβ by carrying it on the exosome surface GSLs and suggest a role of exosomes in Aβ clearance in the central nervous system. Improving Aβ clearance by exosome administration would provide a novel therapeutic intervention for Alzheimer disease. PMID:25037226

  14. Neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) slows down Alzheimer's disease-like pathology in amyloid precursor protein-transgenic mice

    PubMed Central

    Rat, Dorothea; Schmitt, Ulrich; Tippmann, Frank; Dewachter, Ilse; Theunis, Clara; Wieczerzak, Ewa; Postina, Rolf; van Leuven, Fred; Fahrenholz, Falk; Kojro, Elzbieta

    2011-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) has neuroprotective and neurotrophic properties and is a potent α-secretase activator. As PACAP peptides and their specific receptor PAC1 are localized in central nervous system areas affected by Alzheimer's disease (AD), this study aims to examine the role of the natural peptide PACAP as a valuable approach in AD therapy. We investigated the effect of PACAP in the brain of an AD transgenic mouse model. The long-term intranasal daily PACAP application stimulated the nonamyloidogenic processing of amyloid precursor protein (APP) and increased expression of the brain-derived neurotrophic factor and of the antiapoptotic Bcl-2 protein. In addition, it caused a strong reduction of the amyloid β-peptide (Aβ) transporter receptor for advanced glycation end products (RAGE) mRNA level. PACAP, by activation of the somatostatin-neprilysin cascade, also enhanced expression of the Aβ-degrading enzyme neprilysin in the mouse brain. Furthermore, daily PAC1-receptor activation via PACAP resulted in an increased mRNA level of both the PAC1 receptor and its ligand PACAP. Our behavioral studies showed that long-term PACAP treatment of APP[V717I]-transgenic mice improved cognitive function in animals. Thus, nasal application of PACAP was effective, and our results indicate that PACAP could be of therapeutic value in treating AD.—Rat, D., Schmitt, U., Tippmann, F., Dewachter, I., Theunis, C., Wieczerzak, E, Postina, R., van Leuven, F., Fahrenholz, F., Kojro, E. Neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) slows down Alzheimer's disease-like pathology in amyloid precursor protein-transgenic mice. PMID:21593432

  15. Oxidative Stress during the Progression of β-Amyloid Pathology in the Neocortex of the Tg2576 Mouse Model of Alzheimer's Disease

    PubMed Central

    Porcellotti, Sara; Fanelli, Francesca; Fracassi, Anna; Sepe, Sara; Cecconi, Francesco; Bernardi, Cinzia; Cimini, AnnaMaria; Cerù, Maria Paola; Moreno, Sandra

    2015-01-01

    Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive neurodegeneration. Pathogenetic mechanisms, triggered by β-amyloid (Aβ) accumulation, include oxidative stress, derived from energy homeostasis deregulation and involving mitochondria and peroxisomes. We here addressed the oxidative stress status and the elicited cellular response at the onset and during the progression of Aβ pathology, studying the neocortex of Tg2576 model of AD. Age-dependent changes of oxidative damage markers, antioxidant enzymes, and related transcription factors were analysed in relation to the distribution of Aβ peptide and oligomers, by a combined molecular/morphological approach. Nucleic acid oxidative damage, accompanied by defective antioxidant defences, and decreased PGC1α expression are already detected in 3-month-old Tg2576 neurons. Conversely, PPARα is increased in these cells, with its cytoplasmic localization suggesting nongenomic, anti-inflammatory actions. At 6 months, when intracellular Aβ accumulates, PMP70 is downregulated, indicating impairment of fatty acids peroxisomal translocation and their consequent harmful accumulation. In 9-month-old Tg2576 neocortex, Aβ oligomers and acrolein deposition correlate with GFAP, GPX1, and PMP70 increases, supporting a compensatory response, involving astroglial peroxisomes. At severe pathological stages, when senile plaques disrupt cortical cytoarchitecture, antioxidant capacity is gradually lost. Overall, our data suggest early therapeutic intervention in AD, also targeting peroxisomes. PMID:25973140

  16. Oxidative Stress during the Progression of β-Amyloid Pathology in the Neocortex of the Tg2576 Mouse Model of Alzheimer's Disease.

    PubMed

    Porcellotti, Sara; Fanelli, Francesca; Fracassi, Anna; Sepe, Sara; Cecconi, Francesco; Bernardi, Cinzia; Cimini, AnnaMaria; Cerù, Maria Paola; Moreno, Sandra

    2015-01-01

    Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive neurodegeneration. Pathogenetic mechanisms, triggered by β-amyloid (Aβ) accumulation, include oxidative stress, derived from energy homeostasis deregulation and involving mitochondria and peroxisomes. We here addressed the oxidative stress status and the elicited cellular response at the onset and during the progression of Aβ pathology, studying the neocortex of Tg2576 model of AD. Age-dependent changes of oxidative damage markers, antioxidant enzymes, and related transcription factors were analysed in relation to the distribution of Aβ peptide and oligomers, by a combined molecular/morphological approach. Nucleic acid oxidative damage, accompanied by defective antioxidant defences, and decreased PGC1α expression are already detected in 3-month-old Tg2576 neurons. Conversely, PPARα is increased in these cells, with its cytoplasmic localization suggesting nongenomic, anti-inflammatory actions. At 6 months, when intracellular Aβ accumulates, PMP70 is downregulated, indicating impairment of fatty acids peroxisomal translocation and their consequent harmful accumulation. In 9-month-old Tg2576 neocortex, Aβ oligomers and acrolein deposition correlate with GFAP, GPX1, and PMP70 increases, supporting a compensatory response, involving astroglial peroxisomes. At severe pathological stages, when senile plaques disrupt cortical cytoarchitecture, antioxidant capacity is gradually lost. Overall, our data suggest early therapeutic intervention in AD, also targeting peroxisomes. PMID:25973140

  17. Redox Proteomics Analysis to Decipher the Neurobiology of Alzheimer-like Neurodegeneration: Overlaps in Down Syndrome and Alzheimer Disease Brain

    PubMed Central

    Butterfield, D. Allan; Di Domenico, Fabio; Swomley, Aaron M.; Head, Elizabeth; Perluigi, Marzia

    2015-01-01

    Accumulation of oxidative damage is a common feature of neurodegeneration that together with mitochondrial dysfunction point to the fact that reactive oxygen species are major contributors to loss of neuronal homeostasis and cell death. Among several targets of oxidative stress, free radical-mediated damage to proteins is particularly important in aging and age-related neurodegenerative diseases. In the majority of cases, oxidative stress mediated post-translational modifications cause non-reversible modifications of protein structure that consistently lead to impaired function. Redox proteomics methods are powerful tools to unravel the complexity of neurodegeneration, by identifying brain proteins with oxidative post-translational modifications that are detrimental for protein function. The present review discusses the current literature showing evidence of impaired pathways linked to oxidative stress possibly involved in the neurodegenerative process leading to the development of Alzheimer-like dementia. In particular, we focus attention on dysregulated pathways that underlie neurodegeneration in both aging adults with Down syndrome (DS) and AD. Since AD pathology is age-dependent in DS and shows similarities with AD, identification of common oxidized proteins by redox proteomics in both DS and AD can improve our understanding of the overlapping mechanisms that lead from normal aging to development of AD. The most relevant proteomics findings highlight that disturbance of protein homeostasis and energy production are central mechanisms of neurodegeneration and overlap in aging DS and AD. Protein oxidation impacts crucial intracellular functions and may be considered a “leitmotif” of degenerating neurons. Therapeutic strategies aimed at preventing/reducing multiple components of processes leading to accumulation of oxidative damage will be critical in future studies. PMID:25242166

  18. Anti-11[E]-pyroglutamate-modified amyloid β antibodies cross-react with other pathological Aβ species: relevance for immunotherapy.

    PubMed

    Perez-Garmendia, Roxanna; Ibarra-Bracamontes, Vanessa; Vasilevko, Vitaly; Luna-Muñoz, Jose; Mena, Raul; Govezensky, Tzipe; Acero, Gonzalo; Manoutcharian, Karen; Cribbs, David H; Gevorkian, Goar

    2010-12-15

    N-truncated/modified forms of amyloid beta (Aß) peptide are found in diffused and dense core plaques in Alzheimer's disease (AD) and Down's syndrome patients as well as animal models of AD, and represent highly desirable therapeutic targets. In the present study we have focused on N-truncated/modified Aβ peptide bearing amino-terminal pyroglutamate at position 11 (AβN11(pE)). We identified two B-cell epitopes recognized by rabbit anti-AβN11(pE) polyclonal antibodies. Interestingly, rabbit anti-AβN11(pE) polyclonal antibodies bound also to full-length Aβ1-42 and N-truncated/modified AβN3(pE), suggesting that the three peptides may share a common B-cell epitope. Importantly, rabbit anti-AβN11(pE) antibodies bound to naturally occurring Aβ aggregates present in brain samples from AD patients. These results are potentially important for developing novel immunogens for targeting N-truncated/modified Aβ aggregates as well, since the most commonly used immunogens in the majority of vaccine studies have been shown to induce antibodies that recognize the N-terminal immunodominant epitope (EFRH) of the full length Aβ, which is absent in N-amino truncated peptides. PMID:20864186

  19. ANTI-11[E]-PYROGLUTAMATE-MODIFIED AMYLOID β ANTIBODIES CROSS-REACT WITH OTHER PATHOLOGICAL Aβ SPECIES: RELEVANCE FOR IMMUNOTHERAPY

    PubMed Central

    Perez-Garmendia, Roxanna; Ibarra-Bracamontes, Vanessa; Vasilevko, Vitaly; Luna-Muñoz, Jose; Mena, Raul; Govezensky, Tzipe; Acero, Gonzalo; Manoutcharian, Karen; Cribbs, David H.; Gevorkian, Goar

    2010-01-01

    N-truncated/modified forms of amyloid beta (Aß) peptide are found in diffused and dense core plaques in Alzheimer's disease (AD) and Down's syndrome patients as well as animal models of AD, and represent highly desirable therapeutic targets. In the present study we have focused on Ntruncated/modified Aβ peptide bearing amino-terminal pyroglutamate at position 11 (AβN11(pE)). We identified two B-cell epitopes recognized by rabbit anti-AβN11(pE) polyclonal antibodies. Interestingly, rabbit anti-AβN11(pE) polyclonal antibodies bound also to full-length Aβ1-42 and N-truncated/modified AβN3(pE), suggesting that the three peptides may share a common B-cell epitope. Importantly, rabbit anti-AβN11(pE) antibodies bound to naturally occurring Aβ aggregates present in brain samples from AD patients. These results are potentially important for developing novel immunogens for targeting N-truncated/modified Aβ aggregates as well, since the most commonly used immunogens in the majority of vaccine studies have been shown to induce antibodies that recognize the N-terminal immunodominant epitope (EFRH) of the full length Aβ, which is absent in N-amino truncated peptides. PMID:20864186

  20. Potential role of PCTAIRE-2, PCTAIRE-3 and P-Histone H4 in amyloid precursor protein-dependent Alzheimer pathology

    PubMed Central

    Chaput, Dale; Kirouac, Lisa; Stevens, Stanley M.; Padmanabhan, Jaya

    2016-01-01

    Amyloid Precursor Protein (APP) is regulated in a mitosis-specific manner and plays a role in proliferative signaling in cells. Though APP-derived Aβ generation has a well-established role in neurodegeneration, the mechanistic role of APP in this process is not fully understood. Here, we performed an unbiased, comprehensive analysis of the phosphoproteome signature in APP-null neuroblastoma cells (B103) compared to those expressing APP-695 isoform (B103-695) to determine if APP expression affects protein phosphorylation. Stable isotope labeling by amino acids in cell culture (SILAC) followed by mass spectrometry-based phosphoproteomic analysis with PolyMAC identified a total of 2,478 phosphopeptides in the B103 and B103-695 cell culture model system. We observed that phosphorylation of PCTAIRE-2 (CDK17), PCTAIRE-3 (CDK18), and Histone H4 are significantly elevated in B103-695 cells; western blot analysis confirmed overexpression of PCTAIREs and increased phosphorylation of Histone H4. More importantly, analysis of primary neurons treated with Aβ, as well as brain samples from MCI (mild cognitive impaired) and AD patients recapitulated these results, showing increased levels of PCTAIREs and P-Histone H4. These novel findings identify a hitherto uncharacterized mechanism by which APP and/or Aβ may promote AD neurodegeneration, and raises the possibility that their inhibition may protect against pathology development in AD. PMID:26885753

  1. Potential role of PCTAIRE-2, PCTAIRE-3 and P-Histone H4 in amyloid precursor protein-dependent Alzheimer pathology.

    PubMed

    Chaput, Dale; Kirouac, Lisa; Stevens, Stanley M; Padmanabhan, Jaya

    2016-02-23

    Amyloid Precursor Protein (APP) is regulated in a mitosis-specific manner and plays a role in proliferative signaling in cells. Though APP-derived Aβ generation has a well-established role in neurodegeneration, the mechanistic role of APP in this process is not fully understood. Here, we performed an unbiased, comprehensive analysis of the phosphoproteome signature in APP-null neuroblastoma cells (B103) compared to those expressing APP-695 isoform (B103-695) to determine if APP expression affects protein phosphorylation. Stable isotope labeling by amino acids in cell culture (SILAC) followed by mass spectrometry-based phosphoproteomic analysis with PolyMAC identified a total of 2,478 phosphopeptides in the B103 and B103-695 cell culture model system. We observed that phosphorylation of PCTAIRE-2 (CDK17), PCTAIRE-3 (CDK18), and Histone H4 are significantly elevated in B103-695 cells; western blot analysis confirmed overexpression of PCTAIREs and increased phosphorylation of Histone H4. More importantly, analysis of primary neurons treated with Aβ, as well as brain samples from MCI (mild cognitive impaired) and AD patients recapitulated these results, showing increased levels of PCTAIREs and P-Histone H4. These novel findings identify a hitherto uncharacterized mechanism by which APP and/or Aβ may promote AD neurodegeneration, and raises the possibility that their inhibition may protect against pathology development in AD. PMID:26885753

  2. Neurofilament light gene deletion exacerbates amyloid, dystrophic neurite, and synaptic pathology in the APP/PS1 transgenic model of Alzheimer's disease.

    PubMed

    Fernandez-Martos, Carmen M; King, Anna E; Atkinson, Rachel A K; Woodhouse, Adele; Vickers, James C

    2015-10-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with the loss of cognitive function. Neurofilament (NF) triplet proteins, the major structural (intermediate filament) proteins of neurons, are expressed in a subset of pyramidal cells that show a high degree of vulnerability to degeneration in AD. Alterations in the NF triplet proteins in amyloid-beta (Aβ) plaque-associated dystrophic neurites (DNs) represent the first cytoskeletal aberration to occur in the neocortex in the earliest stages of AD. We generated transgenic APP/PS1 (APPswe/PSEN1dE9) mice on the neurofilament light knockout (NFL KO) background to explore the role of NFL deletion in the context of DN formation, synaptic changes, and other neuropathologic features. Our analysis demonstrated that NFL deficiency significantly increased neocortical DN pathology, Aβ deposition, synapse vulnerability, and microgliosis in APP/PS1 mice. Thus, NFs may have a role in protecting neurites from dystrophy and in regulating cellular pathways related to the generation of Aβ plaques. PMID:26344875

  3. Ablation of Prion Protein in Wild Type Human Amyloid Precursor Protein (APP) Transgenic Mice Does Not Alter The Proteolysis of APP, Levels of Amyloid-β or Pathologic Phenotype.

    PubMed

    Whitehouse, Isobel J; Brown, Deborah; Baybutt, Herbert; Diack, Abigail B; Kellett, Katherine A B; Piccardo, Pedro; Manson, Jean C; Hooper, Nigel M

    2016-01-01

    The cellular prion protein (PrPC) has been proposed to play an important role in the pathogenesis of Alzheimer's disease. In cellular models PrPC inhibited the action of the β-secretase BACE1 on wild type amyloid precursor protein resulting in a reduction in amyloid-β (Aβ) peptides. Here we have assessed the effect of genetic ablation of PrPC in transgenic mice expressing human wild type amyloid precursor protein (line I5). Deletion of PrPC had no effect on the α- and β-secretase proteolysis of the amyloid precursor protein (APP) nor on the amount of Aβ38, Aβ40 or Aβ42 in the brains of the mice. In addition, ablation of PrPC did not alter Aβ deposition or histopathology phenotype in this transgenic model. Thus using this transgenic model we could not provide evidence to support the hypothesis that PrPC regulates Aβ production. PMID:27447728

  4. Ablation of Prion Protein in Wild Type Human Amyloid Precursor Protein (APP) Transgenic Mice Does Not Alter The Proteolysis of APP, Levels of Amyloid-β or Pathologic Phenotype

    PubMed Central

    Baybutt, Herbert; Diack, Abigail B.; Kellett, Katherine A. B.; Piccardo, Pedro; Manson, Jean C.

    2016-01-01

    The cellular prion protein (PrPC) has been proposed to play an important role in the pathogenesis of Alzheimer’s disease. In cellular models PrPC inhibited the action of the β-secretase BACE1 on wild type amyloid precursor protein resulting in a reduction in amyloid-β (Aβ) peptides. Here we have assessed the effect of genetic ablation of PrPC in transgenic mice expressing human wild type amyloid precursor protein (line I5). Deletion of PrPC had no effect on the α- and β-secretase proteolysis of the amyloid precursor protein (APP) nor on the amount of Aβ38, Aβ40 or Aβ42 in the brains of the mice. In addition, ablation of PrPC did not alter Aβ deposition or histopathology phenotype in this transgenic model. Thus using this transgenic model we could not provide evidence to support the hypothesis that PrPC regulates Aβ production. PMID:27447728

  5. A novel DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro.

    PubMed

    Coutadeur, Séverine; Benyamine, Hélène; Delalonde, Laurence; de Oliveira, Catherine; Leblond, Bertrand; Foucourt, Alicia; Besson, Thierry; Casagrande, Anne-Sophie; Taverne, Thierry; Girard, Angélique; Pando, Matthew P; Désiré, Laurent

    2015-05-01

    The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene is located within the Down Syndrome (DS) critical region on chromosome 21 and is implicated in the generation of Tau and amyloid pathologies that are associated with the early onset Alzheimer's Disease (AD) observed in DS. DYRK1A is also found associated with neurofibrillary tangles in sporadic AD and phosphorylates key AD players (Tau, amyloid precursor, protein, etc). Thus, DYRK1A may be an important therapeutic target to modify the course of Tau and amyloid beta (Aβ) pathologies. Here, we describe EHT 5372 (methyl 9-(2,4-dichlorophenylamino) thiazolo[5,4-f]quinazoline-2-carbimidate), a novel, highly potent (IC50 = 0.22 nM) DYRK1A inhibitor with a high degree of selectivity over 339 kinases. Models in which inhibition of DYRK1A by siRNA reduced and DYRK1A over-expression induced Tau phosphorylation or Aβ production were used. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation at multiple AD-relevant sites in biochemical and cellular assays. EHT 5372 also normalizes both Aβ-induced Tau phosphorylation and DYRK1A-stimulated Aβ production. DYRK1A is thus as a key element of Aβ-mediated Tau hyperphosphorylation, which links Tau and amyloid pathologies. EHT 5372 and other compounds in its class warrant in vivo investigation as a novel, high-potential therapy for AD and other Tau opathies. Inhibition of the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a new high-potential therapeutic approach for Alzheimer disease. Here we describe EHT 5372, a novel potent and selective DYRK1A inhibitor. EHT 5372 inhibits DYRK1A-induced Tau phosphorylation, Aβ production and Aβ effects on phospho-Tau, including Tau aggregation. PMID:25556849

  6. Early AD pathology in a [C-11]PiB-negative case: a PiB-amyloid imaging, biochemical, and immunohistochemical study

    PubMed Central

    Abrahamson, Eric E.; Price, Julie C.; Hamilton, Ronald L.; Mathis, Chester A.; Paljug, William R.; Debnath, Manik L.; Cohen, Anne D.; Mizukami, Katsuyoshi; DeKosky, Steven T.; Lopez, Oscar L.; Klunk, William E.

    2012-01-01

    Amyloid-β (Aβ) deposits are detectable in the brain in vivo using positron emission tomography (PET) and [C-11]-labeled Pittsburgh Compound B ([C-11]PiB); however, the sensitivity of this technique is not well understood. In this study, we examined Aβ pathology in an individual who had clinical diagnoses of probable dementia with Lewy bodies and possible Alzheimer’s disease (AD) but with no detectable [C-11]PiB PET retention ([C-11]PiB(−)) when imaged 17 months prior to death. Brain samples were processed in parallel with region-matched samples from an individual with a clinical diagnosis of probable AD and a positive [C-11]PiB PET scan ([C-11]PiB(+)) when imaged 10 months prior to death. In the [C-11]PiB(−) case, Aβ plaques were sparse, occupying less than 2% cortical area, and were weakly labeled with 6-CN-PiB, a highly fluorescent derivative of PiB. In contrast, Aβ plaques occupied up to 12% cortical area in the [C-11]PiB(+) case, and were intensely labeled with 6-CN-PIB. The [C-11]PiB(−) case had low levels of [H-3]PiB binding (<100 pmol/g) and Aβ1–42 (<500 pmol/g) concentration except in the frontal cortex where Aβ1–42 values (788 pmol/g) approached cortical values in the [C-11]PiB(+) case (800–1,700 pmol/g). In several cortical regions of the [C-11]PiB(−) case, Aβ1–40 levels were within the range of cortical Aβ1–40 values in the [C-11]PiB(+) case. Antemortem [C-11]PiB DVR values correlated well with region-matched postmortem measures of Aβ1–42 and Aβ1–40 in the [C-11]PiB(+), and with Aβ1–42 only in the [C-11]PiB(−) case. The low ratios of [H-3]PiB binding levels to Aβ concentrations and 6-CN-PiB to Aβ plaque loads in the [C-11]PiB(−) case indicate that Aβ pathology in the brain may be associated with low or undetectable levels of [C-11]PiB retention. Studies in greater numbers of [C-11]PiB PET autopsy cases are needed to define the Aβ concentration and [H-3]PiB binding levels required to produce a positive [C-11

  7. Novel Levetiracetam Derivatives That Are Effective against the Alzheimer-like Phenotype in Mice: Synthesis, in Vitro, ex Vivo, and in Vivo Efficacy Studies.

    PubMed

    Sola, Irene; Aso, Ester; Frattini, Daniela; López-González, Irene; Espargaró, Alba; Sabaté, Raimon; Di Pietro, Ornella; Luque, F Javier; Clos, M Victòria; Ferrer, Isidro; Muñoz-Torrero, Diego

    2015-08-13

    We have synthesized a series of heptamethylene-linked levetiracetam-huprine and levetiracetam-(6-chloro)tacrine hybrids to hit amyloid, tau, and cholinergic pathologies as well as β-amyloid (Aβ)-induced epileptiform activity, some of the mechanisms that eventually lead to cognitive deficits in Alzheimer's disease patients. These hybrids are potent inhibitors of human acetylcholinesterase and butyrylcholinesterase in vitro and moderately potent Aβ42 and tau antiaggregating agents in a simple E. coli model of amyloid aggregation. Ex vivo determination of the brain acetylcholinesterase inhibitory activity of these compounds after intraperitoneal injection to C57BL6J mice has demonstrated their ability to enter the brain. The levetiracetam-huprine hybrid 10 significantly reduced the incidence of epileptic seizures, cortical amyloid burden, and neuroinflammation in APP/PS1 mice after a 4-week treatment with a 5 mg/kg dose. Moreover, the hybrid 10 rescued transgenic mice from cognitive deficits, thereby emerging as an interesting disease-modifying anti-Alzheimer drug candidate. PMID:26181606

  8. 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.

  9. Transmissible amyloid.

    PubMed

    Tjernberg, L O; Rising, A; Johansson, J; Jaudzems, K; Westermark, P

    2016-08-01

    There are around 30 human diseases associated with protein misfolding and amyloid formation, each one caused by a certain protein or peptide. Many of these diseases are lethal and together they pose an enormous burden to society. The prion protein has attracted particular interest as being shown to be the pathogenic agent in transmissible diseases such as kuru, Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Whether similar transmission could occur also in other amyloidoses such as Alzheimer's disease, Parkinson's disease and serum amyloid A amyloidosis is a matter of intense research and debate. Furthermore, it has been suggested that novel biomaterials such as artificial spider silk are potentially amyloidogenic. Here, we provide a brief introduction to amyloid, prions and other proteins involved in amyloid disease and review recent evidence for their potential transmission. We discuss the similarities and differences between amyloid and silk, as well as the potential hazards associated with protein-based biomaterials. PMID:27002185

  10. A novel approach to the identification and quantitative elemental analysis of amyloid deposits-Insights into the pathology of Alzheimer's disease

    SciTech Connect

    Rajendran, Reshmi; Minqin, Ren; Ynsa, Maria Dolores; Casadesus, Gemma; Smith, Mark A.; Perry, George; Halliwell, Barry; Watt, Frank

    2009-04-24

    There is considerable interest in the role of metals such as iron, copper, and zinc in amyloid plaque formation in Alzheimer's disease. However to convincingly establish their presence in plaques in vivo, a sensitive technique is required that is both quantitatively accurate and avoids isolation of plaques or staining/fixing brain tissue, since these processes introduce contaminants and redistribute elements within the tissue. Combining the three ion beam techniques of scanning transmission ion microscopy, Rutherford back scattering spectrometry and particle induced X-ray emission in conjunction with a high energy (MeV) proton microprobe we have imaged plaques in freeze-dried unstained brain sections from CRND-8 mice, and simultaneously quantified iron, copper, and zinc. Our results show increased metal concentrations within the amyloid plaques compared with the surrounding tissue: iron (85 ppm compared with 42 ppm), copper (16 ppm compared to 6 ppm), and zinc (87 ppm compared to 34 ppm).

  11. The Polyphenol Oleuropein Aglycone Protects TgCRND8 Mice against Aß Plaque Pathology

    PubMed Central

    Grossi, Cristina; Rigacci, Stefania; Ambrosini, Stefano; Ed Dami, Teresa; Luccarini, Ilaria; Traini, Chiara; Failli, Paola; Berti, Andrea; Casamenti, Fiorella; Stefani, Massimo

    2013-01-01

    The claimed beneficial effects of the Mediterranean diet include prevention of several age-related dysfunctions including neurodegenerative diseases and Alzheimer-like pathology. These effects have been related to the protection against cognitive decline associated with aging and disease by a number of polyphenols found in red wine and extra virgin olive oil. The double transgenic TgCRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein), aged 1.5 and 4, and age-matched wild type control mice were used to examine in vivo the effects of 8 weeks dietary supplementation of oleuropein aglycone (50 mg/kg of diet), the main polyphenol found in extra virgin olive oil. We report here that dietary supplementation of oleuropein aglycone strongly improves the cognitive performance of young/middle-aged TgCRND8 mice, a model of amyloid-ß deposition, respect to age-matched littermates with un-supplemented diet. Immunofluorescence analysis of cerebral tissue in oleuropein aglycone-fed transgenic mice showed remarkably reduced ß-amyloid levels and plaque deposits, which appeared less compact and “fluffy”; moreover, microglia migration to the plaques for phagocytosis and a remarkable reduction of the astrocyte reaction were evident. Finally, oleuropein aglycone-fed mice brain displayed an astonishingly intense autophagic reaction, as shown by the increase of autophagic markers expression and of lysosomal activity. Data obtained with cultured cells confirmed the latter evidence, suggesting mTOR regulation by oleuropein aglycone. Our results support, and provide mechanistic insights into, the beneficial effects against Alzheimer-associated neurodegeneration of a polyphenol enriched in the extra virgin olive oil, a major component of the Mediterranean diet. PMID:23951225

  12. Sporadic Cerebral Amyloid Angiopathy: Pathophysiology, Neuroimaging Features, and Clinical Implications.

    PubMed

    Boulouis, Gregoire; Charidimou, Andreas; Greenberg, Steven M

    2016-06-01

    Sporadic cerebral amyloid angiopathy is a small vessel disorder defined pathologically by progressive amyloid deposition in the walls of cortical and leptomeningeal vessels resulting from disruption of a complex balance between production, circulation, and clearance of amyloid-β peptide (Aβ) in the brain. Cerebral amyloid angiopathy is a major cause of lobar symptomatic intracerebral hemorrhage, transient focal neurologic episodes, and a key contributor to vascular cognitive impairment. The mechanisms and consequences of amyloid-β deposition at the pathological level and its neuroimaging manifestations, clinical consequences, and implications for patient care are addressed in this review. PMID:27214698

  13. Template-directed deposition of amyloid

    NASA Astrophysics Data System (ADS)

    Ha, Chanki

    The formation of amyloid plaques in tissue is a pathological feature of many neurodegenerative diseases. Amyloid deposition, the process of amyloid plaque growth by the association of individual soluble amyloid molecules with a pre-existing amyloid template (i.e. plaque), is known to be critical for amyloid formation in vivo. In order to characterize amyloid deposition, we developed novel, synthetic amyloid templates like amyloid plaques in the human Alzheimer's brain by attaching amyloid seeds covalently onto an N-hydroxysuccinimide-activated surface. Amyloid plaques with a characteristic beta-sheet structure formed through a conformational rearrangement of soluble insulin or Abeta monomers upon interaction with the template. The amyloid deposition rate followed saturation kinetics with respect to insulin concentration in the solution. According to visualization of temporal evolution of Abeta plaque deposition on a template, it was found that mature amyloid plaques serve as a sink of soluble Abeta in a solution as well as a reservoir of small aggregates such as oligomers and protofibrils. Quantitative analysis of seeding efficiencies of three different Abeta species revealed that oligomeric forms of Abeta act more efficiently as seeds than monomers or fibrils do. Furthermore, studies on the interaction between Abeta40 and 42 showed an important role of Abeta42 in amyloid deposition. A slightly acidic condition was found to be unfavorable for amyloid plaque formation. Effects of metal ions on amyloid deposition indicated that Fe3+, but not Cu3 and Zn2+, is important for the deposition of amyloid plaques. The binding of Fe3+ to Abeta42 peptide was confirmed by using SIMS analysis. Zn2+ induced nonfibrillar amorphous aggregates, but the release of Zn2+ from Abeta42 deposits by Fe3+ triggered the formation of amyloid fibers. Effects or metal ion chelators such as ethylenediamine tetraacetic acid, deferoxamine, and clioquinol on amyloid deposition were tested to

  14. Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine models of Alzheimer's disease.

    PubMed

    Zhu, H; Wang, X; Wallack, M; Li, H; Carreras, I; Dedeoglu, A; Hur, J-Y; Zheng, H; Li, H; Fine, R; Mwamburi, M; Sun, X; Kowall, N; Stern, R A; Qiu, W Q

    2015-02-01

    Amylin, a pancreatic peptide, and amyloid-beta peptides (Aβ), a major component of Alzheimer's disease (AD) brain, share similar β-sheet secondary structures, but it is not known whether pancreatic amylin affects amyloid pathogenesis in the AD brain. Using AD mouse models, we investigated the effects of amylin and its clinical analog, pramlintide, on AD pathogenesis. Surprisingly, chronic intraperitoneal (i.p.) injection of AD animals with either amylin or pramlintide reduces the amyloid burden as well as lowers the concentrations of Aβ in the brain. These treatments significantly improve their learning and memory assessed by two behavioral tests, Y maze and Morris water maze. Both amylin and pramlintide treatments increase the concentrations of Aβ1-42 in cerebral spinal fluid (CSF). A single i.p. injection of either peptide also induces a surge of Aβ in the serum, the magnitude of which is proportionate to the amount of Aβ in brain tissue. One intracerebroventricular injection of amylin induces a more significant surge in serum Aβ than one i.p. injection of the peptide. In 330 human plasma samples, a positive association between amylin and Aβ1-42 as well as Aβ1-40 is found only in patients with AD or amnestic mild cognitive impairment. As amylin readily crosses the blood-brain barrier, our study demonstrates that peripheral amylin's action on the central nervous system results in translocation of Aβ from the brain into the CSF and blood that could be an explanation for a positive relationship between amylin and Aβ in blood. As naturally occurring amylin may play a role in regulating Aβ in brain, amylin class peptides may provide a new avenue for both treatment and diagnosis of AD. PMID:24614496

  15. Cerebral amyloid angiopathy

    MedlinePlus

    Cerebral amyloid angiopathy is a neurological condition in which proteins called amyloid build up on the walls of the arteries ... The cause of cerebral amyloid angiopathy is unknown. Sometimes, it ... Persons with this condition have deposits of amyloid protein ...

  16. 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

  17. The Influence of Pathological Mutations and Proline Substitutions in TDP-43 Glycine-Rich Peptides on Its Amyloid Properties and Cellular Toxicity

    PubMed Central

    Sun, Chia-Sui; Wang, Cindy Yu-Hsiang; Chen, Bryan Po-Wen; He, Ruei-Yu; Liu, Gerard Chun-Hao; Wang, Chih-Hsien; Chen, Wenlung; Chern, Yijuang; Huang, Joseph Jen-Tse

    2014-01-01

    TAR DNA-binding protein (TDP-43) was identified as the major ubiquitinated component deposited in the inclusion bodies in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) in 2006. Later on, numerous ALS-related mutations were found in either the glycine or glutamine/asparagine-rich region on the TDP-43 C-terminus, which hinted on the importance of mutations on the disease pathogenesis. However, how the structural conversion was influenced by the mutations and the biological significance of these peptides remains unclear. In this work, various peptides bearing pathogenic or de novo designed mutations were synthesized and displayed their ability to form twisted amyloid fibers, cause liposome leakage, and mediate cellular toxicity as confirmed by transmission electron microscopy (TEM), circular dichroism (CD), Thioflavin T (ThT) assay, Raman spectroscopy, calcein leakage assay, and cell viability assay. We have also shown that replacing glycines with prolines, known to obstruct β-sheet formation, at the different positions in these peptides may influence the amyloidogenesis process and neurotoxicity. In these cases, GGG308PPP mutant was not able to form beta-amyloid, cause liposome leakage, nor jeopardized cell survival, which hinted on the importance of the glycines (308–310) during amyloidogenesis. PMID:25090004

  18. Inhibition of glutaminyl cyclase ameliorates amyloid pathology in an animal model of Alzheimer's disease via the modulation of γ-secretase activity.

    PubMed

    Song, Hyundong; Chang, Yu Jin; Moon, Minho; Park, Sarah Kyua; Tran, Phuong-Thao; Hoang, Van-Hai; Lee, Jeewoo; Mook-Jung, Inhee

    2015-01-01

    Alzheimer's disease is the most prevalent neurodegenerative disorder, characterized by neurofibrillary tangles, senile plaques, and neuron loss. Amyloid beta peptides are generated from amyloid beta precursor protein by consecutive catalysis by β and γ-secretases. Diversely modified forms of A have been N3pE-42 Aβ has received considerable attention as one of the major constituents of the senile plaques of AD brains due to its higher aggregation velocity, stability, and hydrophobicity compared to the full-length A. A previous study suggested that is catalyzed by glutaminyl cyclase (QC) following limited proteolysis of Aβ at the N-terminus. Here, we reveal that decreasing the QC activity via application of a QC inhibitor modulates-γ-secretase activity, resulting in diminished plaque formation as well as reduced N3pE 42 Aβ aggregates in the subiculum of the 5XFAD mouse model of AD. This study suggests a possible novel mechanism by which QC regulates Aβ formation , namely modulation of γ-secretase activity. PMID:25114069

  19. The influence of pathological mutations and proline substitutions in TDP-43 glycine-rich peptides on its amyloid properties and cellular toxicity.

    PubMed

    Sun, Chia-Sui; Wang, Cindy Yu-Hsiang; Chen, Bryan Po-Wen; He, Ruei-Yu; Liu, Gerard Chun-Hao; Wang, Chih-Hsien; Chen, Wenlung; Chern, Yijuang; Huang, Joseph Jen-Tse

    2014-01-01

    TAR DNA-binding protein (TDP-43) was identified as the major ubiquitinated component deposited in the inclusion bodies in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) in 2006. Later on, numerous ALS-related mutations were found in either the glycine or glutamine/asparagine-rich region on the TDP-43 C-terminus, which hinted on the importance of mutations on the disease pathogenesis. However, how the structural conversion was influenced by the mutations and the biological significance of these peptides remains unclear. In this work, various peptides bearing pathogenic or de novo designed mutations were synthesized and displayed their ability to form twisted amyloid fibers, cause liposome leakage, and mediate cellular toxicity as confirmed by transmission electron microscopy (TEM), circular dichroism (CD), Thioflavin T (ThT) assay, Raman spectroscopy, calcein leakage assay, and cell viability assay. We have also shown that replacing glycines with prolines, known to obstruct β-sheet formation, at the different positions in these peptides may influence the amyloidogenesis process and neurotoxicity. In these cases, GGG308PPP mutant was not able to form beta-amyloid, cause liposome leakage, nor jeopardized cell survival, which hinted on the importance of the glycines (308-310) during amyloidogenesis. PMID:25090004

  20. Superresolution Imaging of Amyloid Fibrils with Binding-Activated Probes

    PubMed Central

    2013-01-01

    Protein misfolding into amyloid-like aggregates underlies many neurodegenerative diseases. Thus, insights into the structure and function of these amyloids will provide valuable information on the pathological mechanisms involved and aid in the design of improved drugs for treating amyloid-based disorders. However, determining the structure of endogenous amyloids at high resolution has been difficult. Here we employ binding-activated localization microscopy (BALM) to acquire superresolution images of α-synuclein amyloid fibrils with unprecedented optical resolution. We propose that BALM imaging can be extended to study the structure of other amyloids, for differential diagnosis of amyloid-related diseases and for discovery of drugs that perturb amyloid structure for therapy. PMID:23594172

  1. Pretreatment with memantine prevents Alzheimer-like alterations induced by intrahippocampal okadaic acid administration in rats.

    PubMed

    Zimmer, Eduardo Rigon; Kalinine, Eduardo; Haas, Clarissa Branco; Torrez, Vitor Rocco; Souza, Diogo Onofre; Muller, Alexandre Pastoris; Portela, Luis Valmor

    2012-12-01

    Cerebral okadaic acid (OA) administration induces Alzheimer's disease (AD)-like phenotype in rats. Alterations in glutamate levels associated with hyperactivation of cyclin dependent kinase 5 (Cdk5) signaling pathway downstream Tau phosphorylation may participate in the genesis of this pathological phenotype. Here, we examined the efficacy of memantine (MN) pretreatment on reducing OA-induced AD-like phenotypes in rats. Wistar rats were given daily intraperitoneal injections of MN for 3 days and then given an intrahippocampal infusion of OA. Animals were divided into four groups: control (CO), MN, OA and MN/OA. Spontaneous locomotion and spatial memory performance were assessed by open field and Morris water maze respectively. Additionally, we measured glutamate levels in the cerebrospinal fluid (CSF) and the immunocontent of Cdk5, p35, p25 and phosphorylated Tau (pTauSer199/202) in the hippocampus. Spontaneous locomotion did not differ between groups. The OA group showed a significant decrease in spatial memory performance compared to all groups. The OA infusion also increased CSF glutamate levels and the immunocontents of Cdk5, p25 and pTauSer199/202 in the hippocampus. Conversely, pretreatment with MN prevented OA-induced spatial memory deficits and the increment of CSF glutamate level; which paralleled with normal immunocontents of Cdk5, p25 and pTau- Ser199/202 proteins. There were positive correlations between spatial memory performance and the neurochemical parameters. In summary, pretreatment with MN prevents spatial memory deficits induced by intrahippocampal OA administration in rats. The prevention of increase CSF glutamate levels, along with the reduced hippocampal phosphorylation of TauSer199/202 by Cdk5/p25 signaling pathway, are the mechanisms proposed to participate in the prophylactic effects of MN in this AD-like model. PMID:22515493

  2. Oral TNFα Modulation Alters Neutrophil Infiltration, Improves Cognition and Diminishes Tau and Amyloid Pathology in the 3xTgAD Mouse Model

    PubMed Central

    Gabbita, S. Prasad; Johnson, Ming F.; Kobritz, Naomi; Eslami, Pirooz; Poteshkina, Aleksandra; Varadarajan, Sridhar; Turman, John; Zemlan, Frank; Harris-White, Marni E.

    2015-01-01

    Cytokines such as TNFα can polarize microglia/macrophages into different neuroinflammatory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocytosis and has been described in Alzheimer’s Disease (AD). Neuroinflammation can be perpetuated by a cycle of increasing cytokine production and maintenance of a polarized activation state that contributes to AD progression. In this study, 3xTgAD mice, age 6 months, were treated orally with 3 doses of the TNFα modulating compound isoindolin-1,3 dithione (IDT) for 10 months. We demonstrate that IDT is a TNFα modulating compound both in vitro and in vivo. Following long-term IDT administration, mice were assessed for learning & memory and tissue and serum were collected for analysis. Results demonstrate that IDT is safe for long-term treatment and significantly improves learning and memory in the 3xTgAD mouse model. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation. Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFα expression in this population. IDT is a safe and effective TNFα and innate immune system modulator. Thus small molecule, orally bioavailable modulators are promising therapeutics for Alzheimer’s disease. PMID:26436670

  3. Translocation of PKC by Yessotoxin in an in Vitro Model of Alzheimer’s Disease with Improvement of Tau and β-Amyloid Pathology

    PubMed Central

    2013-01-01

    Yessotoxin is a marine phycotoxin that induces motor alterations in mice after intraperitoneal injection. In primary cortical neurons, yessotoxin treatment induced a caspase-independent cell death with an IC50 of 4.27 nM. This neurotoxicity was enhanced by 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid and partially blocked by amiloride. Unlike previous studies, yessotoxin did not increase cyclic adenosine monophosphate levels or produce any change in phosphodiesterase 4 steady state expression in triple transgenic neurons. Since phosphodiesterases (PDEs) are engaged in learning and memory, we studied the in vitro effect of the toxin against Alzheimer’s disease hallmarks and observed that pretreatment of cortical 3xTg-AD neurons with a low nanomolar concentration of yessotoxin showed a decrease expression of hyperphosphorylated tau isoforms and intracellular accumulation of amyloid-beta. These effects were accompanied with an increase in the level of the inactive isoform of the glycogen synthase kinase 3 and also by a translocation of protein kinase C from cytosol to membrane, pointing to its activation. In fact, inhibition of protein kinase C with GF109203X blocked the effect of yessotoxin over tau protein. The data presented here shows that 1 nM yessotoxin activates protein kinase C with beneficial effects over the main Alzheimer’s disease hallmarks, tau and Aβ, in a cellular model obtained from 3xTg-AD fetuses. PMID:23527608

  4. 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.

  5. Role of P-glycoprotein in mediating rivastigmine effect on amyloid-β brain load and related pathology in Alzheimer's disease mouse model.

    PubMed

    Mohamed, Loqman A; Keller, Jeffrey N; Kaddoumi, Amal

    2016-04-01

    Recently, we showed that rivastigmine decreased amyloid-β (Aβ) brain load in aged rats by enhancing its clearance across the blood-brain barrier (BBB) via upregulation of P-glycoprotein (P-gp) and low-density lipoprotein receptor-related protein 1 (LRP1). Here, we extend our previous work to clarify P-gp role in mediating rivastigmine effect on Aβ brain levels and neuroprotection in a mouse model of Alzheimer's disease (AD) that expresses different levels of P-gp. APPSWE mice were bred with mdr1a/b knockout mice to produce littermates that were divided into three groups; APP(+)/mdr1(+/+), APP(+)/mdr1(+/-) and APP(+)/mdr1(-/-). Animals received rivastigmine treatment (0.3mg/kg/day) or vehicle for 8weeks using Alzet osmotic mini-pumps. ELISA analysis of brain homogenates for Aβ showed rivastigmine treatment to significantly decrease Aβ brain load in APP(+)/mdr1(+/+) by 25% and in APP(+)/mdr1(+/-) mice by 21% compared to their vehicle treated littermates, but not in APP(+)/mdr1(-/-) mice. In addition, rivastigmine reduced GFAP immunostaining of astrocytes by 50% and IL-1β brain level by 43% in APP(+)/mdr1(+/+) mice, however its effect was less pronounced in P-gp knockout mice. Moreover, rivastigmine demonstrated a P-gp expression dependent neuroprotective effect that was highest in APP(+)/mdr1(+/+)>APP(+)/mdr1(+/-)>APP(+)/mdr1(-/-) as determined by expression of synaptic markers PSD-95 and SNAP-25 using Western blot analysis. Collectively, our results suggest that P-gp plays important role in mediating rivastigmine non-cholinergic beneficial effects, including Aβ brain load reduction, neuroprotective and anti-inflammatory effects in the AD mouse models. PMID:26780497

  6. 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. PMID:24072071

  7. Alterations in CA1 pyramidal neuronal intrinsic excitability mediated by Ih channel currents in a rat model of amyloid beta pathology.

    PubMed

    Eslamizade, M J; Saffarzadeh, F; Mousavi, S M M; Meftahi, G H; Hosseinmardi, N; Mehdizadeh, M; Janahmadi, M

    2015-10-01

    Amyloid beta (Aβ) accumulation plays an important role in the pathogenesis of Alzheimer's disease (AD) by changing the neuronal excitability. However, the cellular mechanisms by which accumulation of Aβ affects intrinsic neuronal properties are not well understood. The effect of bilateral intra-frontal cortex Aβ (1-42) peptide injection on the intrinsic excitability of hippocampal CA1 pyramidal neurons with particular focus on the contribution of hyperpolarization-activated (Ih) channel currents was examined using whole-cell patch-clamp recording. Passive avoidance memory impairment and morphological changes in rats receiving intra-frontal Aβ treatment were observed, which was associated with significant changes both in passive and active intrinsic electrical membrane properties of CA1 pyramidal neurons. Electrophysiological recording showed a significant decrease in neuronal excitability associated with an augmentation in the first spike after-hyperpolarization (AHP) amplitude. In addition, the depolarizing sag voltage was altered in neurons recorded from Aβ-treated group. In voltage-clamp condition, a hyperpolarizing activated inward current sensitive to ZD7288 and capsaicin was significantly increased in neurons from Aβ-treated rats. The Ih current density was increased and the activation curve was shifted toward less negative potential in the Aβ-treated group as compared to control group. The enhancing effect of Aβ treatment on Ih current was confirmed by showing upregulation of the mRNA of HCN1 channel in the CA1 pyramidal layer of hippocampi. These findings suggest the contribution of Ih and possibly TRPV1 channel currents to the changes induced by Aβ treatment in the intrinsic membrane properties, which, in turn, may provide therapeutic targets for treatment of AD. PMID:26254243

  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. PMID:25459121

  9. Proteomic Screening for Amyloid Proteins

    PubMed Central

    Nizhnikov, Anton A.; Alexandrov, Alexander I.; Ryzhova, Tatyana A.; Mitkevich, Olga V.; Dergalev, Alexander A.; Ter-Avanesyan, Michael D.; Galkin, Alexey P.

    2014-01-01

    Despite extensive study, progress in elucidation of biological functions of amyloids and their role in pathology is largely restrained due to the lack of universal and reliable biochemical methods for their discovery. All biochemical methods developed so far allowed only identification of glutamine/asparagine-rich amyloid-forming proteins or proteins comprising amyloids that form large deposits. In this article we present a proteomic approach which may enable identification of a broad range of amyloid-forming proteins independently of specific features of their sequences or levels of expression. This approach is based on the isolation of protein fractions enriched with amyloid aggregates via sedimentation by ultracentrifugation in the presence of strong ionic detergents, such as sarkosyl or SDS. Sedimented proteins are then separated either by 2D difference gel electrophoresis or by SDS-PAGE, if they are insoluble in the buffer used for 2D difference gel electrophoresis, after which they are identified by mass-spectrometry. We validated this approach by detection of known yeast prions and mammalian proteins with established capacity for amyloid formation and also revealed yeast proteins forming detergent-insoluble aggregates in the presence of human huntingtin with expanded polyglutamine domain. Notably, with one exception, all these proteins contained glutamine/asparagine-rich stretches suggesting that their aggregates arose due to polymerization cross-seeding by human huntingtin. Importantly, though the approach was developed in a yeast model, it can easily be applied to any organism thus representing an efficient and universal tool for screening for amyloid proteins. PMID:25549323

  10. Protein folding pathology in domestic animals*

    PubMed Central

    Gruys, Erik

    2004-01-01

    Fibrillar proteins form structural elements of cells and the extracellular matrix. Pathological lesions of fibrillar microanatomical structures, or secondary fibrillar changes in globular proteins are well known. A special group concerns histologically amorphous deposits, amyloid. The major characteristics of amyloid are: apple green birefringence after Congo red staining of histological sections, and non-branching 7–10 nm thick fibrils on electron microscopy revealing a high content of cross beta pleated sheets. About 25 different types of amyloid have been characterised. In animals, AA-amyloid is the most frequent type. Other types of amyloid in animals represent: AIAPP (in cats), AApoAI, AApoAII, localised AL-amyloid, amyloid in odontogenic or mammary tumors and amyloid in the brain. In old dogs Aβ and in sheep APrPsc-amyloid can be encountered. AA-amyloidosis is a systemic disorder with a precursor in blood, acute phase serum amyloid A (SAA). In chronic inflammatory processes AA-amyloid can be deposited. A rapid crystallization of SAA to amyloid fibrils on small beta-sheeted fragments, the ‘amyloid enhancing factor’ (AEF), is known and the AEF has been shown to penetrate the enteric barrier. Amyloid fibrils can aggregate from various precursor proteins in vitro in particular at acidic pH and when proteolytic fragments are formed. Molecular chaperones influence this process. Tissue data point to amyloid fibrillogenesis in lysosomes and near cell surfaces. A comparison can be made of the fibrillogenesis in prion diseases and in enhanced AA-amyloidosis. In the reactive form, acute phase SAA is the supply of the precursor protein, whereas in the prion diseases, cell membrane proteins form a structural source. Aβ-amyloid in brain tissue of aged dogs showing signs of dementia forms a canine counterpart of senile dementia of the Alzheimer type (ccSDAT) in man. Misfolded proteins remain potential food hazards. Developments concerning prevention of

  11. 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. PMID:26929241

  12. Atomic force microscopy and MD simulations reveal pore-like structures of all-D-enantiomer of Alzheimer's β-amyloid peptide: relevance to the ion channel mechanism of AD pathology.

    PubMed

    Connelly, Laura; Jang, Hyunbum; Arce, Fernando Teran; Capone, Ricardo; Kotler, Samuel A; Ramachandran, Srinivasan; Kagan, Bruce L; Nussinov, Ruth; Lal, Ratnesh

    2012-02-01

    Alzheimer's disease (AD) is a protein misfolding disease characterized by a buildup of β-amyloid (Aβ) peptide as senile plaques, uncontrolled neurodegeneration, and memory loss. AD pathology is linked to the destabilization of cellular ionic homeostasis and involves Aβ peptide-plasma membrane interactions. In principle, there are two possible ways through which disturbance of the ionic homeostasis can take place: directly, where the Aβ peptide either inserts into the membrane and creates ion-conductive pores or destabilizes the membrane organization, or, indirectly, where the Aβ peptide interacts with existing cell membrane receptors. To distinguish between these two possible types of Aβ-membrane interactions, we took advantage of the biochemical tenet that ligand-receptor interactions are stereospecific; L-amino acid peptides, but not their D-counterparts, bind to cell membrane receptors. However, with respect to the ion channel-mediated mechanism, like L-amino acids, D-amino acid peptides will also form ion channel-like structures. Using atomic force microscopy (AFM), we imaged the structures of both D- and L-enantiomers of the full length Aβ(1-42) when reconstituted in lipid bilayers. AFM imaging shows that both L- and D-Aβ isomers form similar channel-like structures. Molecular dynamics (MD) simulations support the AFM imaged 3D structures. Previously, we have shown that D-Aβ(1-42) channels conduct ions similarly to their L- counterparts. Taken together, our results support the direct mechanism of Aβ ion channel-mediated destabilization of ionic homeostasis rather than the indirect mechanism through Aβ interaction with membrane receptors. PMID:22217000

  13. Is the Amyloid Hypothesis of Alzheimer's disease therapeutically relevant?

    PubMed Central

    Teich, Andrew F.; Arancio, Ottavio

    2013-01-01

    The conventional view of AD (Alzheimer's disease) is that much of the pathology is driven by an increased load of β-amyloid in the brain of AD patients (the ‘Amyloid Hypothesis’). Yet, many therapeutic strategies based on lowering β-amyloid have so far failed in clinical trials. This failure of β-amyloid-lowering agents has caused many to question the Amyloid Hypothesis itself. However, AD is likely to be a complex disease driven by multiple factors. In addition, it is increasingly clear that β-amyloid processing involves many enzymes and signalling pathways that play a role in a diverse array of cellular processes. Thus the clinical failure of β-amyloid-lowering agents does not mean that the hypothesis itself is incorrect; it may simply mean that manipulating β-amyloid directly is an unrealistic strategy for therapeutic intervention, given the complex role of β-amyloid in neuronal physiology. Another possible problem may be that toxic β-amyloid levels have already caused irreversible damage to downstream cellular pathways by the time dementia sets in. We argue in the present review that a more direct (and possibly simpler) approach to AD therapeutics is to rescue synaptic dysfunction directly, by focusing on the mechanisms by which elevated levels of β-amyloid disrupt synaptic physiology. PMID:22891628

  14. The multiple mechanisms of amyloid deposition

    PubMed Central

    Mena, Maria A; Rodríguez-Navarro, José A

    2009-01-01

    Amyloid deposition is one of the central neuropathological abnormalities in Alzheimer disease (AD) but it also takes places in many neurodegenerative diseases such as prionic disorders, Huntington's disease (HD) and others. Up to very recently amyloid formation was considered a very slow process of deposition of an abnormal protein due to genetic abnormalities or post-translational modification of the deposited protein. Recent data suggest that the process of amyloidogenesis may be much more rapid in many cases and due to multiple mechanisms. We have found a mouse model of progressive neurodegeneration that resemble motor, behavioral and pathological hallmarks of parkinsonism and tauopathies, but surprisingly, also present amyloid deposits in brain and peripheral organs. Here we review some of these recent works which may provide new insight into the process of formation of amyloid and, perhaps, new ideas for its treatment. PMID:19270506

  15. Matrix Metalloproteinase-9 Reduces Islet Amyloid Formation by Degrading Islet Amyloid Polypeptide*

    PubMed Central

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

    2013-01-01

    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. PMID:23229548

  16. S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in mice.

    PubMed

    Fuso, Andrea; Nicolia, Vincenzina; Ricceri, Laura; Cavallaro, Rosaria A; Isopi, Elisa; Mangia, Franco; Fiorenza, Maria Teresa; Scarpa, Sigfrido

    2012-07-01

    Methylation reactions linked to homocysteine in the one-carbon metabolism are increasingly elicited in Alzheimer's disease, although the association of hyperhomocysteinemia and of low B vitamin levels with the disease is still debated. We previously demonstrated that hyperhomocysteinemia and DNA hypomethylation induced by B vitamin deficiency are associated with PSEN1 and BACE1 overexpression and amyloid production. The present study is aimed at assessing S-adenosylmethionine effects in mice kept under a condition of B vitamin deficiency. To this end, TgCRND8 mice and wild-type littermates were assigned to control or B vitamin deficient diet, with or without S-adenosylmethionine supplementation. We found that S-adenosylmethionine reduced amyloid production, increased spatial memory in TgCRND8 mice and inhibited the upregulation of B vitamin deficiency-induced PSEN1 and BACE1 expression and Tau phosphorylation in TgCRND8 and wild-type mice. Furthermore, S-adenosylmethionine treatment reduced plaque spreading independently on B vitamin deficiency. These results strengthen our previous observations on the possible role of one-carbon metabolism in Alzheimer's disease, highlighting hyperhomocysteinemia-related mechanisms in dementia onset/progression and encourage further studies aimed at evaluating the use of S-adenosylmethionine as a potential candidate drug for the treatment of the disease. PMID:22221883

  17. Direct observation of amyloid nucleation under nanomechanical stretching

    NASA Astrophysics Data System (ADS)

    Varongchayakul, Nitinun

    Self-assembly of amyloid nanofiber is associated with functional and pathological processes such as in neurodegenerative diseases. Despite intensive studies, stochastic nature of the process has made it difficult to elucidate molecular mechanisms for the key amyloid nucleation. Here, we investigated the amyloid nucleation of silk-elastin-like peptide (SELP) using time-lapse lateral force microscopy (LFM). By repeated scanning a single line on a SELP-coated mica surface, we observed sudden stepwise height increases, corresponds to nucleation of an amyloid fiber. The lateral force profiles followed either a worm-like chain model or an exponential function, suggesting that the atomic force microscopy (AFM) tip stretches a single or multiple SELP molecules along the scanning direction, serves as the template for further self-assembly perpendicular to the scan direction. Such mechanically induced nucleation of amyloid fibrils allows positional and directional control of amyloid assembly in vitro , which we demonstrate by generating single nanofibers at predetermined nucleation sites.

  18. Insulin receptor mutation results in insulin resistance and hyperinsulinemia but does not exacerbate Alzheimer's-like phenotypes in mice.

    PubMed

    Murakami, Kazuma; Yokoyama, Shin-ichi; Murata, Nakaba; Ozawa, Yusuke; Irie, Kazuhiro; Shirasawa, Takuji; Shimizu, Takahiko

    2011-05-27

    Obesity is a risk factor for Alzheimer's disease (AD), which is characterized by amyloid β depositions and cognitive dysfunction. Although insulin resistance is one of the phenotypes of obesity, its deleterious effects on AD progression remain to be fully elucidated. We previously reported that the suppression of insulin signaling in a mouse with a heterozygous mutation (P1195L) in the gene for the insulin receptor showed insulin resistance and hyperinsulinemia but did not develop diabetes mellitus [15]. Here, we generated a novel AD mouse model carrying the same insulin receptor mutation and showed that the combination of insulin resistance and hyperinsulinemia did not accelerate plaque formation or memory abnormalities in these mice. Interestingly, the insulin receptor mutation reduced oxidative damage in the brains of the AD mice. These findings suggest that insulin resistance is not always involved in the pathogenesis of AD. PMID:21549686

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

    PubMed

    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

  20. Magnetic fluid - a novel approach to treat amyloid-related diseases

    NASA Astrophysics Data System (ADS)

    Antosova, Andrea; Siposova, Katarina; Koneracka, Martina; Zavisova, Vlasta; Daxnerova, Zuzana; Vavra, Ivo; Fedunova, Diana; Bagelova, Jaroslava; Kopcansky, Peter; Gazova, Zuzana

    Protein amyloid aggregates are associated with several human pathologies termed amyloid-related diseases. We have investigated effect of two magnetic fluids (MFs) - electrostatically stabilized Fe3O4 magnetic nanoparticles (MF1) and sterically stabilized Fe3O4 magnetic nanoparticles by sodium oleate with adsorbed BSA (MF2) on amyloid aggregation of two proteins - human insulin and hen egg lysozyme. We have found that both MF1 and MF2 are able to interact with amyloid fibrils in vitro resulting into decreasing of amyloid aggregates. The extent of fibril disruption depends on MF concentration with extensive reduction of amyloid aggregates, 90% for lysozyme and 70% for insulin (ratio protein: MF=1:5). The obtained results suggest that magnetite component of MF play significant role in the process of amyloid fibril depolymerisation. Our findings indicate that MF1 and MF2 have potential to be used for treatment of amyloid diseases.

  1. Prions, amyloids, and RNA: Pieces of a puzzle.

    PubMed

    Nizhnikov, Anton A; Antonets, Kirill S; Bondarev, Stanislav A; Inge-Vechtomov, Sergey G; Derkatch, Irina L

    2016-05-01

    Amyloids are protein aggregates consisting of fibrils rich in β-sheets. Growth of amyloid fibrils occurs by the addition of protein molecules to the tip of an aggregate with a concurrent change of a conformation. Thus, amyloids are self-propagating protein conformations. In certain cases these conformations are transmissible / infectious; they are known as prions. Initially, amyloids were discovered as pathological extracellular deposits occurring in different tissues and organs. To date, amyloids and prions have been associated with over 30 incurable diseases in humans and animals. However, a number of recent studies demonstrate that amyloids are also functionally involved in a variety of biological processes, from biofilm formation by bacteria, to long-term memory in animals. Interestingly, amyloid-forming proteins are highly overrepresented among cellular factors engaged in all stages of mRNA life cycle: from transcription and translation, to storage and degradation. Here we review rapidly accumulating data on functional and pathogenic amyloids associated with mRNA processing, and discuss possible significance of prion and amyloid networks in the modulation of key cellular functions. PMID:27248002

  2. Self-assembled amyloid fibrils with controllable conformational heterogeneity.

    PubMed

    Lee, Gyudo; Lee, Wonseok; Lee, Hyungbeen; Lee, Chang Young; Eom, Kilho; Kwon, Taeyun

    2015-01-01

    Amyloid fibrils are a hallmark of neurodegenerative diseases and exhibit a conformational diversity that governs their pathological functions. Despite recent findings concerning the pathological role of their conformational diversity, the way in which the heterogeneous conformations of amyloid fibrils can be formed has remained elusive. Here, we show that microwave-assisted chemistry affects the self-assembly process of amyloid fibril formation, which results in their conformational heterogeneity. In particular, microwave-assisted chemistry allows for delicate control of the thermodynamics of the self-assembly process, which enabled us to tune the molecular structure of β-lactoglobulin amyloid fibrils. The heterogeneous conformations of amyloid fibrils, which can be tuned with microwave-assisted chemistry, are attributed to the microwave-driven thermal energy affecting the electrostatic interaction during the self-assembly process. Our study demonstrates how microwave-assisted chemistry can be used to gain insight into the origin of conformational heterogeneity of amyloid fibrils as well as the design principles showing how the molecular structures of amyloid fibrils can be controlled. PMID:26592772

  3. Self-assembled amyloid fibrils with controllable conformational heterogeneity

    NASA Astrophysics Data System (ADS)

    Lee, Gyudo; Lee, Wonseok; Lee, Hyungbeen; Lee, Chang Young; Eom, Kilho; Kwon, Taeyun

    2015-11-01

    Amyloid fibrils are a hallmark of neurodegenerative diseases and exhibit a conformational diversity that governs their pathological functions. Despite recent findings concerning the pathological role of their conformational diversity, the way in which the heterogeneous conformations of amyloid fibrils can be formed has remained elusive. Here, we show that microwave-assisted chemistry affects the self-assembly process of amyloid fibril formation, which results in their conformational heterogeneity. In particular, microwave-assisted chemistry allows for delicate control of the thermodynamics of the self-assembly process, which enabled us to tune the molecular structure of β-lactoglobulin amyloid fibrils. The heterogeneous conformations of amyloid fibrils, which can be tuned with microwave-assisted chemistry, are attributed to the microwave-driven thermal energy affecting the electrostatic interaction during the self-assembly process. Our study demonstrates how microwave-assisted chemistry can be used to gain insight into the origin of conformational heterogeneity of amyloid fibrils as well as the design principles showing how the molecular structures of amyloid fibrils can be controlled.

  4. Self-assembled amyloid fibrils with controllable conformational heterogeneity

    PubMed Central

    Lee, Gyudo; Lee, Wonseok; Lee, Hyungbeen; Lee, Chang Young; Eom, Kilho; Kwon, Taeyun

    2015-01-01

    Amyloid fibrils are a hallmark of neurodegenerative diseases and exhibit a conformational diversity that governs their pathological functions. Despite recent findings concerning the pathological role of their conformational diversity, the way in which the heterogeneous conformations of amyloid fibrils can be formed has remained elusive. Here, we show that microwave-assisted chemistry affects the self-assembly process of amyloid fibril formation, which results in their conformational heterogeneity. In particular, microwave-assisted chemistry allows for delicate control of the thermodynamics of the self-assembly process, which enabled us to tune the molecular structure of β-lactoglobulin amyloid fibrils. The heterogeneous conformations of amyloid fibrils, which can be tuned with microwave-assisted chemistry, are attributed to the microwave-driven thermal energy affecting the electrostatic interaction during the self-assembly process. Our study demonstrates how microwave-assisted chemistry can be used to gain insight into the origin of conformational heterogeneity of amyloid fibrils as well as the design principles showing how the molecular structures of amyloid fibrils can be controlled. PMID:26592772

  5. Polymerizing the fibre between bacteria and host cells: the biogenesis of functional amyloid fibres

    PubMed Central

    Epstein, Elisabeth Ashman; Chapman, Matthew R.

    2009-01-01

    Summary Amyloid fibres are proteinaceous aggregates associated with several human diseases, including Alzheimer’s, Huntington’s and Creutzfeldt Jakob’s. Disease-associated amyloid formation is the result of proteins that misfold and aggregate into β sheet-rich fibre polymers. Cellular toxicity is readily associated with amyloidogenesis, although the molecular mechanism of toxicity remains unknown. Recently, a new class of ‘functional’ amyloid fibres was discovered that demonstrates that amyloids can be utilized as a productive part of cellular biology. These functional amyloids will provide unique insights into how amyloid formation can be controlled and made less cytotoxic. Bacteria produce some of the best-characterized functional amyloids, including a surface amyloid fibre called curli. Assembled by enteric bacteria, curli fibres mediate attachment to surfaces and host tissues. Some bacterial amyloids, like harpins and microcinE492, have exploited amyloid toxicity in a directed and functional manner. Here, we review and discuss the functional amyloids assembled by bacteria. Special emphasis will be paid to the biology of functional amyloid synthesis and the connections between bacterial physiology and pathology. PMID:18373633

  6. PMEL Amyloid Fibril Formation: The Bright Steps of Pigmentation.

    PubMed

    Bissig, Christin; Rochin, Leila; van Niel, Guillaume

    2016-01-01

    In pigment cells, melanin synthesis takes place in specialized organelles, called melanosomes. The biogenesis and maturation of melanosomes is initiated by an unpigmented step that takes place prior to the initiation of melanin synthesis and leads to the formation of luminal fibrils deriving from the pigment cell-specific pre-melanosomal protein (PMEL). In the lumen of melanosomes, PMEL fibrils optimize sequestration and condensation of the pigment melanin. Interestingly, PMEL fibrils have been described to adopt a typical amyloid-like structure. In contrast to pathological amyloids often associated with neurodegenerative diseases, PMEL fibrils represent an emergent category of physiological amyloids due to their beneficial cellular functions. The formation of PMEL fibrils within melanosomes is tightly regulated by diverse mechanisms, such as PMEL traffic, cleavage and sorting. These mechanisms revealed increasing analogies between the formation of physiological PMEL fibrils and pathological amyloid fibrils. In this review we summarize the known mechanisms of PMEL fibrillation and discuss how the recent understanding of physiological PMEL amyloid formation may help to shed light on processes involved in pathological amyloid formation. PMID:27589732

  7. Cerebral amyloid angiopathy severity is linked to dilation of juxtacortical perivascular spaces.

    PubMed

    van Veluw, Susanne J; Biessels, Geert Jan; Bouvy, Willem H; Spliet, Wim Gm; Zwanenburg, Jaco Jm; Luijten, Peter R; Macklin, Eric A; Rozemuller, Annemieke Jm; Gurol, M Edip; Greenberg, Steven M; Viswanathan, Anand; Martinez-Ramirez, Sergi

    2016-03-01

    Perivascular spaces are an emerging marker of small vessel disease. Perivascular spaces in the centrum semiovale have been associated with cerebral amyloid angiopathy. However, a direct topographical relationship between dilated perivascular spaces and cerebral amyloid angiopathy severity has not been established. We examined this association using post-mortem magnetic resonance imaging in five cases with evidence of cerebral amyloid angiopathy pathology. Juxtacortical perivascular spaces dilation was evaluated on T2 images and related to cerebral amyloid angiopathy severity in overlying cortical areas on 34 tissue sections stained for Amyloid β. Degree of perivascular spaces dilation was significantly associated with cerebral amyloid angiopathy severity (odds ratio = 3.3, 95% confidence interval 1.3-7.9, p = 0.011). Thus, dilated juxtacortical perivascular spaces are a promising neuroimaging marker of cerebral amyloid angiopathy severity. PMID:26661250

  8. An in vivo model for the neurodegenerative effects of beta amyloid and protection by substance P.

    PubMed Central

    Kowall, N W; Beal, M F; Busciglio, J; Duffy, L K; Yankner, B A

    1991-01-01

    Deposition of the beta-amyloid protein in senile plaques is a pathologic hallmark of Alzheimer disease (AD). Focal deposition of beta amyloid in the adult rat cerebral cortex caused profound neurodegenerative changes, including neuronal loss and degenerating neurons and neurites. Chronic induction of the Alz-50 antigen appeared in neurons around focal cortical deposits of beta amyloid. Immunoblot analysis showed that beta amyloid induced Alz-50-immunoreactive proteins in rat cerebral cortex that were very similar to the proteins induced in human cerebral cortex from patients with AD. The neuropeptide substance P prevented beta-amyloid-induced neuronal loss and expression of Alz-50 proteins when coadministered into the cerebral cortex. Systemic administration of substance P also provided protection against the effects of intracerebral beta amyloid. Thus, beta amyloid is a potent neurotoxin in the adult brain in vivo, and its effects can be blocked by substance P. Images PMID:1714596

  9. Regional brain hypometabolism is unrelated to regional amyloid plaque burden.

    PubMed

    Altmann, Andre; Ng, Bernard; Landau, Susan M; Jagust, William J; Greicius, Michael D

    2015-12-01

    In its original form, the amyloid cascade hypothesis of Alzheimer's disease holds that fibrillar deposits of amyloid are an early, driving force in pathological events leading ultimately to neuronal death. Early clinicopathological investigations highlighted a number of inconsistencies leading to an updated hypothesis in which amyloid plaques give way to amyloid oligomers as the driving force in pathogenesis. Rather than focusing on the inconsistencies, amyloid imaging studies have tended to highlight the overlap between regions that show early amyloid plaque signal on positron emission tomography and that also happen to be affected early in Alzheimer's disease. Recent imaging studies investigating the regional dependency between metabolism and amyloid plaque deposition have arrived at conflicting results, with some showing regional associations and other not. We extracted multimodal neuroimaging data from the Alzheimer's disease neuroimaging database for 227 healthy controls and 434 subjects with mild cognitive impairment. We analysed regional patterns of amyloid deposition, regional glucose metabolism and regional atrophy using florbetapir ((18)F) positron emission tomography, (18)F-fluordeoxyglucose positron emission tomography and T1-weighted magnetic resonance imaging, respectively. Specifically, we derived grey matter density and standardized uptake value ratios for both positron emission tomography tracers in 404 functionally defined regions of interest. We examined the relation between regional glucose metabolism and amyloid plaques using linear models. For each region of interest, correcting for regional grey matter density, age, education and disease status, we tested the association of regional glucose metabolism with (i) cortex-wide florbetapir uptake; (ii) regional (i.e. in the same region of interest) florbetapir uptake; and (iii) regional florbetapir uptake while correcting in addition for cortex-wide florbetapir uptake. P-values for each setting

  10. Plasticity of amyloid fibrils†

    PubMed Central

    Wetzel, Ronald; Shivaprasad, Shankaramma; Williams, Angela D.

    2008-01-01

    In experiments designed to characterize the basis of amyloid fibril stability through mutational analysis of the Aβ(1-40) molecule, fibrils exhibit consistent, significant structural malleability. In these results, and in other properties, amyloid fibrils appear to more resemble plastic materials generated from synthetic polymers than they do globular proteins. Thus, like synthetic polymers and plastics, amyloid fibrils exhibit both polymorphism, the ability of one polypeptide to form aggregates of different morphologies, and isomorphism, the ability of different polypeptides to grow into a fibrillar amyloid morphology. This view links amyloid with the prehistorical and 20th Century use of proteins as starting materials to make films, fibers, and plastics, and with the classic protein fiber stretching experiments of the Astbury group. Viewing amyloid from the point of view of the polymer chemist may shed new light on issues such as the role of protofibrils in the mechanism of amyloid formation, the biological potency of fibrils, and the prospects for discovering inhibitors of amyloid fibril formation. PMID:17198370

  11. Activated ADF/cofilin sequesters phosphorylated microtubule-associated-protein during the assembly of Alzheimer-like neuritic cytoskeletal striations

    PubMed Central

    Whiteman, Ineka T.; Gervasio, Othon L.; Cullen, Karen M.; Guillemin, Gilles J.; Jeong, Erica V.; Witting, Paul K.; Antao, Shane T.; Minamide, Laurie S.; Bamburg, James R.; Goldsbury, Claire

    2009-01-01

    In Alzheimer disease (AD), rod-like cofilin aggregates (cofilin-actin rods) and thread-like inclusions containing phosphorylated microtubule-associated protein (pMAP) tau form in the brain (neuropil threads) and the extent of their presence correlates with cognitive decline and disease progression. The assembly mechanism of these respective pathological lesions and the relationship between them is poorly understood, yet vital to understanding the causes of sporadic AD. We demonstrate that during mitochondrial inhibition, activated actin-depolymerizing factor (ADF)/cofilin assemble into rods along processes of cultured primary neurons that recruit pMAP/tau and mimic neuropil threads. Fluorescence Resonance Energy Transfer (FRET) analysis revealed co-localization of cofilin-GFP and pMAP in rods, suggesting their close proximity within a cytoskeletal inclusion complex. The relationship between pMAP and cofilin-actin rods was further investigated using actin-modifying drugs and siRNA knockdown of ADF/cofilin in primary neurons. The results suggest that activation of ADF/cofilin and generation of cofilin-actin rods is required for the subsequent recruitment of pMAP into the inclusions. Additionally we were able to induce the formation of pMAP-positive ADF/cofilin rods by exposing cells to exogenous Aβ peptides. These results reveal a common pathway for pMAP and cofilin accumulation in neuronal processes. The requirement of activated ADF/cofilin for the sequestration of pMAP suggests that neuropil thread structures in the AD brain may be initiated by elevated cofilin activation and F-actin bundling that can be caused by oxidative stress, mitochondrial dysfunction or Aβ peptides, all suspected initiators of synaptic loss and neurodegeneration in AD. PMID:19828813

  12. Current and future treatment of amyloid diseases.

    PubMed

    Ankarcrona, M; Winblad, B; Monteiro, C; Fearns, C; Powers, E T; Johansson, J; Westermark, G T; Presto, J; Ericzon, B-G; Kelly, J W

    2016-08-01

    There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross-β-sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid β-peptide (Aβ) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit Aβ formation and aggregation or to enhance Aβ clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aβ aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment. PMID:27165517

  13. Search for Amyloid-Binding Proteins by Affinity Chromatography

    PubMed Central

    Calero, Miguel; Rostagno, Agueda; Ghiso, Jorge

    2013-01-01

    Amyloid binging proteins’ is a generic term used to designate proteins that interact with different forms of amyloidogenic peptides or proteins and that, as a result, may modulate their physiological and pathological functions by altering solubility, transport, clearance, degradation, and fibril formation. We describe a simple affinity chromatography protocol to isolate and characterize amyloid-binding proteins based on the use of sequential elution steps that may provide further information on the type of binding interaction. As an example, we depict the application of this protocol to the study of Alzheimer’s amyloid β (Aβ) peptide-binding proteins derived from human plasma. Biochemical analysis of the proteins eluted under different conditions identified serum amyloid P component (SAP) and apolipoprotein J (clusterin) as the main plasma Aβ-binding proteins while various apolipoproteins (apoA-IV, apoE, and apoA-I), as well as albumin (HSA) and fibulin were identified as minor contributors. PMID:22528093

  14. Immunoglobulin light chains, glycosaminoglycans and amyloid.

    SciTech Connect

    Stevens, F. J.; Kisilevsky, R.; Biosciences Division; Queen's Univ.

    2000-03-01

    Immunoglobulin light chains are the precursor proteins for fibrils that are formed during primary amyloidosis and in amyloidosis associated with multiple myeloma. As found for the approximately 20 currently described forms of focal, localized, or systemic amyloidoses, light chain-related fibrils extracted from physiological deposits are invariably associated with glycosaminoglycans, predominantly heparan sulfate. Other amyloid-related proteins are either structurally normal, such as g2-microglobulin and islet amyloid polypeptide, fragments of normal proteins such as serum amyloid A protein or the precursor protein of the g peptide involved in Alzheimer's disease, or are inherited forms of single amino acid variants of a normal protein such as found in the familial forms of amyloid associated with transthyretin. In contrast, the primary structures of light chains involved in fibril formation exhibit extensive mutational diversity rendering some proteins highly amyloidogenic and others non-pathological. The interactions between light chains and glycosaminoglycans are also affected by amino acid variation and may influence the clinical course of disease by enhancing fibril stability and contributing to resistance to protease degradation. Relatively little is currently known about the mechanisms by which glycosaminoglycans interact with light chains and light-chain fibrils. It is probable that future studies of this uniquely diverse family of proteins will continue o shed light on the processes of amyloidosis, and contribute as well to a greater understanding of the normal physiological roles of glycosaminoglycans.

  15. Cerebral amyloid angiopathy

    MedlinePlus

    ... Fenichel GM, Jankovic J, Mazziotta JC, eds. Bradley's Neurology in Clinical Practice . 6th ed. Philadelphia, PA: Elsevier ... al. Course of cerebral amyloid angiopathy-related inflammation. Neurology. 2007;68:1411-1416. PMID: 17452586 www.ncbi. ...

  16. Clinicians' ability to diagnose dementia with Lewy bodies is not affected by β-amyloid load

    PubMed Central

    Attems, Johannes; Thomas, Alan; Brown, Andrew; Jaros, Evelyn; Lett, Debbie J.; Ossola, Maria; Perry, Robert H.; Ramsay, Lynne; Walker, Lauren; McKeith, Ian G.

    2015-01-01

    Objective: To investigate whether an increasing load of β-amyloid and/or neuritic plaques influences the phenotype, and thus the clinical diagnostic accuracy, of dementia with Lewy bodies (DLB). Methods: A series of 64 subjects with autopsy-proven DLB was studied. Last diagnosis before death was used to determine the clinical diagnostic accuracy of DLB in relation to Lewy body distribution and extent of Alzheimer β-amyloid and/or neuritic pathology. DLB pathologic diagnosis was made according to consensus criteria, using α-synuclein immunostaining for Lewy body identification. β-Amyloid immunostaining was used for quantifying β-amyloid deposits. The Consortium to Establish a Registry for Alzheimer's Disease criteria and Braak stage were applied for semiquantitative grading of neuritic plaque and neurofibrillary tangle pathology. Results: Overall clinical diagnostic accuracy for the entire DLB cohort was high (80%), reflecting the high prevalence of core clinical features (fluctuations [81%], parkinsonism [77%], visual hallucinations [70%]). Lower frequencies of core clinical features of DLB, resulting in lower accuracy of its clinical diagnosis, were associated with decreasing Lewy body distribution (p < 0.0001) and with increasing neuritic plaque pathology (p = 0.035), but not with the number of β-amyloid plaque deposits. Conclusions: The likelihood of occurrence of the DLB clinical syndrome is positively related to the extent of Lewy body pathology and negatively related to the severity of Alzheimer neuritic pathology, while β-amyloid load has no effect. PMID:25552579

  17. 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

  18. β-sheet interfering molecules acting against β-amyloid aggregation and fibrillogenesis.

    PubMed

    Francioso, Antonio; Punzi, Pasqualina; Boffi, Alberto; Lori, Clorinda; Martire, Sara; Giordano, Cesare; D'Erme, Maria; Mosca, Luciana

    2015-04-15

    β-Sheet aggregates and amyloid fibrils rising from conformational changes of proteins are observed in several pathological human conditions. These structures are organized in β-strands that can reciprocally interact by hydrophobic and π-π interactions. The amyloid aggregates can give rise to pathological conditions through complex biochemical mechanisms whose physico-chemical nature has been understood in recent times. This review focuses on the various classes of natural and synthetic small molecules able to act against β-amyloid fibrillogenesis and toxicity that may represent new pharmacological tools in Alzheimer's diseases. Some peptides, named 'β-sheet breaker peptides', are able to hamper amyloid aggregation and fibrillogenesis by interfering with and destabilizing the non native β-sheet structures. Other natural compounds, like polyphenols or indolic molecules such as melatonin, can interfere with β-amyloid peptide pathogenicity by inhibiting aggregation and counteracting oxidative stress that is a key hallmark in Alzheimer's disease. PMID:25769517

  19. Clinical use of amyloid-positron emission tomography neuroimaging: Practical and bioethical considerations.

    PubMed

    Witte, Michael M; Foster, Norman L; Fleisher, Adam S; Williams, Monique M; Quaid, Kimberly; Wasserman, Michael; Hunt, Gail; Roberts, J Scott; Rabinovici, Gil D; Levenson, James L; Hake, Ann Marie; Hunter, Craig A; Van Campen, Luann E; Pontecorvo, Michael J; Hochstetler, Helen M; Tabas, Linda B; Trzepacz, Paula T

    2015-09-01

    Until recently, estimation of β-amyloid plaque density as a key element for identifying Alzheimer's disease (AD) pathology as the cause of cognitive impairment was only possible at autopsy. Now with amyloid-positron emission tomography (amyloid-PET) neuroimaging, this AD hallmark can be detected antemortem. Practitioners and patients need to better understand potential diagnostic benefits and limitations of amyloid-PET and the complex practical, ethical, and social implications surrounding this new technology. To complement the practical considerations, Eli Lilly and Company sponsored a Bioethics Advisory Board to discuss ethical issues that might arise from clinical use of amyloid-PET neuroimaging with patients being evaluated for causes of cognitive decline. To best address the multifaceted issues associated with amyloid-PET neuroimaging, we recommend this technology be used only by experienced imaging and treating physicians in appropriately selected patients and only in the context of a comprehensive clinical evaluation with adequate explanations before and after the scan. PMID:27239516

  20. Islet amyloid inhibitors improve glucose homeostasis in a transgenic mouse model of type 2 diabetes.

    PubMed

    Wijesekara, N; Ahrens, R; Wu, L; Ha, K; Liu, Y; Wheeler, M B; Fraser, P E

    2015-10-01

    Increasing evidence points to the cytotoxicity of islet amyloid polypeptide (IAPP) aggregates as a major contributor to the loss of β-cell mass in type 2 diabetes. Prevention of IAPP formation represents a potential treatment to increase β-cell survival and function. The IAPP inhibitory peptide, D-ANFLVH, has been previously shown to prevent islet amyloid accumulation in cultured human islets. To assess its activity in vivo, D-ANFLVH was administered by intraperitoneal injection into a human IAPP transgenic mouse model, which replicates type 2 diabetes islet amyloid pathology. The peptide was a potent inhibitor of islet amyloid deposition, resulting in reduced islet cell apoptosis and preservation of β-cell area leading to improved glucose tolerance. These findings provide support for a key role of islet amyloid in β-cell survival and validate the application of anti-amyloid compounds as therapeutic strategies to maintain normal insulin secretion in patients with type 2 diabetes. PMID:26095311

  1. Correlation of amyloid PET ligand florbetapir F 18 (18F-AV-45) binding with β-amyloid aggregation and neuritic plaque deposition in postmortem brain tissue

    PubMed Central

    Choi, Seok Rye; Schneider, Julie A.; Bennett, David A.; Beach, Thomas G.; Bedell, Barry J.; Zehntner, Simone P.; Krautkramer, Michael; Kung, Hank F.; Skovronsky, Daniel M.; Hefti, Franz; Clark, Christopher M.

    2011-01-01

    Background Florbetapir F 18 (18F-AV-45) is a positron emission tomography (PET) imaging ligand for the detection of amyloid aggregation associated with Alzheimer’s disease. Earlier data showed that florbetapir F 18 binds with high affinity to β-amyloid plaques in human brain homogenates (Kd = 3.7 nM) and has favorable imaging pharmacokinetic properties, including rapid brain penetration and washout. The present study used human autopsy brain tissue to evaluate the correlation between in vitro florbetapir F 18 binding and β-amyloid density measured by established neuropathological methods. Methods The localization and density of florbetapir F 18 binding in frozen and formalin-fixed paraffin-embedded sections of postmortem brain tissue from 40 subjects with a varying degree of neurodegenerative pathology was assessed by standard florbetapir F 18 autoradiography and correlated with the localization and density of β-amyloid identified by silver staining, thioflavin S staining, and immunohistochemistry. Results There were strong quantitative correlations between florbetapir F 18 tissue binding and both β-amyloid plaques identified by light microscopy (sliver staining and thioflavin S fluorescence) and by immunohistochemical measurements of β-amyloid using three antibodies recognizing different epitopes of the β-amyloid peptide (Aβ). Florbetapir F 18 did not bind to neurofibrillary tangles. Conclusion Florbetapir F 18 selectively binds β-amyloid in human brain tissue. The binding intensity was quantitatively correlated with the density of β-amyloid plaques identified by standard neuropathological techniques and correlated with the density of Aβ measured by immunohistochemistry. Since β-amyloid plaques are a defining neuropathological feature for Alzheimer’s disease, these results support the use of florbetapir F 18 as an amyloid PET ligand to identify the presence of AD pathology in patients with signs and symptoms of progressive late-life cognitive

  2. Decline of microtubule-associated protein tau after experimental stroke in differently aged wild-type and 3xTg mice with Alzheimer-like alterations.

    PubMed

    Michalski, Dominik; Preißler, Hartmut; Hofmann, Sarah; Kacza, Johannes; Härtig, Wolfgang

    2016-08-25

    Stroke therapies are still limited to a minority of patients. Considering time-dependent aspects of stroke, the penumbra concept describes the transition from functional to permanent tissue damage. Thereby, the role of cytoskeletal elements, as for instance microtubules with associated tau remains poorly understood and is therefore not yet considered for therapeutic approaches. This study explored the expression of microtubule-associated protein tau related to neuronal damage in stroke-affected brain regions. Wild-type and triple-transgenic mice of 3, 7 and 12months of age and with an Alzheimer-like background underwent experimental stroke. After 24h, brain sections were used for immunofluorescence labeling of tau and Neuronal Nuclei (NeuN). Potential functional consequences of cellular alterations were explored by statistical relationships to the general health condition, i.e. neurobehavioral deficits and loss of body weight. Immunoreactivity for whole tau decreased significantly in ischemic areas, while the decline at the border zone was more drastic for tau-immunoreactivity compared with the diminished NeuN labeling. Quantitative analyses confirmed pronounced sensitivity for tau-immunoreactivity in the ischemic border zone. Decline of tau- as well as NeuN-immunoreactivity correlated with body weight loss during the 24-h observation period. In conclusion, microtubule-associated protein tau was robustly identified as a highly sensitive cytoskeletal constitute under ischemic conditions, suggesting a pivotal role during the transition process toward long-lasting tissue damage. Consequently, cytoskeletal elements appear as promising targets for novel therapeutic approaches with the objective to impede ischemia-induced irreversible cellular degradation. PMID:27189884

  3. Alzheimer's silent partner: cerebral amyloid angiopathy.

    PubMed

    Cupino, Tanya L; Zabel, Matthew K

    2014-06-01

    Alzheimer's disease (AD) is the most common form of dementia, which completely lacks a viable, long-term therapeutic intervention. This is partly due to an incomplete understanding of AD etiology and the possible confounding factors associated with its genotypic and phenotypic heterogeneity. Cerebral amyloid angiopathy (CAA) is a common, yet frequently overlooked, pathology associated with AD. CAA manifests with deposition amyloid-beta (Aβ) within the smooth muscle layer of cerebral arteries and arterioles. The role of Aβ in AD and CAA pathophysiology has long been controversial. Although it has demonstrated toxicity at super-physiological levels in vitro, Aβ load does not necessarily correlate with cognitive demise in humans. In this review, we describe the contributions of CAA to AD pathophysiology and important pathomechanisms that may lead to vascular fragility and hemorrhages. Additionally, we discuss the effect of Aβ on smooth muscle cell phenotype and viability, especially in terms of the complement cascade. PMID:24323728

  4. A Human Monoclonal IgG That Binds Aβ Assemblies and Diverse Amyloids Exhibits Anti-Amyloid Activities In Vitro and In Vivo

    PubMed Central

    O'Nuallain, Brian; Puligedda, Rama Devudu; Ondrejcak, Tomas; Adekar, Sharad P.; Chen, Cindy; Cruz, Pedro E.; Rosario, Awilda M.; Macy, Sallie; Mably, Alexandra J.; Walsh, Dominic M.; Vidal, Ruben; Solomon, Alan; Brown, Daniel; Rowan, Michael J.; Golde, Todd E.

    2015-01-01

    Alzheimer's disease (AD) and familial Danish dementia (FDD) are degenerative neurological diseases characterized by amyloid pathology. Normal human sera contain IgG antibodies that specifically bind diverse preamyloid and amyloid proteins and have shown therapeutic potential in vitro and in vivo. We cloned one of these antibodies, 3H3, from memory B cells of a healthy individual using a hybridoma method. 3H3 is an affinity-matured IgG that binds a pan-amyloid epitope, recognizing both Aβ and λ Ig light chain (LC) amyloids, which are associated with AD and primary amyloidosis, respectively. The pan-amyloid-binding properties of 3H3 were demonstrated using ELISA, immunohistochemical studies, and competition binding assays. Functional studies showed that 3H3 inhibits both Aβ and LC amyloid formation in vitro and abrogates disruption of hippocampal synaptic plasticity by AD-patient-derived soluble Aβ in vivo. A 3H3 single-chain variable fragment (scFv) retained the binding specificity of the 3H3 IgG and, when expressed in the brains of transgenic mice using an adeno-associated virus (AAV) vector, decreased parenchymal Aβ amyloid deposition in TgCRND8 mice and ADan (Danish Amyloid) cerebral amyloid angiopathy in the mouse model of FDD. These data indicate that naturally occurring human IgGs can recognize a conformational, amyloid-specific epitope and have potent anti-amyloid activities, providing a rationale to test their potential as antibody therapeutics for diverse neurological and other amyloid diseases. PMID:25904780

  5. 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

  6. β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation.

    PubMed

    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

    2015-07-01

    Independent evidence associates β-amyloid pathology with both non-rapid eye movement (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 in medial prefrontal cortex (mPFC) correlates significantly 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 was not direct, but instead statistically depended on the intermediary factor of diminished NREM SWA. By linking β-amyloid pathology with impaired NREM SWA, these data implicate sleep disruption as a mechanistic pathway through which β-amyloid pathology may contribute to hippocampus-dependent cognitive decline in the elderly. PMID:26030850

  7. Will PET amyloid imaging lead to overdiagnosis of Alzheimer dementia?

    PubMed

    Dubroff, Jacob G; Nasrallah, Ilya M

    2015-08-01

    Alzheimer disease (AD), a progressive neurodegenerative disease that causes dementia, affects millions of elderly Americans and represents a growing problem with the aging of the population. There has been an increasing effort for improved and earlier diagnosis for AD. Several newly developed radiolabeled compounds targeting β-amyloid plaques, one of the major pathologic biomarkers of AD, have recently become available for clinical use. These radiopharmaceuticals allow for in vivo noninvasive visualization of abnormal β-amyloid deposits in the brain using positron emission tomography (PET). Amyloid PET imaging has demonstrated high sensitivity for pathologic cerebral amyloid deposition in multiple studies. Principal drawbacks to this new diagnostic test are declining specificity in older age groups and uncertain clinical role given lack of disease-modifying therapy for AD. Although there is strong evidence for the utility of amyloid PET in certain situations, detailed in a set of guidelines for appropriate use from the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging, the question of overdiagnosis, the diagnosis of a disease that would result in neither symptoms nor deaths, using this new medical tool needs to be carefully considered in light of efforts to secure reimbursement for the new technology that is already widely available for use as a clinical tool. PMID:26100192

  8. Inhibition of amyloid-β aggregation in Alzheimer's disease.

    PubMed

    Wang, Qiuming; Yu, Xiang; Li, Lingyan; Zheng, Jie

    2014-01-01

    The assembly of naturally occurring amyloid peptides into cytotoxic oligomeric and fibrillar aggregates is believed to be a major pathologic event in over 25 human diseases. Blocking of or interfering with the aggregation of amyloid peptides such as amyloid-β (Aβ) using small organic molecules, peptides and peptidomimetics, and nanoparticles that selectively bind or inhibit Aβ aggregates is a promising strategy for the development of novel pharmaceutical approaches and agents to treat Alzheimer's disease (AD). In a broad sense, considering many common features in structure, kinetics, and biological activity of amyloid peptides, potent inhibitors and associated inhibition strategies that are developed for targeting Aβ aggregation could also be generally applied to other amyloid-forming peptides in "protein-aggregation diseases". Due to the complex nature of Aβ self-assembly process, increasing knowledge in high-resolution structures of Aβ oligomers, atomic-level Aβ-inhibitor binding information, and cost-effective high-throughput screening method will improve our fundamental understanding of amyloid formation and inhibition mechanisms, as well as practical design of pharmaceutical strategies and drugs to treat AD. This review summarizes major findings, recent advances, and future challenges for the development of new Aβ-aggregation inhibitors, mainly focusing on three major classes of Aβ inhibitors with associated inhibition mechanisms and practical. examples. PMID:23713775

  9. Amyloid fibrils composed of hexameric peptides attenuate neuroinflammation.

    PubMed

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

    2013-04-01

    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. PMID:23552370

  10. Amyloid Fibrils Composed of Hexameric Peptides Attenuate Neuroinflammation

    PubMed Central

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

    2013-01-01

    Amyloid forming proteins Tau, alpha B 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, alpha B 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, 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 (SAP), and insulin B chain were shown to be anti-inflammatory, capable of reducing serological levels of IL-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. PMID:23552370

  11. 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. PMID:26496385

  12. Design and synthesis of skeletal analogues of gambierol: attenuation of amyloid-β and tau pathology with voltage-gated potassium channel and N-methyl-D-aspartate receptor implications.

    PubMed

    Alonso, Eva; Fuwa, Haruhiko; Vale, Carmen; Suga, Yuto; Goto, Tomomi; Konno, Yu; Sasaki, Makoto; LaFerla, Frank M; Vieytes, Mercedes R; Giménez-Llort, Lydia; Botana, Luis M

    2012-05-01

    Gambierol is a potent neurotoxin that belongs to the family of marine polycyclic ether natural products and primarily targets voltage-gated potassium channels (K(v) channels) in excitable membranes. Previous work in the chemistry of marine polycyclic ethers has suggested the critical importance of the full length of polycyclic ether skeleton for potent biological activity. Although we have previously investigated structure-activity relationships (SARs) of the peripheral functionalities of gambierol, it remained unclear whether the whole polycyclic ether skeleton is needed for its cellular activity. In this work, we designed and synthesized two truncated skeletal analogues of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound, both of which surprisingly showed similar potency to gambierol on voltage-gated potassium channels (K(v)) inhibition. Moreover, we examined the effect of these compounds in an in vitro model of Alzheimer's disease (AD) obtained from triple transgenic (3xTg-AD) mice, which expresses amyloid beta (Aβ) accumulation and tau hyperphosphorylation. In vitro preincubation of the cells with the compounds resulted in significant inhibition of K(+) currents, a reduction in the extra- and intracellular levels of Aβ, and a decrease in the levels of hyperphosphorylated tau. In addition, pretreatment with these compounds reduced the steady-state level of the N-methyl-D-aspartate (NMDA) receptor subunit 2A without affecting the 2B subunit. The involvement of glutamate receptors was further suggested by the blockage of the effect of gambierol on tau hyperphosphorylation by glutamate receptor antagonists. The present study constitutes the first discovery of skeletally simplified, designed polycyclic ethers with potent cellular activity and demonstrates the utility of gambierol and its synthetic analogues as chemical probes for understanding the function of K(v) channels as well as the molecular mechanism of Aβ metabolism modulated by

  13. Common molecular mechanism of amyloid pore formation by Alzheimer’s β-amyloid peptide and α-synuclein

    PubMed Central

    Di Scala, Coralie; Yahi, Nouara; Boutemeur, Sonia; Flores, Alessandra; Rodriguez, Léa; Chahinian, Henri; Fantini, Jacques

    2016-01-01

    Calcium-permeable pores formed by small oligomers of amyloid proteins are the primary pathologic species in Alzheimer’s and Parkinson’s diseases. However, the molecular mechanisms underlying the assembly of these toxic oligomers in the plasma membrane of brain cells remain unclear. Here we have analyzed and compared the pore-forming capability of a large panel of amyloid proteins including wild-type, variant and truncated forms, as well as synthetic peptides derived from specific domains of Aβ1-42 and α-synuclein. We show that amyloid pore formation involves two membrane lipids, ganglioside and cholesterol, that physically interact with amyloid proteins through specific structural motifs. Mutation or deletion of these motifs abolished pore formation. Moreover, α-synuclein (Parkinson) and Aβ peptide (Alzheimer) did no longer form Ca2+-permeable pores in presence of drugs that target either cholesterol or ganglioside or both membrane lipids. These results indicate that gangliosides and cholesterol cooperate to favor the formation of amyloid pores through a common molecular mechanism that can be jammed at two different steps, suggesting the possibility of a universal therapeutic approach for neurodegenerative diseases. Finally we present the first successful evaluation of such a new therapeutic approach (coined “membrane therapy”) targeting amyloid pores formed by Aβ1-42 and α-synuclein. PMID:27352802

  14. Common molecular mechanism of amyloid pore formation by Alzheimer's β-amyloid peptide and α-synuclein.

    PubMed

    Di Scala, Coralie; Yahi, Nouara; Boutemeur, Sonia; Flores, Alessandra; Rodriguez, Léa; Chahinian, Henri; Fantini, Jacques

    2016-01-01

    Calcium-permeable pores formed by small oligomers of amyloid proteins are the primary pathologic species in Alzheimer's and Parkinson's diseases. However, the molecular mechanisms underlying the assembly of these toxic oligomers in the plasma membrane of brain cells remain unclear. Here we have analyzed and compared the pore-forming capability of a large panel of amyloid proteins including wild-type, variant and truncated forms, as well as synthetic peptides derived from specific domains of Aβ1-42 and α-synuclein. We show that amyloid pore formation involves two membrane lipids, ganglioside and cholesterol, that physically interact with amyloid proteins through specific structural motifs. Mutation or deletion of these motifs abolished pore formation. Moreover, α-synuclein (Parkinson) and Aβ peptide (Alzheimer) did no longer form Ca(2+)-permeable pores in presence of drugs that target either cholesterol or ganglioside or both membrane lipids. These results indicate that gangliosides and cholesterol cooperate to favor the formation of amyloid pores through a common molecular mechanism that can be jammed at two different steps, suggesting the possibility of a universal therapeutic approach for neurodegenerative diseases. Finally we present the first successful evaluation of such a new therapeutic approach (coined "membrane therapy") targeting amyloid pores formed by Aβ1-42 and α-synuclein. PMID:27352802

  15. Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology.

    PubMed

    Perez-Nievas, Beatriz G; Stein, Thor D; Tai, Hwan-Ching; Dols-Icardo, Oriol; Scotton, Thomas C; Barroeta-Espar, Isabel; Fernandez-Carballo, Leticia; de Munain, Estibaliz Lopez; Perez, Jesus; Marquie, Marta; Serrano-Pozo, Alberto; Frosch, Mathew P; Lowe, Val; Parisi, Joseph E; Petersen, Ronald C; Ikonomovic, Milos D; López, Oscar L; Klunk, William; Hyman, Bradley T; Gómez-Isla, Teresa

    2013-08-01

    Clinico-pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer's pathology in their brains without experiencing dementia. Few details are known about the neuropathological phenotype of these unique cases that might prove relevant to understanding human resilience to Alzheimer's pathology. We conducted detailed quantitative histopathological and biochemical assessments on brains from non-demented individuals before death whose brains were free of substantial Alzheimer's pathology, non-demented individuals before death but whose post-mortem examination demonstrated significant amounts of Alzheimer's changes ('mismatches'), and demented Alzheimer's cases. Quantification of amyloid-β plaque burden, stereologically-based counts of neurofibrillary tangles, neurons and reactive glia, and morphological analyses of axons were performed in the multimodal association cortex lining the superior temporal sulcus. Levels of synaptic integrity markers, and soluble monomeric and multimeric amyloid-β and tau species were measured. Our results indicate that some individuals can accumulate equivalent loads of amyloid-β plaques and tangles to those found in demented Alzheimer's cases without experiencing dementia. Analyses revealed four main phenotypic differences among these two groups: (i) mismatches had striking preservation of neuron numbers, synaptic markers and axonal geometry compared to demented cases; (ii) demented cases had significantly higher burdens of fibrillar thioflavin-S-positive plaques and of oligomeric amyloid-β deposits reactive to conformer-specific antibody NAB61 than mismatches; (iii) strong and selective accumulation of hyperphosphorylated soluble tau multimers into the synaptic compartment was noted in demented cases compared with controls but not in mismatches; and (iv) the robust glial activation accompanying amyloid-β and tau pathologies in

  16. Computational Pathology

    PubMed Central

    Louis, David N.; Feldman, Michael; Carter, Alexis B.; Dighe, Anand S.; Pfeifer, John D.; Bry, Lynn; Almeida, Jonas S.; Saltz, Joel; Braun, Jonathan; Tomaszewski, John E.; Gilbertson, John R.; Sinard, John H.; Gerber, Georg K.; Galli, Stephen J.; Golden, Jeffrey A.; Becich, Michael J.

    2016-01-01

    Context We define the scope and needs within the new discipline of computational pathology, a discipline critical to the future of both the practice of pathology and, more broadly, medical practice in general. Objective To define the scope and needs of computational pathology. Data Sources A meeting was convened in Boston, Massachusetts, in July 2014 prior to the annual Association of Pathology Chairs meeting, and it was attended by a variety of pathologists, including individuals highly invested in pathology informatics as well as chairs of pathology departments. Conclusions The meeting made recommendations to promote computational pathology, including clearly defining the field and articulating its value propositions; asserting that the value propositions for health care systems must include means to incorporate robust computational approaches to implement data-driven methods that aid in guiding individual and population health care; leveraging computational pathology as a center for data interpretation in modern health care systems; stating that realizing the value proposition will require working with institutional administrations, other departments, and pathology colleagues; declaring that a robust pipeline should be fostered that trains and develops future computational pathologists, for those with both pathology and non-pathology backgrounds; and deciding that computational pathology should serve as a hub for data-related research in health care systems. The dissemination of these recommendations to pathology and bioinformatics departments should help facilitate the development of computational pathology. PMID:26098131

  17. Generating local amyloidosis in mice by the subcutaneous injection of human insulin amyloid fibrils.

    PubMed

    Chinisaz, Maryam; Ebrahim-Habibi, Azadeh; Yaghmaei, Parichehreh; Parivar, Kazem; Dehpour, Ahmad-Reza

    2014-08-01

    Localized deposits of amyloid structures are observed in various pathological conditions. One example of when local amyloidosis occurs is following repeated insulin injections in diabetic patients. The present study aimed to simulate the same condition in mice. To obtain the amyloid structures, regular insulin was incubated at 57°C for 24 h. The subsequently formed amyloid fibrils were analyzed using the Congo red absorbance test, as well as transmission electron microscopy images, and then injected into mice once per day for 21 consecutive days. Firm waxy masses were developed following this period, which were excised, prepared as thin sections and stained with hematoxylin and eosin, Congo red and Sudan black. Histological examination revealed that these masses contained adipose cells and connective tissue, in which amyloid deposition was visible. Thus, localized amyloidosis was obtained by the subcutaneous injection of insulin fibrils. The present results may be of further use in the development of models of amyloid tumors. PMID:25009591

  18. Generating local amyloidosis in mice by the subcutaneous injection of human insulin amyloid fibrils

    PubMed Central

    CHINISAZ, MARYAM; EBRAHIM-HABIBI, AZADEH; YAGHMAEI, PARICHEHREH; PARIVAR, KAZEM; DEHPOUR, AHMAD-REZA

    2014-01-01

    Localized deposits of amyloid structures are observed in various pathological conditions. One example of when local amyloidosis occurs is following repeated insulin injections in diabetic patients. The present study aimed to simulate the same condition in mice. To obtain the amyloid structures, regular insulin was incubated at 57°C for 24 h. The subsequently formed amyloid fibrils were analyzed using the Congo red absorbance test, as well as transmission electron microscopy images, and then injected into mice once per day for 21 consecutive days. Firm waxy masses were developed following this period, which were excised, prepared as thin sections and stained with hematoxylin and eosin, Congo red and Sudan black. Histological examination revealed that these masses contained adipose cells and connective tissue, in which amyloid deposition was visible. Thus, localized amyloidosis was obtained by the subcutaneous injection of insulin fibrils. The present results may be of further use in the development of models of amyloid tumors. PMID:25009591

  19. New insight into the molecular control of bacterial functional amyloids

    PubMed Central

    Taylor, Jonathan D.; Matthews, Steve J.

    2015-01-01

    Amyloid protein structure has been discovered in a variety of functional or pathogenic contexts. What distinguishes the former from the latter is that functional amyloid systems possess dedicated molecular control systems that determine the timing, location, and structure of the fibers. Failure to guide this process can result in cytotoxicity, as observed in several pathologies like Alzheimer's and Parkinson's Disease. Many gram-negative bacteria produce an extracellular amyloid fiber known as curli via a multi-component secretion system. During this process, aggregation-prone, semi-folded curli subunits have to cross the periplasm and outer-membrane and self-assemble into surface-attached fibers. Two recent breakthroughs have provided molecular details regarding periplasmic chaperoning and subunit secretion. This review offers a combined perspective on these first mechanistic insights into the curli system. PMID:25905048

  20. Simultaneous Measurement of Amyloid Fibril Formation by Dynamic Light Scattering and Fluorescence Reveals Complex Aggregation Kinetics

    PubMed Central

    Streets, Aaron M.; Sourigues, Yannick; Kopito, Ron R.; Melki, Ronald; Quake, Stephen R.

    2013-01-01

    An apparatus that combines dynamic light scattering and Thioflavin T fluorescence detection is used to simultaneously probe fibril formation in polyglutamine peptides, the aggregating subunit associated with Huntington's disease, in vitro. Huntington's disease is a neurodegenerative disorder in a class of human pathologies that includes Alzheimer's and Parkinson's disease. These pathologies are all related by the propensity of their associated protein or polypeptide to form insoluble, β-sheet rich, amyloid fibrils. Despite the wide range of amino acid sequence in the aggregation prone polypeptides associated with these diseases, the resulting amyloids display strikingly similar physical structure, an observation which suggests a physical basis for amyloid fibril formation. Thioflavin T fluorescence reports β-sheet fibril content while dynamic light scattering measures particle size distributions. The combined techniques allow elucidation of complex aggregation kinetics and are used to reveal multiple stages of amyloid fibril formation. PMID:23349924

  1. Senile plaque neurites in Alzheimer disease accumulate amyloid precursor protein.

    PubMed Central

    Cras, P; Kawai, M; Lowery, D; Gonzalez-DeWhitt, P; Greenberg, B; Perry, G

    1991-01-01

    Senile plaques are polymorphous beta-amyloid protein deposits found in the brain in Alzheimer disease and normal aging. This beta-amyloid protein is derived from a larger precursor molecule of which neurons are the principal producers in brain. We found that amyloid precursor protein (APP)-immunoreactive neurites were involved in senile plaques and that only a subset of these neurites showed markers for the abnormal filaments characteristic of neurofibrillary pathology. In the neocortex of nondemented individuals with senile plaques but spared of neurofibrillary pathology, dystrophic neurites in senile plaques showed only APP accumulation. In contrast, in the brains of Alzheimer patients, virtually all APP-immunoreactive neurites also showed immunoreactivity with ubiquitin, tau, and phosphorylated neurofilaments. The presence of tau and neurofilament epitopes in dystrophic neurites in senile plaques was correlated with the extent of neurofibrillary pathology in the surrounding brain tissue. Accumulation of APP and the formation of neurofibrillary pathology in senile plaque neurites are therefore distinct phenomena. Our findings suggest that APP accumulation in senile plaque neurites occurs prior to tau accumulation and is therefore more closely related to appearance of neuritic dystrophy. Images PMID:1652752

  2. Lipid rafts participate in aberrant degradative autophagic-lysosomal pathway of amyloid-beta peptide in Alzheimer's disease

    PubMed Central

    Zhou, Xin; Yang, Chun; Liu, Yufeng; Li, Peng; Yang, Huiying; Dai, Jingxing; Qu, Rongmei; Yuan, Lin

    2014-01-01

    Amyloid-beta peptide is the main component of amyloid plaques, which are found in Alzheimer's disease. The generation and deposition of amyloid-beta is one of the crucial factors for the onset and progression of Alzheimer's disease. Lipid rafts are glycolipid-rich liquid domains of the plasma membrane, where certain types of protein tend to aggregate and intercalate. Lipid rafts are involved in the generation of amyloid-beta oligomers and the formation of amyloid-beta peptides. In this paper, we review the mechanism by which lipid rafts disturb the aberrant degradative autophagic-lysosomal pathway of amyloid-beta, which plays an important role in the pathological process of Alzheimer's disease. Moreover, we describe this mechanism from the view of the Two-system Theory of fasciology and thus, suggest that lipid rafts may be a new target of Alzheimer's disease treatment. PMID:25206748

  3. Musculoskeletal Pathology.

    PubMed

    Peat, Frances J; Kawcak, Christopher E

    2015-08-01

    The current understanding of pathology as it relates to common diseases of the equine musculoskeletal system is reviewed. Conditions are organized under the fundamental categories of developmental, exercise-induced, infectious, and miscellaneous pathology. The overview of developmental pathology incorporates the new classification system of juvenile osteochondral conditions. Discussion of exercise-induced pathology emphasizes increased understanding of the contribution of cumulative microdamage caused by repetitive cyclic loading. Miscellaneous musculoskeletal pathology focuses on laminitis, which current knowledge indicates should be regarded as a clinical syndrome with a variety of possible distinct mechanisms of structural failure that are outlined in this overview. PMID:26037607

  4. Nucleation of amyloid fibrils

    NASA Astrophysics Data System (ADS)

    Kashchiev, Dimo; Auer, Stefan

    2010-06-01

    We consider nucleation of amyloid fibrils in the case when the process occurs by the mechanism of direct polymerization of practically fully extended protein segments, i.e., β-strands, into β-sheets. Applying the classical nucleation theory, we derive a general expression for the work to form a nanosized amyloid fibril (protofilament) constituted of successively layered β-sheets. Analysis of this expression reveals that with increasing its size, the fibril transforms from one-dimensional to two-dimensional aggregate in order to preserve the equilibrium shape corresponding to minimal formation work. We determine the size of the fibril nucleus, the fibril nucleation work, and the fibril nucleation rate as explicit functions of the concentration and temperature of the protein solution. The results obtained are applicable to homogeneous nucleation, which occurs when the solution is sufficiently pure and/or strongly supersaturated.

  5. Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation

    SciTech Connect

    Sievers, Stuart A.; Karanicolas, John; Chang, Howard W.; Zhao, Anni; Jiang, Lin; Zirafi, Onofrio; Stevens, Jason T.; Münch, Jan; Baker, David; Eisenberg, David

    2011-09-20

    Many globular and natively disordered proteins can convert into amyloid fibrils. These fibrils are associated with numerous pathologies as well as with normal cellular functions, and frequently form during protein denaturation. Inhibitors of pathological amyloid fibril formation could be useful in the development of therapeutics, provided that the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibrils as templates, we have designed and characterized an all-D-amino-acid inhibitor of the fibril formation of the tau protein associated with Alzheimer's disease, and a non-natural L-amino-acid inhibitor of an amyloid fibril that enhances sexual transmission of human immunodeficiency virus. Our results indicate that peptides from structure-based designs can disrupt the fibril formation of full-length proteins, including those, such as tau protein, that lack fully ordered native structures. Because the inhibiting peptides have been designed on structures of dual-{beta}-sheet 'steric zippers', the successful inhibition of amyloid fibril formation strengthens the hypothesis that amyloid spines contain steric zippers.

  6. Deformation behavior and mechanical properties of amyloid protein nanowires.

    PubMed

    Solar, Max; Buehler, Markus J

    2013-03-01

    Amyloid fibrils are most often associated with their pathological role in diseases like Alzheimer's disease and Parkinson's disease, but they are now increasingly being considered for uses in functional engineering materials. They are among the stiffest protein fibers known but they are also rather brittle, and it is unclear how this combination of properties affects the behavior of amyloid structures at larger length scales, such as in films, wires or plaques. Using a coarse-grained model for amyloid fibrils, we study the mechanical response of amyloid nanowires and examine fundamental mechanical properties, including mechanisms of deformation and failure under tensile loading. We also explore the effect of varying the breaking strain and adhesion strength of the constituent amyloid fibrils on the properties of the larger structure. We find that deformation in the nanowires is controlled by a combination of fibril sliding and fibril failure and that there exists a transition from brittle to ductile behavior by either increasing the fibril failure strain or decreasing the strength of adhesion between fibrils. Furthermore, our results reveal that the mechanical properties of the nanowires are quite sensitive to changes in the properties of the individual fibrils, and the larger scale structures are found to be more mechanically robust than the constituent fibrils, for all cases considered. More broadly, this work demonstrates the promise of utilizing self-assembled biological building blocks in the development of hierarchical nanomaterials. PMID:23290516

  7. CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology.

    PubMed

    Bradshaw, Elizabeth M; Chibnik, Lori B; Keenan, Brendan T; Ottoboni, Linda; Raj, Towfique; Tang, Anna; Rosenkrantz, Laura L; Imboywa, Selina; Lee, Michelle; Von Korff, Alina; Morris, Martha C; Evans, Denis A; Johnson, Keith; Sperling, Reisa A; Schneider, Julie A; Bennett, David A; De Jager, Philip L

    2013-07-01

    In our functional dissection of the CD33 Alzheimer's disease susceptibility locus, we found that the rs3865444(C) risk allele was associated with greater cell surface expression of CD33 in the monocytes (t50 = 10.06, P(joint) = 1.3 × 10(-13)) of young and older individuals. It was also associated with diminished internalization of amyloid-β 42 peptide, accumulation of neuritic amyloid pathology and fibrillar amyloid on in vivo imaging, and increased numbers of activated human microglia. PMID:23708142

  8. Are amyloid fibrils molecular spandrels?

    PubMed

    Hane, Francis

    2013-11-15

    Amyloid-β, the protein implicated in Alzheimer's disease, along with a number of other proteins, has been shown to form amyloid fibrils. Fibril forming proteins share no common primary structure and have little known function. Furthermore, all proteins have the ability to form amyloid fibrils under certain conditions as the fibrillar structure lies at the global free energy minimum of proteins. This raises the question of the mechanism of the evolution of the amyloid fibril structure. Experimental evidence supports the hypothesis that the fibril structure is a by-product of the forces of protein folding and lies outside the bounds of evolutionary pressures. PMID:24140343

  9. 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. PMID:26555466

  10. 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

  11. Experimentally Derived Structural Constraints for Amyloid Fibrils of Wild-Type Transthyretin

    PubMed Central

    Bateman, David A.; Tycko, Robert; Wickner, Reed B.

    2011-01-01

    Transthyretin (TTR) is a largely β-sheet serum protein responsible for transporting thyroxine and vitamin A. TTR is found in amyloid deposits of patients with senile systemic amyloidosis. TTR mutants lead to familial amyloidotic polyneuropathy and familial amyloid cardiomyopathy, with an earlier age of onset. Studies of amyloid fibrils of familial amyloidotic polyneuropathy mutant TTR suggest a structure similar to the native state with only a simple opening of a β-strand-loop-strand region exposing the two main β-sheets of the protein for fibril elongation. However, we find that the wild-type TTR sequence forms amyloid fibrils that are considerably different from the previously suggested amyloid structure. Using protease digestion with mass spectrometry, we observe the amyloid core to be primarily composed of the C-terminal region, starting around residue 50. Solid-state NMR measurements prove that TTR differs from other pathological amyloids in not having an in-register parallel β-sheet architecture. We also find that the TTR amyloid is incapable of binding thyroxine as monitored by either isothermal calorimetry or 1,8-anilinonaphthalene sulfonate competition. Taken together, our experiments are consistent with a significantly different configuration of the β-sheets compared to the previously suggested structure. PMID:22098747

  12. Experimentally derived structural constraints for amyloid fibrils of wild-type transthyretin.

    PubMed

    Bateman, David A; Tycko, Robert; Wickner, Reed B

    2011-11-16

    Transthyretin (TTR) is a largely β-sheet serum protein responsible for transporting thyroxine and vitamin A. TTR is found in amyloid deposits of patients with senile systemic amyloidosis. TTR mutants lead to familial amyloidotic polyneuropathy and familial amyloid cardiomyopathy, with an earlier age of onset. Studies of amyloid fibrils of familial amyloidotic polyneuropathy mutant TTR suggest a structure similar to the native state with only a simple opening of a β-strand-loop-strand region exposing the two main β-sheets of the protein for fibril elongation. However, we find that the wild-type TTR sequence forms amyloid fibrils that are considerably different from the previously suggested amyloid structure. Using protease digestion with mass spectrometry, we observe the amyloid core to be primarily composed of the C-terminal region, starting around residue 50. Solid-state NMR measurements prove that TTR differs from other pathological amyloids in not having an in-register parallel β-sheet architecture. We also find that the TTR amyloid is incapable of binding thyroxine as monitored by either isothermal calorimetry or 1,8-anilinonaphthalene sulfonate competition. Taken together, our experiments are consistent with a significantly different configuration of the β-sheets compared to the previously suggested structure. PMID:22098747

  13. Apoptosis induced by islet amyloid polypeptide soluble oligomers is neutralized by diabetes-associated specific antibodies

    PubMed Central

    Bram, Yaron; Frydman-Marom, Anat; Yanai, Inbal; Gilead, Sharon; Shaltiel-Karyo, Ronit; Amdursky, Nadav; Gazit, Ehud

    2014-01-01

    Soluble oligomeric assemblies of amyloidal proteins appear to act as major pathological agents in several degenerative disorders. Isolation and characterization of these oligomers is a pivotal step towards determination of their pathological relevance. Here we describe the isolation of Type 2 diabetes-associated islet amyloid polypeptide soluble cytotoxic oligomers; these oligomers induced apoptosis in cultured pancreatic cells, permeated model lipid vesicles and interacted with cell membranes following complete internalization. Moreover, antibodies which specifically recognized these assemblies, but not monomers or amyloid fibrils, were exclusively identified in diabetic patients and were shown to neutralize the apoptotic effect induced by these oligomers. Our findings support the notion that human IAPP peptide can form highly toxic oligomers. The presence of antibodies identified in the serum of diabetic patients confirms the pathological relevance of the oligomers. In addition, the newly identified structural epitopes may also provide new mechanistic insights and a molecular target for future therapy. PMID:24589570

  14. Dynamics of the formation of a hydrogel by a pathogenic amyloid peptide: islet amyloid polypeptide.

    PubMed

    Jean, Létitia; Lee, Chiu Fan; Hodder, Peter; Hawkins, Nick; Vaux, David J

    2016-01-01

    Many chronic degenerative diseases result from aggregation of misfolded polypeptides to form amyloids. Many amyloidogenic polypeptides are surfactants and their assembly can be catalysed by hydrophobic-hydrophilic interfaces (an air-water interface in-vitro or membranes in-vivo). We recently demonstrated the specificity of surface-induced amyloidogenesis but the mechanisms of amyloidogenesis and more specifically of adsorption at hydrophobic-hydrophilic interfaces remain poorly understood. Thus, it is critical to determine how amyloidogenic polypeptides behave at interfaces. Here we used surface tensiometry, rheology and electron microscopy to demonstrate the complex dynamics of gelation by full-length human islet amyloid polypeptide (involved in type II diabetes) both in the bulk solution and at hydrophobic-hydrophilic interfaces (air-water interface and phospholipids). We show that the hydrogel consists of a 3D supramolecular network of fibrils. We also assessed the role of solvation and dissected the evolution over time of the assembly processes. Amyloid gelation could have important pathological consequences for membrane integrity and cellular functions. PMID:27535008

  15. Dynamics of the formation of a hydrogel by a pathogenic amyloid peptide: islet amyloid polypeptide

    PubMed Central

    Jean, Létitia; Lee, Chiu Fan; Hodder, Peter; Hawkins, Nick; Vaux, David J.

    2016-01-01

    Many chronic degenerative diseases result from aggregation of misfolded polypeptides to form amyloids. Many amyloidogenic polypeptides are surfactants and their assembly can be catalysed by hydrophobic-hydrophilic interfaces (an air-water interface in-vitro or membranes in-vivo). We recently demonstrated the specificity of surface-induced amyloidogenesis but the mechanisms of amyloidogenesis and more specifically of adsorption at hydrophobic-hydrophilic interfaces remain poorly understood. Thus, it is critical to determine how amyloidogenic polypeptides behave at interfaces. Here we used surface tensiometry, rheology and electron microscopy to demonstrate the complex dynamics of gelation by full-length human islet amyloid polypeptide (involved in type II diabetes) both in the bulk solution and at hydrophobic-hydrophilic interfaces (air-water interface and phospholipids). We show that the hydrogel consists of a 3D supramolecular network of fibrils. We also assessed the role of solvation and dissected the evolution over time of the assembly processes. Amyloid gelation could have important pathological consequences for membrane integrity and cellular functions. PMID:27535008

  16. Distinct binding of amyloid imaging ligands to unique amyloid-β deposited in the presubiculum of Alzheimer's disease.

    PubMed

    Ji, Bin; Chen, Chun-Jen; Bando, Kazunori; Ashino, Hiroki; Shiraishi, Hideaki; Sano, Hiroaki; Kasahara, Hiroyuki; Minamizawa, Takao; Yamada, Kazutaka; Ono, Maiko; Zhang, Ming-Rong; Seki, Chie; Farde, Lars; Suhara, Tetsuya; Higuchi, Makoto

    2015-12-01

    Non-invasive determination of amyloid-β peptide (Aβ) deposition with radioligands serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). The polymorphic binding site on multimeric Aβ for current radioligands, however, is little understood. In this study, we investigated the binding of several radioligands including (11)C-Pittsburgh Compound B ((11)C-PiB), (3)H-AZD2184, and two recently developed compounds, (125)I-DRM106 and (125)I-DRK092, with unique presubicular Aβ deposits lacking interaction with the commonly used amyloid dyes FSB. (11)C-PiB, (3)H-AZD2184, and (125)I-DRK092 showed overt binding to presubicular Aβ deposits, while (125)I-DRM106 barely bound to these aggregates despite its strong binding in the hippocampal CA1 sector. Unlike neuritic plaques in the CA1, Aβ lesions in the presubiculum were not accompanied by inflammatory gliosis enriched with 18-kDa translocator protein (TSPO). Thus, there are at least two different components in Aβ aggregates providing distinct binding sites for the current amyloid radioligands, and one of these binding components is distinctly present in the presubicular Aβ deposits. Amyloid radioligands lacking affinity for this component, such as (125)I-DRM106, may selectively capture Aβ deposits tightly associated with TSPO neuroinflammation and neurodegeneration as exemplified by CA1 neuritic plaques. Hence, comparative autoradiographic assessments of radioligand binding in CA1 and presubiculum could serve for the development of an amyloid PET imaging agent visualizing neurotoxicity-related Aβ pathologies. Non-invasive determination of amyloid-β peptide (Aβ) serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). We found that there are at least two different amyloid components in hippocampal CA1 and presubiculum providing distinct binding sites for the current amyloid radioligands. Comparative analysis for

  17. Establishing the fluorescent amyloid ligand h-FTAA for studying human tissues with systemic and localized amyloid.

    PubMed

    Sjölander, Daniel; Röcken, Christoph; Westermark, Per; Westermark, Gunilla T; Nilsson, K Peter R; Hammarström, Per

    2016-06-01

    Rapid and accurate detection of amyloid deposits in routine surgical pathology settings are of great importance. The use of fluorescence microscopy in combination with appropriate amyloid specific dyes is very promising in this regard. Here we report that a luminescent conjugated oligothiophene, h-FTAA, rapidly and with high sensitivity and selectivity detects amyloid deposits in verified clinical samples from systemic amyloidosis patients with AA, AL and ATTR types; as well as in tissues laden with localized amyloidosis of AANF, AIAPP and ASem1 type. The probe h-FTAA emitted yellow red fluorescence on binding to amyloid deposits, whereas no apparent staining was observed in surrounding tissue. The only functional structure stained with h-FTAA showing the amyloidotypic fluorescence spectrum was Paneth cell granules in intestine. Screening of 114 amyloid containing tissues derived from 107 verified (Congo red birefringence and/or immunohistochemistry) amyloidosis patients revealed complete correlation between h-FTAA and Congo red fluorescence (107/107, 100% sensitivity). The majority of Congo red negative control cases (27 of 32, 85% specificity) were negative with h-FTAA. Small Congo red negative aggregates in kidney, liver, pancreas and duodenum were found by h-FTAA fluorescence in five control patients aged 72-83 years suffering from diverse diseases. The clinical significance of these false-positive lesions is currently not known. Because h-FTAA fluorescence is one magnitude brighter than Congo red and as the staining is performed four magnitudes lower than the concentration of dye, we believe that these inclusions are beyond detection by Congo red. We conclude that h-FTAA is a fluorescent hypersensitive, rapid and powerful tool for identifying amyloid deposits in tissue sections. Use of h-FTAA can be exploited as a rapid complementary technique for accurate detection of amyloid in routine surgical pathology settings. Our results also implicate the potential of

  18. Amyloid-Associated Depression

    PubMed Central

    Sun, Xiaoyan; Steffens, David C.; Au, Rhoda; Folstein, Marshal; Summergrad, Paul; Yee, Jacqueline; Rosenberg, Irwin; Mwamburi, D. Mkaya; Qiu, Wei Qiao

    2010-01-01

    Context A high ratio of plasma amyloid-β peptide 40 (Aβ40) toAβ42, determined by both high Aβ40 and low Aβ42 levels, increases the risk of Alzheimer disease. In a previous study, we reported that depression is also associated with low plasma Aβ42 levels in the elderly population. Objective To characterize plasma Aβ40:Aβ42 ratio and cognitive function in elderly individuals with and without depression. Design Cross-sectional study. Setting Homecare agencies. Participants A total of 995 homebound elderly individuals of whom 348 were defined as depressed by a Center for Epidemiological Studies Depression score of 16 or greater. Main Outcome Measures Cognitive domains of memory, language, executive, and visuospatial functions according to levels of plasma Aβ40 and Aβ42 peptides. Results Subjects with depression had lower plasma Aβ42 levels (median, 14.1 vs 19.2 pg/mL; P = .006) and a higher plasma Aβ40:Aβ42 ratio (median, 8.9 vs 6.4; P < .001) than did those without depression in the absence of cardiovascular disease and antidepressant use. The interaction between depression and plasma Aβ40:Aβ42 ratio was associated with lower memory score (β = −1.9, SE = 0.7, P = .006) after adjusting for potentially confounders. Relative to those without depression, “amyloid-associated depression,” defined by presence of depression and a high plasma Aβ40:Aβ42 ratio, was associated with greater impairment in memory, visuospatial ability, and executive function; in contrast, nonamyloid depression was not associated with memory impairment but with other cognitive disabilities. Conclusion Amyloid-associated depression may define a subtype of depression representing a prodromal manifestation of Alzheimer disease. PMID:18458206

  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. 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

  1. 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

  2. Nanomaterials: amyloids reflect their brighter side

    PubMed Central

    Mankar, Shruti; Anoop, A.; Sen, Shamik; Maji, Samir K.

    2011-01-01

    Amyloid fibrils belong to the group of ordered nanostructures that are self-assembled from a wide range of polypeptides/proteins. Amyloids are highly rigid structures possessing a high mechanical strength. Although amyloids have been implicated in the pathogenesis of several human diseases, growing evidence indicates that amyloids may also perform native functions in host organisms. Discovery of such amyloids, referred to as functional amyloids, highlight their possible use in designing novel nanostructure materials. This review summarizes recent advances in the application of amyloids for the development of nanomaterials and prospective applications of such materials in nanotechnology and biomedicine. PMID:22110868

  3. Large Proteins Have a Great Tendency to Aggregate but a Low Propensity to Form Amyloid Fibrils

    PubMed Central

    Ramshini, Hassan; Parrini, Claudia; Relini, Annalisa; Zampagni, Mariagioia; Mannini, Benedetta; Pesce, Alessandra; Saboury, Ali Akbar; Nemat-Gorgani, Mohsen; Chiti, Fabrizio

    2011-01-01

    The assembly of soluble proteins into ordered fibrillar aggregates with cross-β structure is an essential event of many human diseases. The polypeptides undergoing aggregation are generally small in size. To explore if the small size is a primary determinant for the formation of amyloids under pathological conditions we have created two databases of proteins, forming amyloid-related and non-amyloid deposits in human diseases, respectively. The size distributions of the two protein populations are well separated, with the systems forming non-amyloid deposits appearing significantly larger. We have then investigated the propensity of the 486-residue hexokinase-B from Saccharomyces cerevisiae (YHKB) to form amyloid-like fibrils in vitro. This size is intermediate between the size distributions of amyloid and non-amyloid forming proteins. Aggregation was induced under conditions known to be most effective for amyloid formation by normally globular proteins: (i) low pH with salts, (ii) pH 5.5 with trifluoroethanol. In both situations YHKB aggregated very rapidly into species with significant β-sheet structure, as detected using circular dichroism and X-ray diffraction, but a weak Thioflavin T and Congo red binding. Moreover, atomic force microscopy indicated a morphology distinct from typical amyloid fibrils. Both types of aggregates were cytotoxic to human neuroblastoma cells, as indicated by the MTT assay. This analysis indicates that large proteins have a high tendency to form toxic aggregates, but low propensity to form regular amyloid in vivo and that such a behavior is intrinsically determined by the size of the protein, as suggested by the in vitro analysis of our sample protein. PMID:21249193

  4. Tau protein is essential for stress-induced brain pathology.

    PubMed

    Lopes, Sofia; Vaz-Silva, João; Pinto, Vitor; Dalla, Christina; Kokras, Nikolaos; Bedenk, Benedikt; Mack, Natalie; Czisch, Michael; Almeida, Osborne F X; Sousa, Nuno; Sotiropoulos, Ioannis

    2016-06-28

    Exposure to chronic stress is frequently accompanied by cognitive and affective disorders in association with neurostructural adaptations. Chronic stress was previously shown to trigger Alzheimer's-like neuropathology, which is characterized by Tau hyperphosphorylation and missorting into dendritic spines followed by memory deficits. Here, we demonstrate that stress-driven hippocampal deficits in wild-type mice are accompanied by synaptic missorting of Tau and enhanced Fyn/GluN2B-driven synaptic signaling. In contrast, mice lacking Tau [Tau knockout (Tau-KO) mice] do not exhibit stress-induced pathological behaviors and atrophy of hippocampal dendrites or deficits of hippocampal connectivity. These findings implicate Tau as an essential mediator of the adverse effects of stress on brain structure and function. PMID:27274066

  5. Neuronal Cx3cr1 Deficiency Protects against Amyloid β-Induced Neurotoxicity

    PubMed Central

    Dworzak, Jenny; Renvoisé, Benoît; Habchi, Johnny; Yates, Emma V.; Combadière, Christophe; Knowles, Tuomas P.; Dobson, Christopher M.; Blackstone, Craig; Paulsen, Ole; Murphy, Philip M.

    2015-01-01

    Cx3cr1, the receptor for the chemokine Cx3cl1 (fractalkine), has been implicated in the progression and severity of Alzheimer’s disease-like pathology in mice, but the underlying mechanisms remain unclear. A complicating factor is that Cx3cr1 has been demonstrated in both neurons and microglia. Here, we have dissected the differences between neuronal and microglial Cx3cr1, specifically by comparing direct amyloid-β-induced toxicity in cultured, mature, microglia-depleted hippocampal neurons from wild-type and Cx3cr1-/- mice. Wild-type neurons expressed both Cx3cl1 and Cx3cr1 and released Cx3cl1 in response to amyloid-β. Knockout of neuronal Cx3cr1 abated amyloid-β-induced lactate dehydrogenase release. Furthermore, amyloid-β differentially induced depression of pre- and postsynaptic components of miniature excitatory postsynaptic currents, in a peptide conformation-dependent manner. Knockout of neuronal Cx3cr1 abated effects of both amyloid-β conformational states, which were differentiable by aggregation kinetics and peptide morphology. We obtained similar results after both acute and chronic treatment of cultured neurons with the Cx3cr1 antagonist F1. Thus, neuronal Cx3cr1 may impact Alzheimer’s disease-like pathology by modulating conformational state-dependent amyloid-β-induced synaptotoxicity. PMID:26038823

  6. The relationship between complement factor C3, APOE ε4, amyloid and tau in Alzheimer's disease.

    PubMed

    Bonham, Luke W; Desikan, Rahul S; Yokoyama, Jennifer S

    2016-01-01

    Inflammation is becoming increasingly recognized as an important contributor to Alzheimer's disease (AD) pathogenesis. As a part of the innate immune system, the complement cascade enhances the body's ability to destroy and remove pathogens and has recently been shown to influence Alzheimer's associated amyloid and tau pathology. However, little is known in humans about the effects of the complement system and genetic modifiers of AD risk like the ε4 allele of apolioprotein E (APOE ε4) on AD pathobiology. We evaluated cerebrospinal fluid (CSF) protein levels from 267 individuals clinically diagnosed as cognitively normal, mild cognitive impairment, and AD. Using linear models, we assessed the relationship between APOE ε4 genotype, CSF Complement 3 (C3), CSF amyloid-β (amyloid) and CSF hyperphosphorylated tau (ptau). We found a significant interaction between APOE ε4 and CSF C3 on both CSF amyloid and CSF ptau. We also found that CSF C3 is only associated with CSF ptau after accounting for CSF amyloid. Our results support a conceptual model of the AD pathogenic cascade where a synergistic relationship between the complement cascade (C3) and APOE ε4 results in elevated Alzheimer's neurodegeneration and in turn, amyloid further regulates the effect of the complement cascade on downstream tau pathology. PMID:27357286

  7. α-Synuclein: Experimental Pathology.

    PubMed

    Hasegawa, Masato; Nonaka, Takashi; Masuda-Suzukake, Masami

    2016-01-01

    α-Synuclein, which is present as a small, soluble, cytosolic protein in healthy subjects, is converted to amyloid-like fibrils in diseases such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Bulk synthesis of purified α-synuclein has made it more convenient to study the nature of the normal protein and the mechanism of its conversion to an abnormal form in vitro and in vivo. Synthetic α-synuclein fibrils and pathological α-synuclein from diseased brains can act as triggers to convert normal α-synuclein to an abnormal form via prion-like mechanisms. In this article, we describe the experimental pathologies of α-synuclein both in vitro and in vivo in human and animal models. Prion-like spreading of abnormal α-synuclein from cell to cell can account for the progression of these α-synucleinopathies. PMID:27481772

  8. Beta-protein deposition: a pathogenetic link between Alzheimer's disease and cerebral amyloid angiopathies.

    PubMed

    Coria, F; Prelli, F; Castaño, E M; Larrondo-Lillo, M; Fernandez-Gonzalez, J; van Duinen, S G; Bots, G T; Luyendijk, W; Shelanski, M L; Frangione, B

    1988-10-25

    Cerebral amyloid angiopathy (CAA) refers to a group of hereditary (hereditary cerebral hemorrhage with amyloidosis, HCHWA and sporadic (SCAA) disorders characterized by amyloid fibril deposition restricted to the leptomeningeal and cortical vasculature leading to recurrent hemorrhagic and/or ischemic accidents. On clinical and biochemical grounds, two forms of HCHWA can be distinguished. The amyloid subunit of the HCHWA of Icelandic origin is related to Cystatin C, while amyloid from patients of Dutch origin (HCHWA-D) is related to the beta-protein (or A4), the main component of vascular and plaque core amyloid in Alzheimer's disease (AD) and Down's syndrome (DS) [corrected]. SCAA is an increasingly recognized cause of stroke in normotensive individual amounting to 5-10% of all cerebrovascular accidents. We now report the isolation and partial amino acid sequence of the amyloid subunit from a case of SCAA and a new case of HCHWA-D. The recognition that a heterogeneous group of diseases are linked by similar pathological and chemical features suggests that diversity of etiological factors may promote a common pathogenetic mechanism leading to amyloid-beta (A beta) deposition, and open new ways of research in AD and CAA as they are related to dementia and stroke. PMID:3058268

  9. Insulin dysfunction and Tau pathology

    PubMed Central

    El Khoury, Noura B.; Gratuze, Maud; Papon, Marie-Amélie; Bretteville, Alexis; Planel, Emmanuel

    2013-01-01

    The neuropathological hallmarks of Alzheimer's disease (AD) include senile plaques of β-amyloid (Aβ) peptides (a cleavage product of the Amyloid Precursor Protein, or APP) and neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF). NFT pathology is important since it correlates with the degree of cognitive impairment in AD. Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99%) is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease. Insulin dysfunction, manifested by diabetes mellitus (DM) might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since Tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment. Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia. PMID:24574966

  10. C1q binding and complement activation by prions and amyloids.

    PubMed

    Sim, Robert B; Kishore, Uday; Villiers, Christian L; Marche, Patrice N; Mitchell, Daniel A

    2007-01-01

    C1q binds to many non-self and altered-self-materials. These include microorganisms, immune complexes, apoptotic and necrotic cells and their breakdown products, and amyloids. C1q binding to amyloid fibrils found as extracellular deposits in tissues, and subsequent complement activation are involved in the pathology of several amyloid diseases, such as Alzheimer's disease. Prion diseases, such as scrapie also involve formation of amyloid by polymerization of the host prion protein (PrP). Complement activation is likely to contribute to neuronal damage in the end stages of prion diseases, but is also thought to participate in the initial infection, dissemination and replication stages. Infectious prion particles are likely to bind C1q and activate the complement system. Bound complement proteins may then influence the uptake and transport of prion particles by dendritic cells (DCs) and their subsequent proliferation at sites such as follicular DCs. PMID:17544820

  11. Charge Dependent Retardation of Amyloid β Aggregation by Hydrophilic Proteins

    PubMed Central

    2014-01-01

    The aggregation of amyloid β peptides (Aβ) into amyloid fibrils is implicated in the pathology of Alzheimer’s disease. In light of the increasing number of proteins reported to retard Aβ fibril formation, we investigated the influence of small hydrophilic model proteins of different charge on Aβ aggregation kinetics and their interaction with Aβ. We followed the amyloid fibril formation of Aβ40 and Aβ42 using thioflavin T fluorescence in the presence of six charge variants of calbindin D9k and single-chain monellin. The formation of fibrils was verified with transmission electron microscopy. We observe retardation of the aggregation process from proteins with net charge +8, +2, −2, and −4, whereas no effect is observed for proteins with net charge of −6 and −8. The single-chain monellin mutant with the highest net charge, scMN+8, has the largest retarding effect on the amyloid fibril formation process, which is noticeably delayed at as low as a 0.01:1 scMN+8 to Aβ40 molar ratio. scMN+8 is also the mutant with the fastest association to Aβ40 as detected by surface plasmon resonance, although all retarding variants of calbindin D9k and single-chain monellin bind to Aβ40. PMID:24475785

  12. Reexamining Alzheimer's disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta.

    PubMed

    Castellani, Rudy J; Lee, Hyoung-gon; Siedlak, Sandra L; Nunomura, Akihiko; Hayashi, Takaaki; Nakamura, Masao; Zhu, Xiongwei; Perry, George; Smith, Mark A

    2009-01-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-beta-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused, focused on amyloid-beta as the major pathogenic mechanism with the ultimate goal of using amyloid-beta lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectacular failure tends to be the most compelling. We have long contended, as has substantial literature, that proteinaceous accumulations are simply downstream and, often, endstage manifestations of disease. Their overall poor correlation with the level of dementia, and their presence in the cognitively intact is evidence that is often ignored as an inconvenient truth. Current research examining amyloid oligomers, therefore, will add copious details to what is, in essence, a reductionist distraction from upstream pleiotrophic processes such as oxidative stress, cell cycle dysfunction, and inflammation. It is now long overdue that the neuroscientists avoid the pitfall of perseverating on "proteinopathies'' and recognize that the continued targeting of end stage lesions in the face of repeated failure, or worse, is a losing proposition. PMID:19584435

  13. Pituicytoma with gelsolin amyloid deposition.

    PubMed

    Ida, Cristiane M; Yan, Xiaoling; Jentoft, Mark E; Kip, N Sertac; Scheithauer, Bernd W; Morris, Jonathan M; Dogan, Ahmet; Parisi, Joseph E; Kovacs, Kalman

    2013-09-01

    Pituicytoma is a rare low-grade (WHO grade I) sellar region glioma. Among sellar tumors, pituitary adenomas, mainly prolactinomas, may show amyloid deposits. Gelsolin is a ubiquitous calcium-dependent protein that regulates actin filament dynamics. Two known gene point mutations result in gelsolin amyloid deposition, a characteristic feature of a rare type of familial amyloid polyneuropathy (FAP), the Finnish-type FAP, or hereditary gelsolin amyloidosis (HGA). HGA is an autosomal-dominant systemic amyloidosis, characterized by slowly progressive neurological deterioration with corneal lattice dystrophy, cranial neuropathy, and cutis laxa. A unique case of pituicytoma with marked gelsolin amyloid deposition in a 67-year-old Chinese woman is described. MRI revealed a 2.6-cm well-circumscribed, uniformly contrast-enhancing solid sellar mass with suprasellar extension. Histologically, the lesion was characterized by solid sheets and fascicles of spindle cells with slightly fibrillary cytoplasm and oval nuclei with pinpoint nucleoli. Surrounding brain parenchyma showed marked reactive piloid gliosis. Remarkably, conspicuous amyloid deposits were identified as pink homogeneous spherules on light microscopy that showed apple-green birefringence on Congo red with polarization. Mass spectrometric-based proteomic analysis identified the amyloid as gelsolin type. Immunohistochemically, diffuse reactivity to S100 protein and TTF1, focal reactivity for GFAP, and no reactivity to EMA, synaptophysin, and chromogranin were observed. HGA-related mutations were not identified in the tumor. No recurrence was noted 14 months after surgery. To the knowledge of the authors, amyloid deposition in pituicytoma or tumor-associated gelsolin amyloidosis has not been previously described. This novel finding expands the spectrum of sellar tumors that may be associated with amyloid deposition. PMID:23817895

  14. Unzipping a Functional Microbial Amyloid

    PubMed Central

    Alsteens, David; Ramsook, Caleen B.; Lipke, Peter N.; Dufrêne, Yves F.

    2012-01-01

    Bacterial and fungal species produce some of the best-characterized functional amyloids, i.e. extracellular fibres that play key roles in mediating adhesion and biofilm formation. Yet, the molecular details underlying their mechanical strength remain poorly understood. Here, we use single-molecule atomic force microscopy to measure the mechanical properties of amyloids formed by Als cell adhesion proteins from the pathogen Candida albicans. We show that stretching Als proteins through their amyloid sequence yields characteristic force signatures corresponding to the mechanical unzipping of β-sheet interactions formed between surfacearrayed Als proteins. The unzipping probability increases with contact time, reflecting the time necessary for optimal inter β-strand associations. These results demonstrate that amyloid interactions provide cohesive strength to a major adhesion protein from a microbial pathogen, thereby strengthening cell adhesion. We suggest that such functional amyloids may represent a generic mechanism for providing mechanical strength to cell adhesion proteins. In nanotechnology, these single-molecule manipulation experiments provide new opportunities to understand the molecular mechanisms driving the cohesion of functional amyloid-based nanostructures. PMID:22924880

  15. Biomarkers for the clinical evaluation of the cognitively impaired elderly: amyloid is not enough

    PubMed Central

    McEvoy, Linda K; Brewer, James B

    2012-01-01

    The number of elderly patients seeking clinical treatment for memory problems will rise sharply in coming years as our population ages. These patients present a challenge for diagnosis and prognosis since cognitive problems in older patients can arise from many etiologies, some of which are curable. With the development of clinically available biomarkers for detecting Alzheimer’s disease pathology in living patients, evaluation of cognitively impaired elderly patients is about to undergo a major paradigm shift. This article describes the two classes of biomarkers available for assessing Alzheimer’s disease risk: those that indicate presence of amyloid pathology and those that provide evidence of neuronal injury and neurodegeneration. We argue that, currently, incorporation of biomarkers of neurodegeneration can help in patient prognosis whereas tests for amyloid, if used in isolation, have potential for harm. Amyloid tests are clinically useful only when evidence suggests progressive cognitive decline or neurodegeneration. PMID:23420460

  16. Key Points Concerning Amyloid Infectivity and Prion-Like Neuronal Invasion

    PubMed Central

    Espargaró, Alba; Busquets, Maria Antònia; Estelrich, Joan; Sabate, Raimon

    2016-01-01

    Amyloid aggregation has been related to an increasing number of human illnesses, from Alzheimer’s and Parkinson’s diseases (AD/PD) to Creutzfeldt-Jakob disease. Commonly, only prions have been considered as infectious agents with a high capacity of propagation. However, recent publications have shown that many amyloid proteins, including amyloid β-peptide, α-synuclein (α-syn) and tau protein, also propagate in a “prion-like” manner. Meanwhile, no link between propagation of pathological proteins and neurotoxicity has been demonstrated. The extremely low infectivity under natural conditions of most non-prion amyloids is far below the capacity to spread exhibited by prions. Nonetheless, it is important to elucidate the key factors that cause non-prion amyloids to become infectious agents. In recent years, important advances in our understanding of the amyloid processes of amyloid-like proteins and unrelated prions (i.e., yeast and fungal prions) have yielded essential information that can shed light on the prion phenomenon in mammals and humans. As shown in this review, recent evidence suggests that there are key factors that could dramatically modulate the prion capacity of proteins in the amyloid conformation. The concentration of nuclei, the presence of oligomers, and the toxicity, resistance and localization of these aggregates could all be key factors affecting their spread. In short, those factors that favor the high concentration of extracellular nuclei or oligomers, characterized by small size, with a low toxicity could dramatically increase prion propensity; whereas low concentrations of highly toxic intracellular amyloids, with a large size, would effectively prevent infectivity. PMID:27147962

  17. Key Points Concerning Amyloid Infectivity and Prion-Like Neuronal Invasion.

    PubMed

    Espargaró, Alba; Busquets, Maria Antònia; Estelrich, Joan; Sabate, Raimon

    2016-01-01

    Amyloid aggregation has been related to an increasing number of human illnesses, from Alzheimer's and Parkinson's diseases (AD/PD) to Creutzfeldt-Jakob disease. Commonly, only prions have been considered as infectious agents with a high capacity of propagation. However, recent publications have shown that many amyloid proteins, including amyloid β-peptide, α-synuclein (α-syn) and tau protein, also propagate in a "prion-like" manner. Meanwhile, no link between propagation of pathological proteins and neurotoxicity has been demonstrated. The extremely low infectivity under natural conditions of most non-prion amyloids is far below the capacity to spread exhibited by prions. Nonetheless, it is important to elucidate the key factors that cause non-prion amyloids to become infectious agents. In recent years, important advances in our understanding of the amyloid processes of amyloid-like proteins and unrelated prions (i.e., yeast and fungal prions) have yielded essential information that can shed light on the prion phenomenon in mammals and humans. As shown in this review, recent evidence suggests that there are key factors that could dramatically modulate the prion capacity of proteins in the amyloid conformation. The concentration of nuclei, the presence of oligomers, and the toxicity, resistance and localization of these aggregates could all be key factors affecting their spread. In short, those factors that favor the high concentration of extracellular nuclei or oligomers, characterized by small size, with a low toxicity could dramatically increase prion propensity; whereas low concentrations of highly toxic intracellular amyloids, with a large size, would effectively prevent infectivity. PMID:27147962

  18. Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus.

    PubMed

    Jean, Ying Y; Baleriola, Jimena; Fà, Mauro; Hengst, Ulrich; Troy, Carol M

    2015-01-01

    Alzheimer's disease is a neurodegenerative disease affecting the aging population. A key neuropathological feature of the disease is the over-production of amyloid-beta and the deposition of amyloid-beta plaques in brain regions of the afflicted individuals. Throughout the years scientists have generated numerous Alzheimer's disease mouse models that attempt to replicate the amyloid-beta pathology. Unfortunately, the mouse models only selectively mimic the disease features. Neuronal death, a prominent effect in the brains of Alzheimer's disease patients, is noticeably lacking in these mice. Hence, we and others have employed a method of directly infusing soluble oligomeric species of amyloid-beta - forms of amyloid-beta that have been proven to be most toxic to neurons - stereotaxically into the brain. In this report we utilize male C57BL/6J mice to document this surgical technique of increasing amyloid-beta levels in a select brain region. The infusion target is the dentate gyrus of the hippocampus because this brain structure, along with the basal forebrain that is connected by the cholinergic circuit, represents one of the areas of degeneration in the disease. The results of elevating amyloid-beta in the dentate gyrus via stereotaxic infusion reveal increases in neuron loss in the dentate gyrus within 1 week, while there is a concomitant increase in cell death and cholinergic neuron loss in the vertical limb of the diagonal band of Broca of the basal forebrain. These effects are observed up to 2 weeks. Our data suggests that the current amyloid-beta infusion model provides an alternative mouse model to address region specific neuron death in a short-term basis. The advantage of this model is that amyloid-beta can be elevated in a spatial and temporal manner. PMID:26132278

  19. 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 amyloidpathology. 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, amyloidpathology affects cerebral blood flow across the span from controls to

  20. Amyloid pore-channel hypothesis: effect of ethanol on aggregation state using frog oocytes for an Alzheimer’s disease study

    PubMed Central

    Parodi, Jorge; Ormeño, David; la Paz, Lenin D. Ochoa-de

    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. [BMB Reports 2015; 48(1): 13-18] PMID:25047445

  1. Abundant Expression of Zinc Transporters in the Amyloid Plaques of Alzheimer’s Disease Brain

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The pathological key features of Alzheimer’s disease (AD) are ß-amyloid peptide (Aß)-containing senile plaques (SP) and neurofibrillary tangles. Previous studies have suggested that an extracellular elevation of zinc concentrations can initiate the deposition of Aß and lead to the formation of SP. I...

  2. Interactions of Pathological Hallmark Proteins

    PubMed Central

    Oláh, Judit; Vincze, Orsolya; Virók, Dezső; Simon, Dóra; Bozsó, Zsolt; Tőkési, Natália; Horváth, István; Hlavanda, Emma; Kovács, János; Magyar, Anna; Szűcs, Mária; Orosz, Ferenc; Penke, Botond; Ovádi, Judit

    2011-01-01

    The disordered tubulin polymerization promoting protein (TPPP/p25) was found to be co-enriched in neuronal and glial inclusions with α-synuclein in Parkinson disease and multiple system atrophy, respectively; however, co-occurrence of α-synuclein with β-amyloid (Aβ) in human brain inclusions has been recently reported, suggesting the existence of mixed type pathologies that could result in obstacles in the correct diagnosis and treatment. Here we identified TPPP/p25 as an interacting partner of the soluble Aβ oligomers as major risk factors for Alzheimer disease using ProtoArray human protein microarray. The interactions of oligomeric Aβ with proteins involved in the etiology of neurological disorders were characterized by ELISA, surface plasmon resonance, pelleting experiments, and tubulin polymerization assay. We showed that the Aβ42 tightly bound to TPPP/p25 (Kd = 85 nm) and caused aberrant protein aggregation by inhibiting the physiologically relevant TPPP/p25-derived microtubule assembly. The pair-wise interactions of Aβ42, α-synuclein, and tubulin were found to be relatively weak; however, these three components formed soluble ternary complex exclusively in the absence of TPPP/p25. The aggregation-facilitating activity of TPPP/p25 and its interaction with Aβ was monitored by electron microscopy with purified proteins by pelleting experiments with cell-free extracts as well as by confocal microscopy with CHO cells expressing TPPP/p25 or amyloid. The finding that the interaction of TPPP/p25 with Aβ can produce pathological-like aggregates is tightly coupled with unusual pathology of the Alzheimer disease revealed previously; that is, partial co-localization of Aβ and TPPP/p25 in the case of diffuse Lewy body disease with Alzheimer disease. PMID:21832049

  3. Cytoplasmic Retention of Protein Phosphatase 2A Inhibitor 2 (I2PP2A) Induces Alzheimer-like Abnormal Hyperphosphorylation of Tau*

    PubMed Central

    Arif, Mohammad; Wei, Jianshe; Zhang, Qi; Liu, Fei; Basurto-Islas, Gustavo; Grundke-Iqbal, Inge; Iqbal, Khalid

    2014-01-01

    Abnormal hyperphosphorylation of Tau leads to the formation of neurofibrillary tangles, a hallmark of Alzheimer disease (AD), and related tauopathies. The phosphorylation of Tau is regulated by protein phosphatase 2A (PP2A), which in turn is modulated by endogenous inhibitor 2 (I2PP2A). In AD brain, I2PP2A is translocated from neuronal nucleus to cytoplasm, where it inhibits PP2A activity and promotes abnormal phosphorylation of Tau. Here we describe the identification of a potential nuclear localization signal (NLS) in the C-terminal region of I2PP2A containing a conserved basic motif, 179RKR181, which is sufficient for directing its nuclear localization. The current study further presents an inducible cell model (Tet-Off system) of AD-type abnormal hyperphosphorylation of Tau by expressing I2PP2A in which the NLS was inactivated by 179RKR181 → AAA along with 168KR169 → AA mutations. In this model, the mutant NLS (mNLS)-I2PP2A (I2PP2AAA-AAA) was retained in the cell cytoplasm, where it physically interacted with PP2A and inhibited its activity. Inhibition of PP2A was associated with the abnormal hyperphosphorylation of Tau, which resulted in microtubule network instability and neurite outgrowth impairment. Expression of mNLS-I2PP2A activated CAMKII and GSK-3β, which are Tau kinases regulated by PP2A. The immunoprecipitation experiments showed the direct interaction of I2PP2A with PP2A and GSK-3β but not with CAMKII. Thus, the cell model provides insights into the nature of the potential NLS and the mechanistic relationship between I2PP2A-induced inhibition of PP2A and hyperphosphorylation of Tau that can be utilized to develop drugs preventing Tau pathology. PMID:25128526

  4. Genetics Home Reference: hereditary cerebral amyloid angiopathy

    MedlinePlus

    ... recurrent seizures (epilepsy). People with the Flemish and Italian types of hereditary cerebral amyloid angiopathy are prone ... amyloid angiopathy . APP gene mutations cause the Dutch, Italian, Arctic, Iowa, Flemish, and Piedmont types of this ...

  5. Comparisons with Amyloid-β Reveal an Aspartate Residue That Stabilizes Fibrils of the Aortic Amyloid Peptide Medin*

    PubMed Central

    Davies, Hannah A.; Madine, Jillian; Middleton, David A.

    2015-01-01

    Aortic medial amyloid (AMA) is the most common localized human amyloid, occurring in virtually all of the Caucasian population over the age of 50. The main protein component of AMA, medin, readily assembles into amyloid-like fibrils in vitro. Despite the prevalence of AMA, little is known about the self-assembly mechanism of medin or the molecular architecture of the fibrils. The amino acid sequence of medin is strikingly similar to the sequence of the Alzheimer disease (AD) amyloid-β (Aβ) polypeptides around the structural turn region of Aβ, where mutations associated with familial, early onset AD, have been identified. Asp25 and Lys30 of medin align with residues Asp23 and Lys28 of Aβ, which are known to form a stabilizing salt bridge in some fibril morphologies. Here we show that substituting Asp25 of medin with asparagine (D25N) impedes assembly into fibrils and stabilizes non-cytotoxic oligomers. Wild-type medin, by contrast, aggregates into β-sheet-rich amyloid-like fibrils within 50 h. A structural analysis of wild-type fibrils by solid-state NMR suggests a molecular repeat unit comprising at least two extended β-strands, separated by a turn stabilized by a Asp25-Lys30 salt bridge. We propose that Asp25 drives the assembly of medin by stabilizing the fibrillar conformation of the peptide and is thus reminiscent of the influence of Asp23 on the aggregation of Aβ. Pharmacological comparisons of wild-type medin and D25N will help to ascertain the pathological significance of this poorly understood protein. PMID:25614623

  6. Comparisons with amyloid-β reveal an aspartate residue that stabilizes fibrils of the aortic amyloid peptide medin.

    PubMed

    Davies, Hannah A; Madine, Jillian; Middleton, David A

    2015-03-20

    Aortic medial amyloid (AMA) is the most common localized human amyloid, occurring in virtually all of the Caucasian population over the age of 50. The main protein component of AMA, medin, readily assembles into amyloid-like fibrils in vitro. Despite the prevalence of AMA, little is known about the self-assembly mechanism of medin or the molecular architecture of the fibrils. The amino acid sequence of medin is strikingly similar to the sequence of the Alzheimer disease (AD) amyloid-β (Aβ) polypeptides around the structural turn region of Aβ, where mutations associated with familial, early onset AD, have been identified. Asp(25) and Lys(30) of medin align with residues Asp(23) and Lys(28) of Aβ, which are known to form a stabilizing salt bridge in some fibril morphologies. Here we show that substituting Asp(25) of medin with asparagine (D25N) impedes assembly into fibrils and stabilizes non-cytotoxic oligomers. Wild-type medin, by contrast, aggregates into β-sheet-rich amyloid-like fibrils within 50 h. A structural analysis of wild-type fibrils by solid-state NMR suggests a molecular repeat unit comprising at least two extended β-strands, separated by a turn stabilized by a Asp(25)-Lys(30) salt bridge. We propose that Asp(25) drives the assembly of medin by stabilizing the fibrillar conformation of the peptide and is thus reminiscent of the influence of Asp(23) on the aggregation of Aβ. Pharmacological comparisons of wild-type medin and D25N will help to ascertain the pathological significance of this poorly understood protein. PMID:25614623

  7. 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

  8. Structure-Based Design of Non-Natural Amino Acid Inhibitors of Amyloid Fibrillation

    PubMed Central

    Sievers, Stuart A.; Karanicolas, John; Chang, Howard W.; Zhao, Anni; Jiang, Lin; Zirafi, Onofrio; Stevens, Jason T.; Münch, Jan; Baker, David; Eisenberg, David

    2014-01-01

    Many globular and natively disordered proteins can convert into amyloid fibers. These fibers are associated with numerous pathologies1 as well as with normal cellular functions2,3, and frequently form during protein denaturation4,5. Inhibitors of pathological amyloid fibers could serve as leads for therapeutics, provided the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibers as templates, we have designed and characterized an all D-amino acid inhibitor of fibrillation of the tau protein found in Alzheimer’s disease, and a non-natural L-amino acid inhibitor of an amyloid fiber that enhances sexual transmission of HIV. Our results indicate that peptides from structure-based designs can disrupt the fibrillation of full-length proteins, including those like tau that lack fully ordered native structures. PMID:21677644

  9. Amyloid fibrils formed by the programmed cell death regulator Bcl-xL.

    PubMed

    Chenal, Alexandre; Vendrely, Charlotte; Vitrac, Heidi; Karst, Johanna C; Gonneaud, Alexis; Blanchet, Clément E; Pichard, Sylvain; Garcia, Elisabeth; Salin, Bénédicte; Catty, Patrice; Gillet, Daniel; Hussy, Nicolas; Marquette, Christel; Almunia, Christine; Forge, Vincent

    2012-01-20

    The accumulation of amyloid fibers due to protein misfolding is associated with numerous human diseases. For example, the formation of amyloid deposits in neurodegenerative pathologies is correlated with abnormal apoptosis. We report here the in vitro formation of various types of aggregates by Bcl-xL, a protein of the Bcl-2 family involved in the regulation of apoptosis. Bcl-xL forms aggregates in three states, micelles, native-like fibrils, and amyloid fibers, and their biophysical characterization has been performed in detail. Bcl-xL remains in its native state within micelles and native-like fibrils, and our results suggest that native-like fibrils are formed by the association of micelles. Formation of amyloid structures, that is, nonnative intermolecular β-sheets, is favored by the proximity of proteins within fibrils at the expense of the Bcl-xL native structure. Finally, we provide evidence of a direct relationship between the amyloid character of the fibers and the tertiary-structure stability of the native Bcl-xL. The potential causality between the accumulation of Bcl-xL into amyloid deposits and abnormal apoptosis during neurodegenerative diseases is discussed. PMID:22119486

  10. The Protective Role of Carnosic Acid against Beta-Amyloid Toxicity in Rats

    PubMed Central

    Rasoolijazi, H.; Azad, N.; Joghataei, M. T.; Kerdari, M.; Nikbakht, F.; Soleimani, M.

    2013-01-01

    Oxidative stress is one of the pathological mechanisms responsible for the beta- amyloid cascade associated with Alzheimer's disease (AD). Previous studies have demonstrated the role of carnosic acid (CA), an effective antioxidant, in combating oxidative stress. A progressive cognitive decline is one of the hallmarks of AD. Thus, we attempted to determine whether the administration of CA protects against memory deficit caused by beta-amyloid toxicity in rats. Beta-amyloid (1–40) was injected by stereotaxic surgery into the Ca1 region of the hippocampus of rats in the Amyloid beta (Aβ) groups. CA was delivered intraperitoneally, before and after surgery in animals in the CA groups. Passive avoidance learning and spontaneous alternation behavior were evaluated using the shuttle box and the Y-maze, respectively. The degenerating hippocampal neurons were detected by fluoro-jade b staining. We observed that beta-amyloid (1–40) can induce neurodegeneration in the Ca1 region of the hippocampus by using fluoro-jade b staining. Also, the behavioral tests revealed that CA may recover the passive avoidance learning and spontaneous alternation behavior scores in the Aβ + CA group, in comparison with the Aβ group. We found that CA may ameliorate the spatial and learning memory deficits induced by the toxicity of beta-amyloid in the rat hippocampus. PMID:24363627

  11. Toll-Like Receptor 2 and NLRP3 Cooperate To Recognize a Functional Bacterial Amyloid, Curli

    PubMed Central

    Rapsinski, Glenn J.; Wynosky-Dolfi, Meghan A.; Oppong, Gertrude O.; Tursi, Sarah A.; Wilson, R. Paul; Brodsky, Igor E.

    2014-01-01

    Amyloids are proteins with cross-β-sheet structure that contribute to pathology and inflammation in complex human diseases, including Alzheimer's disease, Parkinson's disease, type II diabetes, and secondary amyloidosis. Bacteria also produce amyloids as a component of their extracellular matrix during biofilm formation. Recently, several human amyloids were shown to activate the NLRP3 inflammasome, leading to the activation of caspase 1 and production of interleukin 1β (IL-1β). In this study, we investigated the activation of the NLRP3 inflammasome by bacterial amyloids using curli fibers, produced by Salmonella enterica serovar Typhimurium and Escherichia coli. Here, we show that curli fibers activate the NLRP3 inflammasome, leading to the production of IL-1β via caspase 1 activation. Investigation of the underlying mechanism revealed that activation of Toll-like receptor 2 (TLR2) by curli fibers is critical in the generation of IL-1β. Interestingly, activation of the NLRP3 inflammasome by curli fibers or by amyloid β of Alzheimer's disease does not cause cell death in macrophages. Overall, these data identify a cross talk between TLR2 and NLRP3 in response to the bacterial amyloid curli and generation of IL-1β as a product of this interaction. PMID:25422268

  12. Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

    PubMed Central

    Gowrishankar, Swetha; Yuan, Peng; Wu, Yumei; Schrag, Matthew; Paradise, Summer; Grutzendler, Jaime; De Camilli, Pietro; Ferguson, Shawn M.

    2015-01-01

    Through a comprehensive analysis of organellar markers in mouse models of Alzheimer’s disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer’s disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer’s disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology. PMID:26124111

  13. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease.

    PubMed

    Yan, S D; Chen, X; Fu, J; Chen, M; Zhu, H; Roher, A; Slattery, T; Zhao, L; Nagashima, M; Morser, J; Migheli, A; Nawroth, P; Stern, D; Schmidt, A M

    1996-08-22

    Amyloid-beta peptide is central to the pathology of Alzheimer's disease, because it is neurotoxic--directly by inducing oxidant stress, and indirectly by activating microglia. A specific cell-surface acceptor site that could focus its effects on target cells has been postulated but not identified. Here we present evidence that the 'receptor for advanced glycation end products' (RAGE) is such a receptor, and that it mediates effects of the peptide on neurons and microglia. Increased expressing of RAGE in Alzheimer's disease brain indicates that it is relevant to the pathogenesis of neuronal dysfunction and death. PMID:8751438

  14. The Structure of Intrinsically Disordered Peptides Implicated in Amyloid Diseases: Insights from Fully Atomistic Simulations

    NASA Astrophysics Data System (ADS)

    Wu, Chun; Shea, Joan-Emma

    Protein aggregation involves the self-assembly of proteins into large β-sheet-rich complexes. This process can be the result of aberrant protein folding and lead to "amyloidosis," a condition characterized by deposits of protein aggregates known as amyloids on various organs of the body [1]. Amyloid-related diseases include, among others, Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and type II diabetes [2, 3, 4]. In other instances, however, protein aggregation is not a pathological process, but rather a functional one, with aggregates serving as structural scaffolds in a number of organisms [5].

  15. 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

  16. Atrophy, hypometabolism and clinical trajectories in patients with amyloid-negative Alzheimer's disease.

    PubMed

    Chételat, Gaël; Ossenkoppele, Rik; Villemagne, Victor L; Perrotin, Audrey; Landeau, Brigitte; Mézenge, Florence; Jagust, William J; Dore, Vincent; Miller, Bruce L; Egret, Stéphanie; Seeley, William W; van der Flier, Wiesje M; La Joie, Renaud; Ames, David; van Berckel, Bart N M; Scheltens, Philip; Barkhof, Frederik; Rowe, Christopher C; Masters, Colin L; de La Sayette, Vincent; Bouwman, Femke; Rabinovici, Gil D

    2016-09-01

    -negative cases whose post-positon emission tomography diagnosis remained Alzheimer's disease. While the non-amnestic and non-specific amyloid-negative cases usually showed patterns of atrophy and hypometabolism suggestive of another degenerative disorder, the amnestic amyloid-negative cases had subtle atrophy and hypometabolism, restricted to the retrosplenial/posterior cingulate cortex. Patients with a negative amyloid positon emission tomography scan following an initial clinical diagnosis of Alzheimer's disease have heterogeneous clinical presentations and neuroimaging profiles; a majority showed a clinical progression that was consistent with a neurodegenerative condition. In contrast, in the subgroup of amnestic amyloid-negative cases, the clinical presentation and follow-up usually remained consistent with Alzheimer's disease. An alternative diagnosis was not made in about half of the amnestic amyloid-negative cases, highlighting the need for a clinical framework and terminology to define these patients, who may have underlying limbic-predominant, non-amyloid-related pathologies. PMID:27357349

  17. Spatial patterns of brain amyloid-beta burden and atrophy rate associations in mild cognitive impairment.

    PubMed

    Tosun, Duygu; Schuff, Norbert; Mathis, Chester A; Jagust, William; Weiner, Michael W

    2011-04-01

    Amyloid-β accumulation in the brain is thought to be one of the earliest events in Alzheimer's disease, possibly leading to synaptic dysfunction, neurodegeneration and cognitive/functional decline. The earliest detectable changes seen with neuroimaging appear to be amyloid-β accumulation detected by (11)C-labelled Pittsburgh compound B positron emission tomography imaging. However, some individuals tolerate high brain amyloid-β loads without developing symptoms, while others progressively decline, suggesting that events in the brain downstream from amyloid-β deposition, such as regional brain atrophy rates, play an important role. The main purpose of this study was to understand the relationship between the regional distributions of increased amyloid-β and the regional distribution of increased brain atrophy rates in patients with mild cognitive impairment. To simultaneously capture the spatial distributions of amyloid-β and brain atrophy rates, we employed the statistical concept of parallel independent component analysis, an effective method for joint analysis of multimodal imaging data. Parallel independent component analysis identified significant relationships between two patterns of amyloid-β deposition and atrophy rates: (i) increased amyloid-β burden in the left precuneus/cuneus and medial-temporal regions was associated with increased brain atrophy rates in the left medial-temporal and parietal regions; and (ii) in contrast, increased amyloid-β burden in bilateral precuneus/cuneus and parietal regions was associated with increased brain atrophy rates in the right medial temporal regions. The spatial distribution of increased amyloid-β and the associated spatial distribution of increased brain atrophy rates embrace a characteristic pattern of brain structures known for a high vulnerability to Alzheimer's disease pathology, encouraging for the use of (11)C-labelled Pittsburgh compound B positron emission tomography measures as early indicators of

  18. Post-Mortem Evaluation of Amyloid-Dopamine Terminal PET Dementia Classifications

    PubMed Central

    Albin, Roger L.; Fisher-Hubbard, Amanda; Shanmugasundaram, Krithika; Koeppe, Robert A.; Burke, James F.; Camelo-Piragua, Sandra; Lieberman, Andrew P.; Giordani, Bruno; Frey, Kirk A.

    2016-01-01

    Clinical classification of early dementia and mild cognitive impairment is imprecise. We reported previously that molecular imaging classification of early dementia and mild cognitive impairment with dual amyloid and dopamine terminal positron emission tomography differs significantly from expert clinical classification. We now report pathologic diagnoses in a substantial subset of our previously imaged subjects. Among 36 subjects coming to autopsy, imaging classifications and pathologic diagnosis were concordant in 33 cases (κ=0.85). This approach enhanced specificity of Alzheimer disease diagnosis. The strong concordance of imaging based classifications and pathologic diagnoses suggests that this imaging approach will be useful in establishing more accurate and convenient classification biomarkers for dementia research. PMID:26183692

  19. Nanoscale Heterogeneity of the Molecular Structure of Individual hIAPP Amyloid Fibrils Revealed with Tip-Enhanced Raman Spectroscopy.

    PubMed

    vandenAkker, Corianne C; Deckert-Gaudig, Tanja; Schleeger, Michael; Velikov, Krassimir P; Deckert, Volker; Bonn, Mischa; Koenderink, Gijsje H

    2015-09-01

    Type 2 diabetes mellitus is characterized by the pathological deposition of fibrillized protein, known as amyloids. It is thought that oligomers and/or amyloid fibrils formed from human islet amyloid polypeptide (hIAPP or amylin) cause cell death by membrane damage. The molecular structure of hIAPP amyloid fibrils is dominated by β-sheet structure, as probed with conventional infrared and Raman vibrational spectroscopy. However, with these techniques it is not possible to distinguish between the core and the surface structure of the fibrils. Since the fibril surface crucially affects amyloid toxicity, it is essential to know its structure. Here the surface molecular structure and amino acid residue composition of hIAPP fibrils are specifically probed with nanoscale resolution using tip-enhanced Raman spectroscopy (TERS). The fibril surface mainly contains unordered or α-helical structures, in contrast to the β-sheet-rich core. This experimentally validates recent models of hIAPP amyloids based on NMR measurements. Spatial mapping of the surface structure reveals a highly heterogeneous surface structure. Finally, TERS can probe fibrils formed on a lipid interface, which is more representative of amyloids in vivo. PMID:25952953

  20. Globular hepatic amyloid: an early stage in the pathway of amyloid formation: a study of 20 new cases.

    PubMed

    Makhlouf, Hala R; Goodman, Zachary D

    2007-10-01

    Only 25 cases of globular hepatic amyloidosis have been reported, mostly from the early 1980s. We reviewed clinical, histopathologic, and immunohistochemical features of 20 cases of hepatic globular amyloid out of 208 cases of liver amyloidosis seen at the Armed Forces Institute of Pathology since 1970. Fourteen (70%) were men and 6 were women with a median age of 67 years (range, 40 to 92 y). More than half of the patients were Hispanic. Ten of 20 patients were diagnosed with systemic amyloidosis. Histologically, all cases revealed round to oval-shaped sometimes laminated globules, 1 to 40 mum in diameter, and 6 cases had evidence of transition from globular to the more usual linear form. In all 20 cases, Congo red and/or Sirius red stained the globules red and showed an apple green birefringence under polarized light. Portal tracts and parenchyma were involved in 15/20 the cases, and sinusoidal deposition alone in 5 cases. Vascular deposition was very common with more than 3/4 of the cases showing mainly perivenular amyloid with both the terminal hepatic venules and portal vein branches being equally involved. A few intrahepatocellular globules were present in half of the cases. In conclusion, hepatic amyloidosis can rarely occur as a globular form, and the finding of intracellular amyloid globules and transitional forms of globular to linear patterns of deposition suggest that this is an early form of hepatic involvement by systemic amyloidosis. PMID:17895765

  1. Pathological gambling.

    PubMed

    Hollander, E; Buchalter, A J; DeCaria, C M

    2000-09-01

    With increasing access to gambling facilities through casinos, the Internet, and other venues, PG is a rapidly emerging mental health concern. This impulse-control disorder tends to be comorbid with a wide range of other disorders and is reportedly associated with a high rate of suicide. For most gamblers, gambling is a form of entertainment, but for many individuals, the activity leads to far-reaching disruption of family and work. The personal and societal financial ramifications are severe, and many individuals with PG end up in the criminal justice system. An understanding of the neurobiology of PG is beginning to surface. 5-HT is linked to behavioral initiation and disinhibition, which are important in the onset of the gambling cycle and the difficulty in ceasing the behavior. Norepinephrine is associated with the arousal and risk taking in patients with PG. Dopamine is linked to positive and negative reward, the addictive component of this disorder. Effective treatment strategies for pathological gamblers are emerging. Potentially useful pharmacologic agents include SRIs (clomipramine and fluvoxamine), mood stabilizers for pathological gamblers with comorbid bipolar disorders (lithium), and naltrexone. Cognitive-behavioral psychotherapies offer promising results in the treatment of patients with this disorder. To devise prevention and early-intervention programs, research is needed to identify specific features of the individuals at risk for gambling problems. Education targeting vulnerable youth that show early signs of gambling behavior may be worthwhile and should be investigated further. Funding is necessary to support these endeavors, so perhaps a portion of tax revenues generated from the gambling industry should go toward specialized treatment facilities, educational efforts, and research into the neurobiology and treatment of PG. PMID:10986732

  2. Amyloid formation: functional friend or fearful foe?

    PubMed

    Bergman, P; Roan, N R; Römling, U; Bevins, C L; Münch, J

    2016-08-01

    Amyloid formation has been most studied in the context of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, as well as in amyloidosis. However, it is becoming increasingly clear that amyloid is also present in the healthy setting; for example nontoxic amyloid formation is important for melanin synthesis and in innate immunity. Furthermore, bacteria have mechanisms to produce functional amyloid structures with important roles in bacterial physiology and interaction with host cells. Here, we will discuss some novel aspects of fibril-forming proteins in humans and bacteria. First, the amyloid-forming properties of the antimicrobial peptide human defensin 6 (HD6) will be considered. Intriguingly, unlike other antimicrobial peptides, HD6 does not kill bacteria. However, recent data show that HD6 can form amyloid structures at the gut mucosa with strong affinity for bacterial surfaces. These so-called nanonets block bacterial invasion by entangling the bacteria in net-like structures. Next, the role of functional amyloid fibrils in human semen will be discussed. These fibrils were discovered through their property to enhance HIV infection but they may also have other yet unknown functions. Finally, the role of amyloid formation in bacteria will be reviewed. The recent finding that bacteria can make amyloid in a controlled fashion without toxic effects is of particular interest and may have implications for human disease. The role of amyloid in health and disease is beginning to be unravelled, and here, we will review some of the most recent findings in this exciting area. PMID:27151743

  3. Visual Hallucinations and Amyloid Deposition in Parkinson's Disease Dementia: A Case Report.

    PubMed

    Um, Yoo Hyun; Kim, Tae-Won; Jeong, Jong-Hyun; Seo, Ho-Jun; Han, Jin-Hee; Hong, Seung-Chul; Jung, Won-Sang; Choi, Woo Hee; Lee, Chang-Uk; Lim, Hyun Kook

    2016-05-01

    Parkinson's disease dementia (PDD) is notorious for its debilitating clinical course and high mortality rates. Consequently, various attempts to investigate predictors of cognitive decline in Parkinson's disease (PD) have been made. Here we report a case of a 75-year-old female patient with PD who visited the clinic with complaints of recurrent visual hallucinations and cognitive decline, whose symptoms were ameliorated by the titration of rivastigmine. Imaging results showed pronounced diffuse cortical amyloid deposition evidenced by 18F-florbetaben amyloid positron emission tomography (PET) imaging. This observation suggests that pronounced amyloid deposition and visual hallucinations in PD patients could be clinically significant predictors of cognitive decline in PD patients. Future research should concentrate on accumulating more evidence for possible predictors of cognitive decline and their association with PD pathology that can enable an early intervention and standardized treatment in PDD patients. PMID:27247605

  4. Visual Hallucinations and Amyloid Deposition in Parkinson's Disease Dementia: A Case Report

    PubMed Central

    Um, Yoo Hyun; Kim, Tae-Won; Jeong, Jong-Hyun; Seo, Ho-Jun; Han, Jin-Hee; Hong, Seung-Chul; Jung, Won-Sang; Choi, Woo Hee; Lee, Chang-Uk

    2016-01-01

    Parkinson's disease dementia (PDD) is notorious for its debilitating clinical course and high mortality rates. Consequently, various attempts to investigate predictors of cognitive decline in Parkinson's disease (PD) have been made. Here we report a case of a 75-year-old female patient with PD who visited the clinic with complaints of recurrent visual hallucinations and cognitive decline, whose symptoms were ameliorated by the titration of rivastigmine. Imaging results showed pronounced diffuse cortical amyloid deposition evidenced by 18F-florbetaben amyloid positron emission tomography (PET) imaging. This observation suggests that pronounced amyloid deposition and visual hallucinations in PD patients could be clinically significant predictors of cognitive decline in PD patients. Future research should concentrate on accumulating more evidence for possible predictors of cognitive decline and their association with PD pathology that can enable an early intervention and standardized treatment in PDD patients. PMID:27247605

  5. Beta-Amyloid Deposition and Alzheimer's Type Changes Induced by Borrelia Spirochetes

    SciTech Connect

    Miklossy,J.; Kis, A.; Radenovic, A.; Miller, L.; Forro, L.; Martins, R.; Reiss, K.; Darbinian, N.; Darekar, P.; et al.

    2006-01-01

    The pathological hallmarks of Alzheimer's disease (AD) consist of {beta}-amyloid plaques and neurofibrillary tangles in affected brain areas. The processes, which drive this host reaction are unknown. To determine whether an analogous host reaction to that occurring in AD could be induced by infectious agents, we exposed mammalian glial and neuronal cells in vitro to Borrelia burgdorferi spirochetes and to the inflammatory bacterial lipopolysaccharide (LPS). Morphological changes analogous to the amyloid deposits of AD brain were observed following 2-8 weeks of exposure to the spirochetes. Increased levels of {beta}-amyloid presursor protein (A{beta}PP) and hyperphosphorylated tau were also detected by Western blots of extracts of cultured cells that had been treated with spirochetes or LPS. These observations indicate that, by exposure to bacteria or to their toxic products, host responses similar in nature to those observed in AD may be induced.

  6. Alzheimer disease identification using amyloid imaging and reserve variables

    PubMed Central

    Roe, C.M.; Mintun, M.A.; Ghoshal, N.; Williams, M.M.; Grant, E.A.; Marcus, D.S.; Morris, J.C.

    2010-01-01

    Objective: Several factors may influence the relationship between Alzheimer disease (AD) lesions and the expression of dementia, including those related to brain and cognitive reserve. Other factors may confound the association between AD pathology and dementia. We tested whether factors thought to influence the association of AD pathology and dementia help to accurately identify dementia of the Alzheimer type (DAT) when considered together with amyloid imaging. Methods: Participants with normal cognition (n = 180) and with DAT (n = 25), aged 50 years or older, took part in clinical, neurologic, and psychometric assessments. PET with the Pittsburgh compound B (PiB) tracer was used to measure brain amyloid, yielding a mean cortical binding potential (MCBP) reflecting PiB uptake. Logistic regression was used to generate receiver operating characteristic curves, and the areas under those curves (AUC), to compare the predictive accuracy of using MCBP alone vs MCBP together with other variables selected using a stepwise selection procedure to identify participants with DAT vs normal cognition. Results: The AUC resulting from MCBP alone was 0.84 (95% confidence interval [CI] = 0.73–0.94; cross-validated AUC = 0.80, 95% CI = 0.68–0.92). The AUC for the predictive equation generated by a stepwise model including education, normalized whole brain volume, physical health rating, gender, and use of medications that may interfere with cognition was 0.94 (95% CI = 0.90–0.98; cross-validated AUC = 0.91, 95% CI = 0.85–0.96), an improvement (p = 0.025) over that yielded using MCBP alone. Conclusion: Results suggest that factors reported to influence associations between AD pathology and dementia can improve the predictive accuracy of amyloid imaging for the identification of symptomatic AD. GLOSSARY A β = amyloid-β; AD = Alzheimer disease; AUC = area under receiver operating characteristic curve; BP = binding potential; CDR = Clinical Dementia Rating; CI = confidence

  7. Are elevated serum amyloid A levels and amyloid-enhancing factor sufficient to induce inflammation-associated amyloid deposition?

    PubMed

    Kisilevsky, R; Tan, R; Subrahmanyan, L; Snow, A

    1984-01-01

    During inflammation-associated amyloidosis two coincident factors, serum amyloid A (SAA) and amyloid-enhancing factor (AEF) are apparently necessary for amyloid A (AA) deposition. It is shown by passive transfer of cytokines, which stimulate SAA production, and AEF that these are not sufficient. A further factor(s) is necessary, which stems from the acute inflammatory response. Potential candidates are serum or tissue glycosaminoglycans. PMID:6400464

  8. Calorie restriction attenuates astrogliosis but not amyloid plaque load in aged rhesus macaques: a preliminary quantitative imaging study

    PubMed Central

    Sridharan, Aadhavi; Pehar, Mariana; Salamat, M Shahriar; Pugh, Thomas D; Bendlin, Barbara B; Willette, Auriel A; Anderson, Rozalyn M; Kemnitz, Joseph W; Colman, Ricki J; Weindruch, Richard H; Puglielli, Luigi; Johnson, Sterling C

    2013-01-01

    While moderate calorie restriction (CR) in the absence of malnutrition has been consistently shown to have a systemic, beneficial effect against aging in several animals models, its effect on the brain microstructure in a non-human primate model remains to be studied using post-mortem histopathologic techniques. In the present study, we investigated differences in expression levels of glial fibrillary acid protein (GFAP) and β-amyloid plaque load in the hippocampus and the adjacent cortical areas of 7 Control (ad libitum)-fed and 6 CR male rhesus macaques using immunostaining methods. CR monkeys expressed significantly lower levels (∼30% on average) of GFAP than Controls in the CA region of the hippocampus and entorhinal cortex, suggesting a protective effect of CR in limiting astrogliosis. These results recapitulate the neuroprotective effects of CR seen in shorter-lived animal models. There was a significant positive association between age and average amyloid plaque pathology in these animals, but there was no significant difference in amyloid plaque distribution between the two groups. Two of the seven Control animals (28.6%) and one of the six CR animal (16.7%) did not express any amyloid plaques, five of seven Controls (71.4%) and four of six CR animals (66.7%) expressed minimal to moderate amyloid pathology, and one of six CR animals (16.7%) expressed severe amyloid pathology. That CR affects levels of GFAP expression but not amyloid plaque load provides some insight into the means by which CR is beneficial at the microstructural level, potentially by offsetting the increased load of oxidatively damaged proteins, in this non-human primate model of aging. The present study is a preliminary post-mortem histological analysis of the effects of CR on brain health, and further studies using molecular and biochemical techniques are warranted to elucidate underlying mechanisms. PMID:23473840

  9. Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity.

    PubMed

    Bales, Kelly R; O'Neill, Sharon M; Pozdnyakov, Nikolay; Pan, Feng; Caouette, David; Pi, YeQing; Wood, Kathleen M; Volfson, Dmitri; Cirrito, John R; Han, Byung-Hee; Johnson, Andrew W; Zipfel, Gregory J; Samad, Tarek A

    2016-02-01

    Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer's disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-β isoform(s) (predominantly amyloid-β40) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly. We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-β40 selective antibody, to attenuate amyloid-β accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-β accumulation both in leptomeningeal and brain vessels when measured by intravital multiphoton imaging and immunohistochemistry. By enriching for cerebral vascular elements, we also measured a significant reduction in the levels of soluble amyloid-β biochemically. We hypothesized that the reduction in vascular amyloid-β40 after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-β40 in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid-β40 levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following acute administration of ponezumab, even in vessels where there was a severe cerebral amyloid angiopathy burden. Taken together, the beneficial effects ponezumab administration has on reducing the rate of cerebral amyloid angiopathy deposition and restoring cerebral vascular health favours a mechanism that involves rapid removal and/or neutralization of amyloid-β species that may otherwise be detrimental to normal vessel function. PMID:26493635

  10. Imaging of cerebrovascular pathology in animal models of Alzheimer's disease

    PubMed Central

    Klohs, Jan; Rudin, Markus; Shimshek, Derya R.; Beckmann, Nicolau

    2014-01-01

    In Alzheimer's disease (AD), vascular pathology may interact with neurodegeneration and thus aggravate cognitive decline. As the relationship between these two processes is poorly understood, research has been increasingly focused on understanding the link between cerebrovascular alterations and AD. This has at last been spurred by the engineering of transgenic animals, which display pathological features of AD and develop cerebral amyloid angiopathy to various degrees. Transgenic models are versatile for investigating the role of amyloid deposition and vascular dysfunction, and for evaluating novel therapeutic concepts. In addition, research has benefited from the development of novel imaging techniques, which are capable of characterizing vascular pathology in vivo. They provide vascular structural read-outs and have the ability to assess the functional consequences of vascular dysfunction as well as to visualize and monitor the molecular processes underlying these pathological alterations. This article focusses on recent in vivo small animal imaging studies addressing vascular aspects related to AD. With the technical advances of imaging modalities such as magnetic resonance, nuclear and microscopic imaging, molecular, functional and structural information related to vascular pathology can now be visualized in vivo in small rodents. Imaging vascular and parenchymal amyloid-β (Aβ) deposition as well as Aβ transport pathways have been shown to be useful to characterize their dynamics and to elucidate their role in the development of cerebral amyloid angiopathy and AD. Structural and functional imaging read-outs have been employed to describe the deleterious affects of Aβ on vessel morphology, hemodynamics and vascular integrity. More recent imaging studies have also addressed how inflammatory processes partake in the pathogenesis of the disease. Moreover, imaging can be pivotal in the search for novel therapies targeting the vasculature. PMID:24659966

  11. Amyloid Fibrils: Formation, Polymorphism, and Inhibition.

    PubMed

    Härd, Torleif

    2014-02-01

    Amyloid fibrils with cross-β spine basic architectures are prevalent and stable forms of peptides and proteins. Recent research has provided significant contributions to our understanding of the mechanisms of fibril formation and to the surprising diversity and persistence of structural polymorphism in amyloid fibrils. There have also been successful demonstrations of how molecules can be engineered to inhibit unwanted amyloid formation by different mechanisms. Future research in these areas will include investigations of mechanisms for primary nucleation and the structure of oligomeric intermediates, the general role of secondary nucleation events (autocatalysis), elucidation of the mechanisms and implications of preservation of structural morphology in amyloid propagation, and research into the largely unexplored phenomenon of cross-seeding, by which amyloid fibrils of one species induce the formation of amyloid by another species. PMID:26276617

  12. 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

  13. Amyloid Goiter Secondary to Ulcerative Colitis

    PubMed Central

    Aydin, Bunyamin; Koca, Tugba; Yildiz, Ihsan; Gerek Celikden, Sevda; Ciris, Metin

    2016-01-01

    Diffuse amyloid goiter (AG) is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn's disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis. PMID:27051538

  14. Amyloid Structures as Biofilm Matrix Scaffolds.

    PubMed

    Taglialegna, Agustina; Lasa, Iñigo; Valle, Jaione

    2016-10-01

    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

  15. Amyloid Goiter Secondary to Ulcerative Colitis.

    PubMed

    Aydin, Bunyamin; Koca, Yavuz Savas; Koca, Tugba; Yildiz, Ihsan; Gerek Celikden, Sevda; Ciris, Metin

    2016-01-01

    Diffuse amyloid goiter (AG) is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn's disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis. PMID:27051538

  16. Molecular basis for amyloid-[beta] polymorphism

    SciTech Connect

    Colletier, Jacques-Philippe; Laganowsky, Arthur; Landau, Meytal; Zhao, Minglei; Soriaga, Angela B.; Goldschmidt, Lukasz; Flot, David; Cascio, Duilio; Sawaya, Michael R.; Eisenberga, David

    2011-10-19

    Amyloid-beta (A{beta}) aggregates are the main constituent of senile plaques, the histological hallmark of Alzheimer's disease. A{beta} molecules form {beta}-sheet containing structures that assemble into a variety of polymorphic oligomers, protofibers, and fibers that exhibit a range of lifetimes and cellular toxicities. This polymorphic nature of A{beta} has frustrated its biophysical characterization, its structural determination, and our understanding of its pathological mechanism. To elucidate A{beta} polymorphism in atomic detail, we determined eight new microcrystal structures of fiber-forming segments of A{beta}. These structures, all of short, self-complementing pairs of {beta}-sheets termed steric zippers, reveal a variety of modes of self-association of A{beta}. Combining these atomic structures with previous NMR studies allows us to propose several fiber models, offering molecular models for some of the repertoire of polydisperse structures accessible to A{beta}. These structures and molecular models contribute fundamental information for understanding A{beta} polymorphic nature and pathogenesis.

  17. Amyloid Beta-Weighted Cortical Thickness: A New Imaging Biomarker in Alzheimer's Disease.

    PubMed

    Kim, Chan Mi; Hwang, Jihye; Lee, Jong-Min; Roh, Jee Hoon; Lee, Jae-Hong; Koh, Jae-Young

    2015-01-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder pathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The aggregation of Aβ precedes tau pathologies in AD; however, the causal relation between the two pathologies and the mechanisms by which aggregated forms of Aβ contribute to cortical thinning are not fully understood. We proposed quantitative Aβ-weighted cortical thickness analysis to investigate the regional relationship between cortical thinning and amyloid plaque deposition using magnetic resonance (MR) and Pittsburg Compound B (PiB) positron emission tomography (PET) images in patients with AD, mild cognitive impairment (MCI), and subjects with normal cognition. We hypothesized that there are cortical areas that have prominent changes associated with Aβ deposition and there are areas that are relatively independent from Aβ deposition where pathologies other than Aβ (such as tau) are predominant. The study was performed using MRI and PiB PET data from the Alzheimer's Disease Neuroimaging Initiative. We measured accuracy of classification models in three different pairs of groups comparing AD, MCI, and normal cognition. Classification models that used Aβ-weighted cortical thickness were not inferior to classification models that used only cortical thickness or amyloid deposition. In addition, based on timing of changes in cortical thinning and Aβ deposition such as Aβ deposition after cortical thinning; cortical thinning after Aβ deposition, or concurrent Aβ deposition and cortical thinning, we identified three types of relationships between cortical thinning and Aβ deposition: (1) Aβ-associated cortical thinning; (2) Aβ-independent cortical thinning; and (3) Aβ deposition only without cortical thinning. Taken together, these findings suggest that Aβ-weighted cortical thickness values can be used as an objective biomarker of structural changes caused by amyloid pathology in the brain. PMID

  18. Plasma based markers of [11C] PiB-PET brain amyloid burden.

    PubMed

    Kiddle, Steven John; Thambisetty, Madhav; Simmons, Andrew; Riddoch-Contreras, Joanna; Hye, Abdul; Westman, Eric; Pike, Ian; Ward, Malcolm; Johnston, Caroline; Lupton, Michelle Katharine; Lunnon, Katie; Soininen, Hilkka; Kloszewska, Iwona; Tsolaki, Magda; Vellas, Bruno; Mecocci, Patrizia; Lovestone, Simon; Newhouse, Stephen; Dobson, Richard

    2012-01-01

    Changes in brain amyloid burden have been shown to relate to Alzheimer's disease pathology, and are believed to precede the development of cognitive decline. There is thus a need for inexpensive and non-invasive screening methods that are able to accurately estimate brain amyloid burden as a marker of Alzheimer's disease. One potential method would involve using demographic information and measurements on plasma samples to establish biomarkers of brain amyloid burden; in this study data from the Alzheimer's Disease Neuroimaging Initiative was used to explore this possibility. Sixteen of the analytes on the Rules Based Medicine Human Discovery Multi-Analyte Profile 1.0 panel were found to associate with [(11)C]-PiB PET measurements. Some of these markers of brain amyloid burden were also found to associate with other AD related phenotypes. Thirteen of these markers of brain amyloid burden--c-peptide, fibrinogen, alpha-1-antitrypsin, pancreatic polypeptide, complement C3, vitronectin, cortisol, AXL receptor kinase, interleukin-3, interleukin-13, matrix metalloproteinase-9 total, apolipoprotein E and immunoglobulin E--were used along with co-variates in multiple linear regression, and were shown by cross-validation to explain >30% of the variance of brain amyloid burden. When a threshold was used to classify subjects as PiB positive, the regression model was found to predict actual PiB positive individuals with a sensitivity of 0.918 and a specificity of 0.545. The number of APOE [Symbol: see text] 4 alleles and plasma apolipoprotein E level were found to contribute most to this model, and the relationship between these variables and brain amyloid burden was explored. PMID:23028511

  19. ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing.

    PubMed

    Satoh, Kanayo; Abe-Dohmae, Sumiko; Yokoyama, Shinji; St George-Hyslop, Peter; Fraser, Paul E

    2015-10-01

    The ATP-binding cassette transporter A7 (ABCA7) has been identified as a susceptibility factor of late onset Alzheimer disease in genome-wide association studies. ABCA7 has been shown to mediate phagocytosis and affect membrane trafficking. The current study examined the impact of ABCA7 loss of function on amyloid precursor protein (APP) processing and generation of amyloid-β (Aβ). Suppression of endogenous ABCA7 in several different cell lines resulted in increased β-secretase cleavage and elevated Aβ. ABCA7 knock-out mice displayed an increased production of endogenous murine amyloid Aβ42 species. Crossing ABCA7-deficient animals to an APP transgenic model resulted in significant increases in the soluble Aβ as compared with mice expressing normal levels of ABCA7. Only modest changes in the amount of insoluble Aβ and amyloid plaque densities were observed once the amyloid pathology was well developed, whereas Aβ deposition was enhanced in younger animals. In vitro studies indicated a more rapid endocytosis of APP in ABCA7 knock-out cells that is mechanistically consistent with the increased Aβ production. These in vitro and in vivo findings indicate a direct role of ABCA7 in amyloid processing that may be associated with its primary biological function to regulate endocytic pathways. Several potential loss-of-function ABCA7 mutations and deletions linked to Alzheimer disease that in some instances have a greater impact than apoE allelic variants have recently been identified. A reduction in ABCA7 expression or loss of function would be predicted to increase amyloid production and that may be a contributing factor in the associated Alzheimer disease susceptibility. PMID:26260791

  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. 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

  2. Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor

    NASA Astrophysics Data System (ADS)

    Middleton, Chris T.; Marek, Peter; Cao, Ping; Chiu, Chi-Cheng; Singh, Sadanand; Woys, Ann Marie; de Pablo, Juan J.; Raleigh, Daniel P.; Zanni, Martin T.

    2012-05-01

    Amyloid formation has been implicated in the pathology of over 20 human diseases, but the rational design of amyloid inhibitors is hampered by a lack of structural information about amyloid-inhibitor complexes. We use isotope labelling and two-dimensional infrared spectroscopy to obtain a residue-specific structure for the complex of human amylin (the peptide responsible for islet amyloid formation in type 2 diabetes) with a known inhibitor (rat amylin). Based on its sequence, rat amylin should block formation of the C-terminal β-sheet, but at 8 h after mixing, rat amylin blocks the N-terminal β-sheet instead. At 24 h after mixing, rat amylin blocks neither β-sheet and forms its own β-sheet, most probably on the outside of the human fibrils. This is striking, because rat amylin is natively disordered and not previously known to form amyloid β-sheets. The results show that even seemingly intuitive inhibitors may function by unforeseen and complex structural processes.

  3. The amyloid fold of Gad m 1 epitopes governs IgE binding.

    PubMed

    Sánchez, Rosa; Martínez, Javier; Castro, Ana; Pedrosa, María; Quirce, Santiago; Rodríguez-Pérez, Rosa; Gasset, María

    2016-01-01

    Amyloids are polymeric structural states formed from locally or totally unfolded protein chains that permit surface reorganizations, stability enhancements and interaction properties that are absent in the precursor monomers. β-Parvalbumin, the major allergen in fish allergy, forms amyloids that are recognized by IgE in the patient sera, suggesting a yet unknown pathological role for these assemblies. We used Gad m 1 as the fish β-parvalbumin model and a combination of approaches, including peptide arrays, recombinant wt and mutant chains, biophysical characterizations, protease digestions, mass spectrometry, dot-blot and ELISA assays to gain insights into the role of amyloids in the IgE interaction. We found that Gad m 1 immunoreactive regions behave as sequence-dependent conformational epitopes that provide a 1000-fold increase in affinity and the structural repetitiveness required for optimal IgE binding and cross-linking upon folding into amyloids. These findings support the amyloid state as a key entity in type I food allergy. PMID:27597317

  4. The amyloid fold of Gad m 1 epitopes governs IgE binding

    PubMed Central

    Sánchez, Rosa; Martínez, Javier; Castro, Ana; Pedrosa, María; Quirce, Santiago; Rodríguez-Pérez, Rosa; Gasset, María

    2016-01-01

    Amyloids are polymeric structural states formed from locally or totally unfolded protein chains that permit surface reorganizations, stability enhancements and interaction properties that are absent in the precursor monomers. β-Parvalbumin, the major allergen in fish allergy, forms amyloids that are recognized by IgE in the patient sera, suggesting a yet unknown pathological role for these assemblies. We used Gad m 1 as the fish β-parvalbumin model and a combination of approaches, including peptide arrays, recombinant wt and mutant chains, biophysical characterizations, protease digestions, mass spectrometry, dot-blot and ELISA assays to gain insights into the role of amyloids in the IgE interaction. We found that Gad m 1 immunoreactive regions behave as sequence-dependent conformational epitopes that provide a 1000-fold increase in affinity and the structural repetitiveness required for optimal IgE binding and cross-linking upon folding into amyloids. These findings support the amyloid state as a key entity in type I food allergy. PMID:27597317

  5. Amyloid-modifying therapies for Alzheimer’s disease: therapeutic progress and its implications

    PubMed Central

    Milgram, Norton W.

    2010-01-01

    Alzheimer’s disease (AD) is the most prevalent form of dementia, affecting an estimated 4.8 million people in North America. For the past decade, the amyloid cascade hypothesis has dominated the field of AD research. This theory posits that the deposition of amyloid-beta protein (Aβ) in the brain is the key pathologic event in AD, which induces a series of neuropathological changes that manifest as cognitive decline and eventual dementia. Based on this theory, interventions that reduce Aβ burden in the brain would be expected to alleviate both the neuropathological changes and dementia, which characterize AD. Several diverse pharmacological strategies have been developed to accomplish this. These include inhibiting the formation of Aβ, preventing the aggregation of Aβ into insoluble aggregates, preventing the entry of Aβ into the brain from the periphery and enhancing the clearance of Aβ from the central nervous system. To date, no amyloid-modifying therapy has yet been successful in phase 3 clinical trials; however, several trials are currently underway. This article provides a review of the status of amyloid-modifying therapies and the implications for the amyloid cascade hypothesis. PMID:20640545

  6. Trifluoroethanol modulates α-synuclein amyloid-like aggregate formation, stability and dissolution.

    PubMed

    Di Carlo, Maria Giovanna; Vetri, Valeria; Buscarino, Gianpiero; Leone, Maurizio; Vestergaard, Bente; Foderà, Vito

    2016-09-01

    The conversion of proteins into amyloid fibrils and other amyloid-like aggregates is closely connected to the onset of a series of age-related pathologies. Upon changes in environmental conditions, amyloid-like aggregates may also undergo disassembly into oligomeric aggregates, the latter being recognized as key effectors in toxicity. This indicates new possible routes for in vivo accumulation of toxic species. In the light of the recognized implication of α-Synuclein (αSN) in Parkinson's disease, we present an experimental study on supramolecular assembly of αSN with a focus on stability and disassembly paths of such supramolecular aggregate species. Using spectroscopic techniques, two-photon microscopy, small-angle X-ray scattering and atomic force microscopy, we report evidences on how the stability of αSN amyloid-like aggregates can be altered by changing solution conditions. We show that amyloid-like aggregate formation can be induced at high temperature in the presence of trifluoroethanol (TFE). Moreover, sudden disassembly or further structural reorganisation toward higher hierarchical species can be induced by varying TFE concentration. Our results may contribute in deciphering fundamental mechanisms and interactions underlying supramolecular clustering/dissolution of αSN oligomers in cells. PMID:27372900

  7. Early Treatment Critical: Bexarotene Reduces Amyloid-Beta Burden In Silico

    PubMed Central

    Belfort, Georges; Isaacson, David

    2016-01-01

    Amyloid-beta peptides have long been implicated in the pathology of Alzheimer’s disease. Bexarotene, a drug approved by the U.S. Food and Drug Administration for treating a class of non-Hodgkin’s lymphoma, has been reported to facilitate the removal of amyloid-beta. We have developed a mathematical model to explore the efficacy of bexarotene treatment in reducing amyloid-beta load, and simulate amyloid-beta production throughout the lifespan of diseased mice. Both aspects of the model are based on and consistent with previous experimental results. Beyond what is known empirically, our model shows that low dosages of bexarotene are unable to reverse symptoms in diseased mice, but dosages at and above an age-dependent critical concentration can recover healthy brain cells. Further, early treatment was shown to have significantly improved efficacy versus treatment in older mice. Relevance with respect to bexarotene-based amyloid-beta-clearance mechanism and direct treatment for Alzheimer’s disease is emphasized. PMID:27073866

  8. Methionine oxidation of amyloid peptides by peroxovanadium complexes: inhibition of fibril formation through a distinct mechanism.

    PubMed

    He, Lei; Wang, Xuesong; Zhu, Dengsen; Zhao, Cong; Du, Weihong

    2015-12-01

    Fibril formation of amyloid peptides is linked to a number of pathological states. The prion protein (PrP) and amyloid-β (Aβ) are two remarkable examples that are correlated with prion disorders and Alzheimer's disease, respectively. Metal complexes, such as those formed by platinum and ruthenium compounds, can act as inhibitors against peptide aggregation primarily through metal coordination. This study revealed the inhibitory effect of two peroxovanadium complexes, (NH4)[VO(O2)2(bipy)]·4H2O (1) and (NH4)[VO(O2)2(phen)]·2H2O (2), on amyloid fibril formation of PrP106-126 and Aβ1-42via site-specific oxidation of methionine residues, besides direct binding of the complexes with the peptides. Complexes 1 and 2 showed higher anti-amyloidogenic activity on PrP106-126 aggregation than on Aβ1-42, though their regulation on the cytotoxicity induced by the two peptides could not be differentiated. The action efficacy may be attributed to the different molecular structures of the vanadium complex and the peptide sequence. Results reflected that methionine oxidation may be a crucial action mode in inhibiting amyloid fibril formation. This study offers a possible application value for peroxovanadium complexes against amyloid proteins. PMID:26444976

  9. A look into amyloid formation by transthyretin: aggregation pathway and a novel kinetic model.

    PubMed

    Faria, Tiago Q; Almeida, Zaida L; Cruz, Pedro F; Jesus, Catarina S H; Castanheira, Pedro; Brito, Rui M M

    2015-03-21

    The aggregation of proteins into insoluble amyloid fibrils is the hallmark of many, highly debilitating, human pathologies such as Alzheimer's or Parkinson's disease. Transthyretin (TTR) is a homotetrameric protein implicated in several amyloidoses like Senile Systemic Amyloidosis (SSA), Familial Amyloid Polyneuropathy (FAP), Familial Amyloid Cardiomyopathy (FAC), and the rare Central Nervous System selective Amyloidosis (CNSA). In this work, we have investigated the kinetics of TTR aggregation into amyloid fibrils produced by the addition of NaCl to acid-unfolded TTR monomers and we propose a mathematically simple kinetic mechanism to analyse the aggregation kinetics of TTR. We have conducted circular dichroism, intrinsic tryptophan fluorescence and thioflavin-T emission experiments to follow the conformational changes accompanying amyloid formation at different TTR concentrations. Kinetic traces were adjusted to a two-step model with the first step being second-order and the second being unimolecular. The molecular species present in the pathway of TTR oligomerization were characterized by size exclusion chromatography coupled to multi-angle light scattering and by transmission electron microscopy. The results show the transient accumulation of oligomers composed of 6 to 10 monomers in agreement with reports suggesting that these oligomers may be the causative agent of cell toxicity. The results obtained may prove to be useful in understanding the mode of action of different compounds in preventing fibril formation and, therefore, in designing new drugs against TTR amyloidosis. PMID:25694367

  10. The polyphenol Oleuropein aglycone hinders the growth of toxic transthyretin amyloid assemblies.

    PubMed

    Leri, Manuela; Nosi, Daniele; Natalello, Antonino; Porcari, Riccardo; Ramazzotti, Matteo; Chiti, Fabrizio; Bellotti, Vittorio; Doglia, Silvia Maria; Stefani, Massimo; Bucciantini, Monica

    2016-04-01

    Transthyretin (TTR) is involved in a subset of familial or sporadic amyloid diseases including senile systemic amyloidosis (SSA), familial amyloid polyneuropathy and cardiomyopathy (FAP/FAC) for which no effective therapy has been found yet. These conditions are characterized by extracellular deposits primarily found in the heart parenchyma and in peripheral nerves whose main component are amyloid fibrils, presently considered the main culprits of cell sufferance. The latter are polymeric assemblies grown from misfolded TTR, either wt or carrying one out of many identified mutations. The recent introduction in the clinical practice of synthetic TTR-stabilizing molecules that reduce protein aggregation provides the rationale to search natural effective molecules able to interfere with TTR amyloid aggregation by hindering the appearance of toxic species or by favoring the growth of harmless aggregates. Here we carried out an in depth biophysical and morphological study on the molecular features of the aggregation of wt- and L55P-TTR involved in SSA or FAP/FAC, respectively, and on the interference with fibril aggregation, stability and toxicity to cardiac HL-1 cells to demonstrate the ability of Oleuropein aglycone (OleA), the main phenolic component of the extra virgin olive oil. We describe the molecular basis of such interference and the resulting reduction of TTR amyloid aggregate cytotoxicity. Our data offer the possibility to validate and optimize the use of OleA or its molecular scaffold to rationally design promising drugs against TTR-related pathologies that could enter a clinical experimental phase. PMID:27012632

  11. Prion Protein Prolines 102 and 105 and the Surrounding Lysine Cluster Impede Amyloid Formation.

    PubMed

    Kraus, Allison; Anson, Kelsie J; Raymond, Lynne D; Martens, Craig; Groveman, Bradley R; Dorward, David W; Caughey, Byron

    2015-08-28

    Human prion diseases can have acquired, sporadic, or genetic origins, each of which results in the conversion of prion protein (PrP) to transmissible, pathological forms. The genetic prion disease Gerstmann-Straussler-Scheinker syndrome can arise from point mutations of prolines 102 or 105. However, the structural effects of these two prolines, and mutations thereof, on PrP misfolding are not well understood. Here, we provide evidence that individual mutations of Pro-102 or Pro-105 to noncyclic aliphatic residues such as the Gerstmann-Straussler-Scheinker-linked leucines can promote the in vitro formation of PrP amyloid with extended protease-resistant cores reminiscent of infectious prions. This effect was enhanced by additional charge-neutralizing mutations of four nearby lysine residues comprising the so-called central lysine cluster. Substitution of these proline and lysine residues accelerated PrP conversion such that spontaneous amyloid formation was no longer slower than scrapie-seeded amyloid formation. Thus, Pro-102 and Pro-105, as well as the lysines in the central lysine cluster, impede amyloid formation by PrP, implicating these residues as key structural modulators in the conversion of PrP to disease-associated types of amyloid. PMID:26175152

  12. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar Aβ phagocytosis

    PubMed Central

    Liu, Zhiqiang; Condello, Carlo; Schain, Aaron; Harb, Roa; Grutzendler, Jaime

    2010-01-01

    In Alzheimer’s disease (AD), amyloid-β (Aβ) deposits are frequently surrounded by activated microglia but the precise role of these cells in disease progression remains unclear. The chemokine receptor CX3CR1 is selectively expressed in microglia and is thought to modulate their activity. To study the specific effects of microglia activation on amyloid pathology in vivo, we crossbred mice lacking CX3CR1 with the Alzheimer’s mouse model CRND8. Surprisingly, we found that CX3CR1 deficient mice had lower brain levels of Aβ40 and Aβ42 and reduced amyloid deposits. Quantification of Aβ within microglia and time-lapse two photon microscopy in live mice revealed that these cells were highly effective at the uptake of protofibrillar amyloid but were incapable of phagocytosis of fibrillar congophilic Aβ. CX3CR1 deletion was associated with increased phagocytic ability which led to greater amyloid content within microglial phagolysosomes. Furthermore, CX3CR1 deficient mice had an increased number of microglia around individual plaques due to higher proliferative rates, which likely contributed to an overall greater phagocytic capacity. CX3CR1 deletion did not affect the degree of neuronal or synaptic damage around plaques despite increased microglia density. Our results demonstrate that microglia can regulate brain Aβ levels and plaque deposition via selective protofibrillar Aβ phagocytosis. Modulation of microglia activity and proliferation by CX3CR1 signaling may represent a therapeutic strategy for AD. PMID:21159979

  13. [Amyloid deposition in chronic joint disease].

    PubMed

    Saitou, H

    1994-07-01

    As a screening procedure for the detection of amyloidosis secondary to rheumatoid arthritis, abdominal subcutaneous fat tissues were aspirated, and were examined after Congo red staining by polarized microscopy. Positive amyloid deposits were found in 7.1 percent of the rheumatoid patients, and the amyloid in the subcutaneous fat was determined to be AA type by permanganate oxidation. The occurrence of amyloid deposition was significantly correlated with the duration of the articular symptoms, the progression of the class, and also with proteinuria. Additionally the joint capsules, including the synovium and synovial fluid sediment, from patients with rheumatoid arthritis and osteoarthritis were examined for amyloid deposition. Deposits of amyloid in the hip and knee joints were found more frequently in those with rheumatoid arthritis than in those with osteoarthritis. In osteoarthritis, the frequency of amyloid deposition tended to increase with advancing age. However these amyloid deposits in the joint structure were discovered to be resistant to permanganate oxidation. Therefore it was suspected that these amyloid deposits were of a type different from AA amyloid. PMID:8071579

  14. Experimental microembolism induces localized neuritic pathology in guinea pig cerebrum

    PubMed Central

    Li, Jian-Ming; Cai, Yan; Liu, Fei; Yang, La; Hu, Xia; Patrylo, Peter R.; Cai, Huaibin; Luo, Xue-Gang; Xiao, Dong; Yan, Xiao-Xin

    2015-01-01

    Microbleeds are a common finding in aged human brains. In Alzheimer's disease (AD), neuritic plaques composed of β-amyloid (Aβ) deposits and dystrophic neurites occur frequently around cerebral vasculature, raising a compelling question as to whether, and if so, how, microvascular abnormality and amyloid/neuritic pathology might be causally related. Here we used a guinea pig model of cerebral microembolism to explore a potential inductive effect of vascular injury on neuritic and amyloid pathogenesis. Brains were examined 7-30 days after experimental microvascular embolization occupying ~0.5% of total cortical area. Compared to sham-operated controls, glial fibrillary acidic protein immunoreactivity was increased in the embolized cerebrum, evidently around intracortical vasculature. Swollen/sprouting neurites exhibiting increased reactivity of nicotinamide adenine dinucleotide phosphate diaphorase, parvalbumin, vesicular glutamate transporter 1 and choline acetyltransferase appeared locally in the embolized brains in proximity to intracortical vasculature. The embolization-induced swollen/sprouting neurites were also robustly immunoreactive for β-amyloid precursor protein and β-secretase-1, the substrate and initiating enzyme for Aβ genesis. These experimental data suggest that microvascular injury can induce multisystem neuritic pathology associated with an enhanced amyloidogenic potential in wild-type mammalian brain. PMID:25871402

  15. Experimental microembolism induces localized neuritic pathology in guinea pig cerebrum.

    PubMed

    Li, Jian-Ming; Cai, Yan; Liu, Fei; Yang, La; Hu, Xia; Patrylo, Peter R; Cai, Huaibin; Luo, Xue-Gang; Xiao, Dong; Yan, Xiao-Xin

    2015-05-10

    Microbleeds are a common finding in aged human brains. In Alzheimer's disease (AD), neuritic plaques composed of β-amyloid (Aβ) deposits and dystrophic neurites occur frequently around cerebral vasculature, raising a compelling question as to whether, and if so, how, microvascular abnormality and amyloid/neuritic pathology might be causally related. Here we used a guinea pig model of cerebral microembolism to explore a potential inductive effect of vascular injury on neuritic and amyloid pathogenesis. Brains were examined 7-30 days after experimental microvascular embolization occupying ~0.5% of total cortical area. Compared to sham-operated controls, glial fibrillary acidic protein immunoreactivity was increased in the embolized cerebrum, evidently around intracortical vasculature. Swollen/sprouting neurites exhibiting increased reactivity of nicotinamide adenine dinucleotide phosphate diaphorase, parvalbumin, vesicular glutamate transporter 1 and choline acetyltransferase appeared locally in the embolized brains in proximity to intracortical vasculature. The embolization-induced swollen/sprouting neurites were also robustly immunoreactive for β-amyloid precursor protein and β-secretase-1, the substrate and initiating enzyme for Aβ genesis. These experimental data suggest that microvascular injury can induce multisystem neuritic pathology associated with an enhanced amyloidogenic potential in wild-type mammalian brain. PMID:25871402

  16. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease.

    PubMed

    Kumar, Deepak Kumar Vijaya; Choi, Se Hoon; Washicosky, Kevin J; Eimer, William A; Tucker, Stephanie; Ghofrani, Jessica; Lefkowitz, Aaron; McColl, Gawain; Goldstein, Lee E; Tanzi, Rudolph E; Moir, Robert D

    2016-05-25

    The amyloid-β peptide (Aβ) is a key protein in Alzheimer's disease (AD) pathology. We previously reported in vitro evidence suggesting that Aβ is an antimicrobial peptide. We present in vivo data showing that Aβ expression protects against fungal and bacterial infections in mouse, nematode, and cell culture models of AD. We show that Aβ oligomerization, a behavior traditionally viewed as intrinsically pathological, may be necessary for the antimicrobial activities of the peptide. Collectively, our data are consistent with a model in which soluble Aβ oligomers first bind to microbial cell wall carbohydrates via a heparin-binding domain. Developing protofibrils inhibited pathogen adhesion to host cells. Propagating β-amyloid fibrils mediate agglutination and eventual entrapment of unatttached microbes. Consistent with our model, Salmonella Typhimurium bacterial infection of the brains of transgenic 5XFAD mice resulted in rapid seeding and accelerated β-amyloid deposition, which closely colocalized with the invading bacteria. Our findings raise the intriguing possibility that β-amyloid may play a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis. These data suggest a dual protective/damaging role for Aβ, as has been described for other antimicrobial peptides. PMID:27225182

  17. Endoplasmic Reticulum Quality Control and Systemic Amyloid Disease: Impacting Protein Stability from the Inside Out

    PubMed Central

    Chen, John J.; Genereux, Joseph C.; Wiseman, R. Luke

    2015-01-01

    The endoplasmic reticulum (ER) is responsible for regulating proteome integrity throughout the secretory pathway. The ER protects downstream secretory environments such as the extracellular space by partitioning proteins between ER protein folding, trafficking and degradation pathways in a process called ER quality control. In this process, ER quality control factors identify misfolded, aggregation-prone protein conformations and direct them towards ER protein folding or degradation, reducing their secretion to the extracellular space where they could further misfold or aggregate into proteotoxic conformations. Despite the general efficiency of ER quality control, many human diseases, such as the systemic amyloidoses, involve aggregation of destabilized, aggregation-prone proteins in the extracellular space. A common feature for all systemic amyloid diseases is the ability for amyloidogenic proteins to evade ER quality control and be efficiently secreted. The efficient secretion of these amyloidogenic proteins increases their serum concentrations available for the distal proteotoxic aggregation characteristic of these diseases. This indicates that ER quality control, and the regulation thereof, is a critical determinant in defining the onset and pathology of systemic amyloid diseases. Here, we discuss the pathologic and potential therapeutic relationship between ER quality control, protein secretion and distal deposition of amyloidogenic proteins involved in systemic amyloid diseases. Furthermore, we present evidence that the Unfolded Protein Response, the stress-responsive signaling pathway that regulates ER quality control, is involved in the pathogenesis of systemic amyloid diseases and represents a promising emerging therapeutic target to intervene in this class of human disease. PMID:26018985

  18. Phosphorylated human tau associates with mouse prion protein amyloid in scrapie-infected mice but does not increase progression of clinical disease.

    PubMed

    Race, Brent; Phillips, Katie; Kraus, Allison; Chesebro, Bruce

    2016-07-01

    Tauopathies are a family of neurodegenerative diseases in which fibrils of human hyperphosphorylated tau (P-tau) are believed to cause neuropathology. In Alzheimer disease, P-tau associates with A-beta amyloid and contributes to disease pathogenesis. In familial human prion diseases and variant CJD, P-tau often co-associates with prion protein amyloid, and might also accelerate disease progression. To test this latter possibility, here we compared progression of amyloid prion disease in vivo after scrapie infection of mice with and without expression of human tau. The mice used expressed both anchorless prion protein (PrP) and membrane-anchored PrP, that generate disease associated amyloid and non-amyloid PrP (PrPSc) after scrapie infection. Human P-tau induced by scrapie infection was only rarely associated with non-amyloid PrPSc, but abundant human P-tau was detected at extracellular, perivascular and axonal deposits associated with amyloid PrPSc. This pathology was quite similar to that seen in familial prion diseases. However, association of human and mouse P-tau with amyloid PrPSc did not diminish survival time following prion infection in these mice. By analogy, human P-tau may not affect prion disease progression in humans. Alternatively, these results might be due to other factors, including rapidity of disease, blocking effects by mouse tau, or low toxicity of human P-tau in this model. PMID:27463540

  19. Histological Staining of Amyloid and Pre-Amyloid Peptides and Proteins in Mouse Tissue

    PubMed Central

    Rajamohamedsait, Hameetha B.; Sigurdsson, Einar M.

    2013-01-01

    The increased availability of transgenic mouse models for studying human diseases has shifted the focus of many laboratories from in vitro to in vivo assays. Herein, methods are described to allow investigators to obtain well preserved mouse tissue to be stained with the standard histological dyes for amyloid, Congo Red and Thioflavin S. These sections can as well be used for immunohistological procedures that allow detection of tissue amyloid and pre-amyloid, such as those composed of the amyloid-β peptide, the tau protein, and the islet amyloid polypeptide. PMID:22528106

  20. Biomarkers in Amyloid-β Immunotherapy Trials in Alzheimer's Disease

    PubMed Central

    Blennow, Kaj; Hampel, Harald; Zetterberg, Henrik

    2014-01-01

    Drug candidates directed against amyloid-β (Aβ) are mainstream in Alzheimer's disease (AD) drug development. Active and passive Aβ immunotherapy is the principle that has come furthest, both in number and in stage of clinical trials. However, an increasing number of reports on major difficulties in identifying any clinical benefit in phase II–III clinical trials on this type of anti-Aβ drug candidates have caused concern among researchers, pharmaceutical companies, and other stakeholders. This has provided critics of the amyloid cascade hypothesis with fire for their arguments that Aβ deposition may merely be a bystander, and not the cause, of the disease or that the amyloid hypothesis may only be valid for the familial form of AD. On the other hand, most researchers argue that it is the trial design that will need refinement to allow for identifying a positive clinical effect of anti-Aβ drugs. A consensus in the field is that future trials need to be performed in an earlier stage of the disease and that biomarkers are essential to guide and facilitate drug development. In this context, it is reassuring that, in contrast to most brain disorders, research advances in the AD field have led to both imaging (magnetic resonance imaging (MRI) and PET) and cerebrospinal fluid (CSF) biomarkers for the central pathogenic processes of the disease. AD biomarkers will have a central role in future clinical trials to enable early diagnosis, and Aβ biomarkers (CSF Aβ42 and amyloid PET) may be essential to allow for testing a drug on patients with evidence of brain Aβ pathology. Pharmacodynamic Aβ and amyloid precursor protein biomarkers will be of use to verify target engagement of a drug candidate in humans, thereby bridging the gap between mechanistic data from transgenic AD models (that may not be relevant to the neuropathology of human AD) and large and expensive phase III trials. Last, downstream biomarker evidence (CSF tau proteins and MRI volumetry) that the

  1. Common Variants in PLD3 and Correlation to Amyloid-Related Phenotypes in Alzheimer's Disease.

    PubMed

    Wang, Chong; Tan, Lan; Wang, Hui-Fu; Yu, Wan-Jiang; Liu, Ying; Jiang, Teng; Tan, Meng-Shan; Hao, Xiao-Ke; Zhang, Dao-Qiang; Yu, Jin-Tai

    2015-01-01

    The phospholipase D3 (PLD3) gene has shown association with Alzheimer's disease (AD). However, the role of PLD3 common variants in amyloid-β (Aβ) pathology remains unclear. We examined the association of thirteen common single nucleotide polymorphisms (SNPs) with cerebrospinal fluid (CSF) Aβ(1- 42) levels and florbetapir retention on florbetapir 18F amyloid positron emission tomography (AV45-PET) in a large population. We found that one SNP (rs11667768) was significantly associated with CSF Aβ(1- 42) levels in the normal cognition group. We did not observe an association of any SNP with florbetapir retention. Our study predicted the potential role of PLD3 variants in Aβ pathology. PMID:26402410

  2. Focally Elevated Creatine Detected in Amyloid Precursor Protein (APP) Transgenic Mice and Alzheimer Disease Brain Tissue

    SciTech Connect

    Gallant,M.; Rak, M.; Szeghalmi, A.; Del Bigio, M.; Westaway, D.; Yang, J.; Julian, R.; Gough, K.

    2006-01-01

    The creatine/phosphocreatine system, regulated by creatine kinase, plays an important role in maintaining energy balance in the brain. Energy metabolism and the function of creatine kinase are known to be affected in Alzheimer diseased brain and in cells exposed to the {beta}-amyloid peptide. We used infrared microspectroscopy to examine hippocampal, cortical, and caudal tissue from 21-89-week-old transgenic mice expressing doubly mutant (K670N/M671L and V717F) amyloid precursor protein and displaying robust pathology from an early age. Microcrystalline deposits of creatine, suggestive of perturbed energetic status, were detected by infrared microspectroscopy in all animals with advanced plaque pathology. Relatively large creatine deposits were also found in hippocampal sections from post-mortem Alzheimer diseased human brain, compared with hippocampus from non-demented brain. We therefore speculate that this molecule is a marker of the disease process.

  3. The amyloid in familial amyloid cardiomyopathy of Danish origin is related to pre-albumin.

    PubMed Central

    Husby, G; Ranløv, P J; Sletten, K; Marhaug, G

    1985-01-01

    Amyloid obtained from the myocardium of a patient (Han) with familial amyloid cardiomyopathy of Danish origin was studied. Gel filtration and electrophoresis of purified and denatured amyloid fibrils Han revealed various fractions ranging in mol. wt from 40,000 to 8,000 daltons. Amyloid Han and fractions reacted with an antiserum against amyloid Han showing a reaction of identity with each other; partial identity between Han and human pre-albumin was observed, while no reaction was seen with AA or AL proteins. Cardiac tissue sections from Han showed reactivity with antisera to amyloid Han, pre-albumin and protein AP, but not with anti-AA or anti-AL in indirect immunofluorescence. Amino acid composition and sequence studies of a protein fraction of amyloid Han with mol. wt 15,000 daltons confirmed the structural relationship with pre-albumin. Images Fig. 2 Fig. 3 PMID:3924450

  4. The amyloid in familial amyloid cardiomyopathy of Danish origin is related to pre-albumin.

    PubMed

    Husby, G; Ranløv, P J; Sletten, K; Marhaug, G

    1985-04-01

    Amyloid obtained from the myocardium of a patient (Han) with familial amyloid cardiomyopathy of Danish origin was studied. Gel filtration and electrophoresis of purified and denatured amyloid fibrils Han revealed various fractions ranging in mol. wt from 40,000 to 8,000 daltons. Amyloid Han and fractions reacted with an antiserum against amyloid Han showing a reaction of identity with each other; partial identity between Han and human pre-albumin was observed, while no reaction was seen with AA or AL proteins. Cardiac tissue sections from Han showed reactivity with antisera to amyloid Han, pre-albumin and protein AP, but not with anti-AA or anti-AL in indirect immunofluorescence. Amino acid composition and sequence studies of a protein fraction of amyloid Han with mol. wt 15,000 daltons confirmed the structural relationship with pre-albumin. PMID:3924450

  5. The loss of c-Jun N-terminal protein kinase activity prevents the amyloidogenic cleavage of amyloid precursor protein and the formation of amyloid plaques in vivo.

    PubMed

    Mazzitelli, Sonia; Xu, Ping; Ferrer, Isidre; Davis, Roger J; Tournier, Cathy

    2011-11-23

    Phosphorylation plays a central role in the dynamic regulation of the processing of the amyloid precursor protein (APP) and the production of amyloid-β (Aβ), one of the clinically most important factors that determine the onset of Alzheimer's disease (AD). This has led to the hypothesis that aberrant Aβ production associated with AD results from regulatory defects in signal transduction. However, conflicting findings have raised a debate over the identity of the signaling pathway that controls APP metabolism. Here, we demonstrate that activation of the c-Jun N-terminal protein kinase (JNK) is essential for mediating the apoptotic response of neurons to Aβ. Furthermore, we discovered that the functional loss of JNK signaling in neurons significantly decreased the number of amyloid plaques present in the brain of mice carrying familial AD-linked mutant genes. This correlated with a reduction in Aβ production. Biochemical analyses indicate that the phosphorylation of APP at threonine 668 by JNK is required for γ-mediated cleavage of the C-terminal fragment of APP produced by β-secretase. Overall, this study provides genetic evidence that JNK signaling is required for the formation of amyloid plaques in vivo. Therefore, inhibition of increased JNK activity associated with aging or with a pathological condition constitutes a potential strategy for the treatment of AD. PMID:22114267

  6. Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity

    PubMed Central

    Wiste, Heather J.; Weigand, Stephen D.; Knopman, David S.; Lowe, Val; Vemuri, Prashanthi; Mielke, Michelle M.; Jones, David T.; Senjem, Matthew L.; Gunter, Jeffrey L.; Gregg, Brian E.; Pankratz, Vernon S.; Petersen, Ronald C.

    2013-01-01

    Objective: To estimate the incidence of and to characterize cognitive and imaging findings associated with incident amyloid PET positivity. Methods: Cognitively normal (CN) participants in the Mayo Clinic Study of Aging who had 2 or more serial imaging assessments, which included amyloid PET, FDG-PET, and MRI at each time point, were eligible for analysis (n = 207). Twelve subjects with Alzheimer disease dementia were included for comparison. Results: Of the 123 CN participants who were amyloid-negative at baseline, 26 met criteria for incident amyloid PET positivity. Compared to the 69 subjects who remained stable amyloid-negative, on average these 26 did not differ on any imaging, demographic, or cognitive variables except amyloid PET (by definition) and task-free functional connectivity, which at baseline was greater in the incident amyloid-positive group. Eleven of the 26 incident amyloid-positive subjects had abnormal hippocampal volume, FDG-PET, or both at baseline. Conclusions: The incidence of amyloid PET positivity is approximately 13% per year among CN participants over age 70 sampled from a population-based cohort. In 15/26 (58%), incident amyloid positivity occurred prior to abnormalities in FDG-PET and hippocampal volume. However, 11/26 (42%) incident amyloid-positive subjects had evidence of neurodegeneration prior to incident amyloid positivity. These 11 could be subjects with combinations of preexisting non-Alzheimer pathophysiologies and tau-mediated neurodegeneration who newly entered the amyloid pathway. Our findings suggest that both “amyloid-first” and “neurodegeneration-first” biomarker profile pathways to preclinical AD exist. PMID:24132377

  7. The Structure and Dynamics of Higher-Order Assemblies: Amyloids, Signalosomes, and Granules.

    PubMed

    Wu, Hao; Fuxreiter, Monika

    2016-05-19

    We here attempt to achieve an integrated understanding of the structure and dynamics of a number of higher-order assemblies, including amyloids, various kinds of signalosomes, and cellular granules. We propose that the synergy between folded domains, linear motifs, and intrinsically disordered regions regulates the formation and intrinsic fuzziness of all higher-order assemblies, creating a structural and dynamic continuum. We describe how such regulatory mechanisms could be influenced under pathological conditions. PMID:27203110

  8. Curriculum Guidelines for Pathology and Oral Pathology.

    ERIC Educational Resources Information Center

    Journal of Dental Education, 1985

    1985-01-01

    Guidelines for dental school pathology courses describe the interrelationships of general, systemic, and oral pathology; primary educational goals; prerequisites; a core curriculum outline and behavioral objectives for each type of pathology. Notes on sequencing, faculty, facilities, and occupational hazards are included. (MSE)

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

    NASA Astrophysics Data System (ADS)

    Nussinov, Ruth

    2012-02-01

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

  10. Structural and mechanistic basis behind the inhibitory interaction of PcTS on α-synuclein amyloid fibril formation

    PubMed Central

    Lamberto, Gonzalo R.; Binolfi, Andrés; Orcellet, María L.; Bertoncini, Carlos W.; Zweckstetter, Markus; Griesinger, Christian; Fernández, Claudio O.

    2009-01-01

    The identification of aggregation inhibitors and the investigation of their mechanism of action are fundamental in the quest to mitigate the pathological consequences of amyloid formation. Here, characterization of the structural and mechanistic basis for the antiamyloidogenic effect of phthalocyanine tetrasulfonate (PcTS) on α-synuclein (AS) allowed us to demonstrate that specific aromatic interactions are central for ligand-mediated inhibition of amyloid formation. We provide evidence indicating that the mechanism behind the antiamyloidogenic effect of PcTS is correlated with the trapping of prefibrillar AS species during the early stages of the assembly process. By using NMR spectroscopy, we have located the primary binding region for PcTS to a specific site in the N terminus of AS, involving the amino acid Tyr-39 as the anchoring residue. Moreover, the residue-specific structural characterization of the AS-PcTS complex provided the basis for the rational design of nonamyloidogenic species of AS, highlighting the role of aromatic interactions in driving AS amyloid assembly. A comparative analysis with other proteins involved in neurodegenerative disorders reveals that aromatic recognition interfaces might constitute a key structural element to target their aggregation pathways. These findings emphasize the use of aggregation inhibitors as molecular probes to assess structural and toxic mechanisms related to amyloid formation and the potential of small molecules as therapeutics for amyloid-related pathologies. PMID:19948969

  11. 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

  12. The Luminescent Oligothiophene p-FTAA Converts Toxic Aβ1-42 Species into Nontoxic Amyloid Fibers with Altered Properties.

    PubMed

    Civitelli, Livia; Sandin, Linnea; Nelson, Erin; Khattak, Sikander Iqbal; Brorsson, Ann-Christin; Kågedal, Katarina

    2016-04-22

    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

  13. 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

  14. Amyloid Beta1–42 and the Phoshorylated Tau Threonine 231 in Brains of Aged Cynomolgus Monkeys (Macaca fascicularis)

    PubMed Central

    Darusman, Huda Shalahudin; Gjedde, Albert; Sajuthi, Dondin; Schapiro, Steven J.; Kalliokoski, Otto; Kristianingrum, Yuli P.; Handaryani, Ekowati; Hau, Jann

    2014-01-01

    Pathological hallmarks indicative of Alzheimer’s disease (AD), which are the plaques of amyloid beta1–42 and neurofibrillary tangles, were found in brain of aged cynomolgus monkey. The aim of this study was to investigate if aged monkeys exhibiting spatial memory impairment and levels of biomarkers indicative of AD, had brain lesions similar to human patients suffering from senile dementia. Generating immunohistochemistry technique to biomarkers of amyloid beta1–42 and the phosphorylated tau 231, our study assessed the amyloidopathy, such as indicative to the senile plaques and cerebral amyloid angiopathy, and the tauopathy, to possible neurofibrillary tangles. Six aged monkeys were selected based on their spatial memory performance and profile of biomarkers of AD, divided equally to affected aged subject – with Memory-affected and low amyloid level, and aged with higher performance in memory and amyloid, as the age-matched subjects. Using immunohistochemistry, plaques of amyloid beta1–42 were observed in two out of three brains of aged subjects with memory impairment and biomarkers indicative of AD. The cerebral amyloid angiopathy was observed in both aged monkey groups, and unlike in the human, the amyloids were found to deposit in the small veins and capillaries. In one of the affected individuals, phosphorylated tau was positively stained intracellularly of the neurons, indicating a possibility of an early stage of the formation of tangles. These findings add to the body of evidence of the utility of the aged cynomolgus monkeys as a spontaneous model for Alzheimer-related disease. PMID:25426069

  15. Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice.

    PubMed

    Yan, Ping; Bero, Adam W; Cirrito, John R; Xiao, Qingli; Hu, Xiaoyan; Wang, Yan; Gonzales, Ernesto; Holtzman, David M; Lee, Jin-Moo

    2009-08-26

    Amyloid plaques are primarily composed of extracellular aggregates of amyloid-beta (Abeta) peptide and are a pathological signature of Alzheimer's disease. However, the factors that influence the dynamics of amyloid plaque formation and growth in vivo are largely unknown. Using serial intravital multiphoton microscopy through a thinned-skull cranial window in APP/PS1 transgenic mice, we found that amyloid plaques appear and grow over a period of weeks before reaching a mature size. Growth was more prominent early after initial plaque formation: plaques grew faster in 6-month-old compared with 10-month-old mice. Plaque growth rate was also size-related, as smaller plaques exhibited more rapid growth relative to larger plaques. Alterations in interstitial Abeta concentrations were associated with changes in plaque growth. Parallel studies using multiphoton microscopy and in vivo microdialysis revealed that pharmacological reduction of soluble extracellular Abeta by as little as 20-25% was associated with a dramatic decrease in plaque formation and growth. Furthermore, this small reduction in Abeta synthesis was sufficient to reduce amyloid plaque load in 6-month-old but not 10-month-old mice, suggesting that treatment early in disease pathogenesis may be more effective than later treatment. In contrast to thinned-skull windows, no significant plaque growth was observed under open-skull windows, which demonstrated extensive microglial and astrocytic activation. Together, these findings indicate that individual amyloid plaque growth in vivo occurs over a period of weeks and may be influenced by interstitial Abeta concentration as well as reactive gliosis. PMID:19710322

  16. Early cortical thickness changes predict β-amyloid deposition in a mouse model of Alzheimer's disease.

    PubMed

    Grand'maison, Marilyn; Zehntner, Simone P; Ho, Ming-Kai; Hébert, François; Wood, Andrew; Carbonell, Felix; Zijdenbos, Alex P; Hamel, Edith; Bedell, Barry J

    2013-06-01

    Magnetic resonance imaging (MRI) studies have identified aberrant cortical structure in Alzheimer's disease (AD). The association between MRI-derived cortical morphometry measures and β-amyloid, however, remains poorly understood. In this study, we explored the potential relationship between early alterations in cortical thickness and later stage β-amyloid deposition, using a novel approach, in a transgenic AD mouse model. We acquired longitudinal anatomical MRI scans from mutant amyloid precursor protein (APP) transgenic mice and age-matched wild-type mice at 1 and 3.5months-of-age, and employed fully-automated image processing methods to derive objective, quantitative measures of cortical thickness on a region-of-interest basis. We also generated 3D quantitative immunohistochemistry (qIHC) volumes of deposited β-amyloid burden from 18month-old transgenic mice using an automated, production-level process. These studies revealed thinner cortex in most regions in the 1month-old transgenic mice relative to age-matched wild-types, with the exception of the frontal, perirhinal/entorhinal, posterior cingulate, and retrosplenial cortical regions. Between 1 and 3.5months-of-age, the transgenic mice demonstrated stable or increasing cortical thickness, while the wild-type mice showed cortical thinning. Based on data from co-registered 3D MRI and qIHC volumes, we identified an association between abnormal, early, regional cortical thickness change over 2.5months and later β-amyloid deposition. These observations suggest that the spatio-temporal pattern of early (pre-plaque) alterations in cerebral cortical structure is indicative of regional predisposition to later β-amyloid pathology in a transgenic AD mouse model. PMID:23454197

  17. Amyloid Load in Nondemented Brains Correlates with APOE e4

    PubMed Central

    Caselli, Richard J.; Walker, Douglas; Sue, Lucia; Sabbagh, Marwan; Beach, Thomas

    2010-01-01

    179 cognitively healthy adults enrolled in the Sun Health Brain Donation program between 7/91 and 12/07 were at least 60 years old and nondemented at the time of death (21 had developed mild cognitive impairment [MCI]). Amyloid plaque density, congophilic amyloid angiopathy (CAA), and neurofibrillary tangle (NFT) density scores were based on CERAD criteria and compared in apolipoprotein E (APOE) e4 carriers (n=42) and noncarriers (NC) (n=137). Mean age (83.4+/−.6), gender (45% women), interval between death and brain harvest (3.1+/−2.4 hours), and brain weight (1200+/−119 grams) did not differ between e4 carriers (n=42) and NC. Total plaque density was higher in e4 carriers than NC (6.8+/−4.9 vs 4.3+/−4.4, p=.002), and this was true in each of 5 subregions examined. Total CAA (p=.002) and all subregion CAA burden was also higher in e4 carriers. Total neuritic plaque density (1.2+/−1.0 vs 1.0+/−1.0, p=.18) and total NFT density (3.9+/−2.4 vs 3.6+/−2.3, p=.50) did not differ between e4 carriers and NC, nor in any subregion. Eliminating the 21 with MCI did not alter these results. Nondemented APOE e4 carriers over age 60 have a higher burden of total parenchymal and vascular amyloid neuropathology than NC, but no difference in neuritic plaque and NFT pathology. PMID:20153809

  18. A 'danse macabre': tau and Fyn in STEP with amyloid beta to facilitate induction of synaptic depression and excitotoxicity.

    PubMed

    Boehm, Jannic

    2013-06-01

    Alzheimer's disease, with its two most prominent pathological factors amyloid beta and tau protein, can be described as a disease of the synapse. It therefore comes as little surprise that NMDA receptor-related synaptic dysfunction had been thought for several years to underlie the synaptic pathophysiology seen in Alzheimer's disease. In this review I will summarise recent evidence showing that the NMDA receptor links the effects of extracellular amyloid beta with intracellular tau protein. Furthermore, the antagonistic roles of Fyn and STEP in NMDA receptor regulation, synaptic plasticity and induction of synaptic depression will be discussed. PMID:23773061

  19. Nucleation of polymorphic amyloid fibrils.

    PubMed

    Auer, Stefan

    2015-03-10

    One and the same protein can self-assemble into amyloid fibrils with different morphologies. The phenomenon of fibril polymorphism is relevant biologically because different fibril polymorphs can have different toxicity, but there is no tool for predicting which polymorph forms and under what conditions. Here, we consider the nucleation of polymorphic amyloid fibrils occurring by direct polymerization of monomeric proteins into fibrils. We treat this process within the framework of our newly developed nonstandard nucleation theory, which allows prediction of the concentration dependence of the nucleation rate for different fibril polymorphs. The results highlight that the concentration dependence of the nucleation rate is closely linked with the protein solubility and a threshold monomer concentration below which fibril formation becomes biologically irrelevant. The relation between the nucleation rate, the fibril solubility, the threshold concentration, and the binding energies of the fibril building blocks within fibrils might prove a valuable tool for designing new experiments to control the formation of particular fibril polymorphs. PMID:25762329

  20. Yokukansan, a traditional Japanese medicine, ameliorates memory disturbance and abnormal social interaction with anti-aggregation effect of cerebral amyloid β proteins in amyloid precursor protein transgenic mice.

    PubMed

    Fujiwara, H; Takayama, S; Iwasaki, K; Tabuchi, M; Yamaguchi, T; Sekiguchi, K; Ikarashi, Y; Kudo, Y; Kase, Y; Arai, H; Yaegashi, N

    2011-04-28

    The deposition of amyloid β protein (Aβ) is a consistent pathological hallmark of Alzheimer's disease (AD) brains. Therefore, inhibition of Aβ aggregation in the brain is an attractive therapeutic and preventive strategy in the development of disease-modifying drugs for AD. An in vitro study demonstrated that yokukansan (YKS), a traditional Japanese medicine, inhibited Aβ aggregation in a concentration-dependent manner. An in vivo study demonstrated that YKS and Uncaria hook (UH), a constituent of YKS, prevented the accumulation of cerebral Aβ. YKS also improved the memory disturbance and abnormal social interaction such as increased aggressive behavior and decreased social behavior in amyloid precursor protein transgenic mice. These results suggest that YKS is likely to be a potent and novel therapeutic agent to prevent and/or treat AD, and that this may be attributed to UH. PMID:21303686

  1. Amyloid-Associated Nucleic Acid Hybridisation

    PubMed Central

    Braun, Sebastian; Humphreys, Christine; Fraser, Elizabeth; Brancale, Andrea; Bochtler, Matthias; Dale, Trevor C.

    2011-01-01

    Nucleic acids promote amyloid formation in diseases including Alzheimer's and Creutzfeldt-Jakob disease. However, it remains unclear whether the close interactions between amyloid and nucleic acid allow nucleic acid secondary structure to play a role in modulating amyloid structure and function. Here we have used a simplified system of short basic peptides with alternating hydrophobic and hydrophilic amino acid residues to study nucleic acid - amyloid interactions. Employing biophysical techniques including X-ray fibre diffraction, circular dichroism spectroscopy and electron microscopy we show that the polymerized charges of nucleic acids concentrate and enhance the formation of amyloid from short basic peptides, many of which would not otherwise form fibres. In turn, the amyloid component binds nucleic acids and promotes their hybridisation at concentrations below their solution Kd, as shown by time-resolved FRET studies. The self-reinforcing interactions between peptides and nucleic acids lead to the formation of amyloid nucleic acid (ANA) fibres whose properties are distinct from their component polymers. In addition to their importance in disease and potential in engineering, ANA fibres formed from prebiotically-produced peptides and nucleic acids may have played a role in early evolution, constituting the first entities subject to Darwinian evolution. PMID:21625537

  2. Novel neuritic clusters with accumulations of amyloid precursor protein and amyloid precursor-like protein 2 immunoreactivity in brain regions damaged by thiamine deficiency.

    PubMed Central

    Calingasan, N. Y.; Gandy, S. E.; Baker, H.; Sheu, K. F.; Smith, J. D.; Lamb, B. T.; Gearhart, J. D.; Buxbaum, J. D.; Harper, C.; Selkoe, D. J.; Price, D. L.; Sisodia, S. S.; Gibson, G. E.

    1996-01-01

    Experimental thiamine deficiency (TD) is a classical model of a nutritional deficit associated with a generalized impairment of oxidative metabolism and selective cell loss in the brain. In rats, TD-induced cell degeneration is accompanied by an accumulation of amyloid precursor protein (APP)/amyloid precursor-like protein 2 (APLP2) immunoreactivity in abnormal neurites and perikarya along the periphery of, or scattered within, the lesion. Prompted by these data and our previous findings of a genetic variation in the development of TD symptoms, we extended our studies to mice. C57BL/6, ApoE knockout, and APP YAC transgenic mice received thiamine-deficient diet and pyrithiamine injections. Unlike rats, APP/APLP2-immunoreactive neurites in all strains of mice were sparsely scattered within damaged areas and did not delimit the thalamic lesion. In addition, abnormal clusters of intensely immunoreactive neurites occurred only in areas of damage including the thalamus, mammillary body, and inferior colliculus. The clusters appeared as either irregular clumps or round or oval rosettes that strikingly resembled the neuritic component of Alzheimer amyloid plaques. However, immunostaining using various antisera to synthetic amyloid beta-protein (A beta 1-40) and thioflavine S histochemistry failed to show evidence of a component of A beta Neither APP/APLP2-immunoreactive clusters nor amyloid plaques were observed in the brain from patients with Wernicke-Korsakoff syndrome, the clinical manifestation of TD in man. Our results demonstrate species (i.e., genetic) differences in the response to TD-induced damage and support a role for APP and APLP2 in the response to brain injury. This is the first report that chronic oxidative deficits can lead to this novel pathology. Images Figure 1 Figure 2 PMID:8780408

  3. The ups and downs of the posteromedial cortex: age- and amyloid-related functional alterations of the encoding/retrieval flip in cognitively normal older adults.

    PubMed

    Vannini, Patrizia; Hedden, Trey; Huijbers, Willem; Ward, Andrew; Johnson, Keith A; Sperling, Reisa A

    2013-06-01

    Neural networks supporting memory function decline with increasing age. Accumulation of amyloid-β, a histopathological finding in Alzheimer's disease, is a likely contributor. Posteromedial cortices (PMCs) are particularly vulnerable to early amyloid pathology and play a role in both encoding and retrieval processes. The extent to which aging and amyloid influence the ability to modulate activity between these processes within the PMC was investigated by combining positron emission tomography-amyloid imaging with functional magnetic resonance imaging in cognitively normal older and young adults. Young subjects exhibited a marked decrease in activity during encoding and an increase during retrieval (also known as encoding/retrieval "flip"). Impaired ability to modulate activity was associated with increasing age, greater amyloid burden, and worse memory performance. In contrast, the hippocampus showed increased activity during both encoding and retrieval, which was not related to these variables. These findings support a specific link between amyloid pathology and neural dysfunction in PMC and elucidate the underpinnings of age-related memory dysfunction. PMID:22586140

  4. Amyloid-linked cellular toxicity triggered by bacterial inclusion bodies

    SciTech Connect

    Gonzalez-Montalban, Nuria; Villaverde, Antonio; Aris, Anna; E-mail: Anna.Aris@irta.es

    2007-04-13

    The aggregation of proteins in the form of amyloid fibrils and plaques is the characteristic feature of some pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. The mechanisms by which the aggregation processes result in cell damage are under intense investigation but recent data indicate that prefibrillar aggregates are the most proximate mediators of toxicity rather than mature fibrils. Since it has been shown that prefibrillar forms of the nondisease-related misfolded proteins are highly toxic to cultured mammalian cells we have studied the cytoxicity associated to bacterial inclusion bodies that have been recently described as protein deposits presenting amyloid-like structures. We have proved that bacterial inclusion bodies composed by a misfolding-prone {beta}-galactosidase fusion protein are clearly toxic for mammalian cells but the {beta}-galactosidase wild type enzyme forming more structured thermal aggregates does not impair cell viability, despite it also binds and enter into the cells. These results are in the line that the most cytotoxic aggregates are early prefibrilar assemblies but discard the hypothesis that the membrane destabilization is Key event to subsequent disruption of cellular processes, such as ion balance, oxidative state and the eventually cell death.

  5. In vivo labeling of amyloid with BF-108.

    PubMed

    Suemoto, Takahiro; Okamura, Nobuyuki; Shiomitsu, Tsuyoshi; Suzuki, Masako; Shimadzu, Hiroshi; Akatsu, Hiroyasu; Yamamoto, Takayuki; Kudo, Yukitsuka; Sawada, Tohru

    2004-01-01

    Detection of aggregated amyloid-beta (Abeta) with a non-invasive imaging modality such as positron emission tomography (PET) was suggested to be ideal for the diagnosis of Alzheimer's disease (AD) prior to the onset of clinical symptoms. We have been searching for imaging probe candidates with a high affinity for aggregated Abeta in vitro and in vivo and high lipophilicity, a characteristic that allows for the permeation of the blood-brain barrier (BBB). As analyzed by Thioflavin T (ThT) assay and octanol/water partition coefficient test (PC), 3-diethylamino-6-(2-fluoroethyl)ethylaminoacridine (BF-108) were found to have high affinity for Abeta aggregates in vitro and high lipophilicity. Intravenously administrated BF-108 labeled Abeta aggregates injected into the amygdala as observed under a fluorescence microscope, showing this compound's permeability of BBB and an ability to label Abeta in vivo. BF-108 also labeled neuritic senile plaques (SPs), neurofibrillary tangles, and amyloid-laden vessels in temporal and hippocampal sections from AD patients. Following intravenous administration of BF-108 to an APP23 transgenic (TG) mouse, in vivo labeling of endogenous plaques was seen in brain sections by fluorescence microscopy. These properties suggest the potential utility of BF-108 for in vivo imaging of AD pathology. PMID:14687882

  6. Foldamer-mediated manipulation of a pre-amyloid toxin

    PubMed Central

    Kumar, Sunil; Birol, Melissa; Schlamadinger, Diana E.; Wojcik, Slawomir P.; Rhoades, Elizabeth; Miranker, Andrew D.

    2016-01-01

    Disordered proteins, such as those central to Alzheimer's and Parkinson's, are particularly intractable for structure-targeted therapeutic design. Here we demonstrate the capacity of a synthetic foldamer to capture structure in a disease relevant peptide. Oligoquinoline amides have a defined fold with a solvent-excluded core that is independent of its outwardly projected, derivatizable moieties. Islet amyloid polypeptide (IAPP) is a peptide central to β-cell pathology in type II diabetes. A tetraquinoline is presented that stabilizes a pre-amyloid, α-helical conformation of IAPP. This charged, dianionic compound is readily soluble in aqueous buffer, yet crosses biological membranes without cellular assistance: an unexpected capability that is a consequence of its ability to reversibly fold. The tetraquinoline docks specifically with intracellular IAPP and rescues β-cells from toxicity. Taken together, our work here supports the thesis that stabilizing non-toxic conformers of a plastic protein is a viable strategy for cytotoxic rescue addressable using oligoquinoline amides. PMID:27108700

  7. Gelsolin amyloid angiopathy causes severe disruption of the arterial wall.

    PubMed

    Koskelainen, Susanna; Pihlamaa, Tiia; Suominen, Sinikka; Zhao, Fang; Salo, Tuula; Risteli, Juha; Baumann, Marc; Kalimo, Hannu; Kiuru-Enari, Sari

    2016-08-01

    Hereditary gelsolin amyloidosis (HGA) is a dominantly inherited systemic disease reported worldwide. HGA is characterized by ophthalmological, neurological, and dermatological manifestations. AGel amyloid accumulates at basal lamina of epithelial and muscle cells, thus amyloid angiopathy is encountered in nearly every organ. HGA patients have cardiovascular, hemorrhagic, and potentially vascularly induced neurological problems. To clarify pathomechanisms of AGel angiopathy, we performed histological, immunohistochemical, and electron microscopic analyses on facial temporal artery branches from 8 HGA patients and 13 control subjects. We demonstrate major pathological changes in arteries: disruption of the tunica media, disorganization of vascular smooth muscle cells, and accumulation of AGel fibrils in arterial walls, where they associate with the lamina elastica interna, which becomes fragmented and diminished. We also provide evidence of abnormal accumulation and localization of collagen types I and III and an increase of collagen type I degradation product in the tunica media. Vascular smooth muscle cells appear to be morphologically and semi-quantitatively normal, only their basal lamina is often thickened. In conclusion, angiopathy in HGA results in severe disruption of arterial walls, characterized by prominent AGel deposition, collagen derangement and severe elastolysis, and it may be responsible for several, particularly hemorrhagic, disease manifestations in HGA. PMID:27198069

  8. Foldamer-mediated manipulation of a pre-amyloid toxin.

    PubMed

    Kumar, Sunil; Birol, Melissa; Schlamadinger, Diana E; Wojcik, Slawomir P; Rhoades, Elizabeth; Miranker, Andrew D

    2016-01-01

    Disordered proteins, such as those central to Alzheimer's and Parkinson's, are particularly intractable for structure-targeted therapeutic design. Here we demonstrate the capacity of a synthetic foldamer to capture structure in a disease relevant peptide. Oligoquinoline amides have a defined fold with a solvent-excluded core that is independent of its outwardly projected, derivatizable moieties. Islet amyloid polypeptide (IAPP) is a peptide central to β-cell pathology in type II diabetes. A tetraquinoline is presented that stabilizes a pre-amyloid, α-helical conformation of IAPP. This charged, dianionic compound is readily soluble in aqueous buffer, yet crosses biological membranes without cellular assistance: an unexpected capability that is a consequence of its ability to reversibly fold. The tetraquinoline docks specifically with intracellular IAPP and rescues β-cells from toxicity. Taken together, our work here supports the thesis that stabilizing non-toxic conformers of a plastic protein is a viable strategy for cytotoxic rescue addressable using oligoquinoline amides. PMID:27108700

  9. Observation of spatial propagation of amyloid assembly from single nuclei

    PubMed Central

    Knowles, Tuomas P. J.; White, Duncan A.; Abate, Adam R.; Agresti, Jeremy J.; Cohen, Samuel I. A.; Sperling, Ralph A.; De Genst, Erwin J.; Dobson, Christopher M.; Weitz, David A.

    2011-01-01

    The crucial early stages of amyloid growth, in which normally soluble proteins are converted into fibrillar nanostructures, are challenging to study using conventional techniques yet are critical to the protein aggregation phenomena implicated in many common pathologies. As with all nucleation and growth phenomena, it is difficult to track individual nuclei in traditional macroscopic experiments, which probe the overall temporal evolution of the sample, but do not yield detailed information on the primary nucleation step as they mix independent stochastic events into an ensemble measurement. To overcome this limitation, we have developed microdroplet assays enabling us to detect single primary nucleation events and to monitor their subsequent spatial as well as temporal evolution, both of which we find to be determined by secondary nucleation phenomena. By deforming the droplets to high aspect ratio, we visualize in real-time propagating waves of protein assembly emanating from discrete primary nucleation sites. We show that, in contrast to classical gelation phenomena, the primary nucleation step is characterized by a striking dependence on system size, and the filamentous protein self-assembly process involves a highly nonuniform spatial distribution of aggregates. These findings deviate markedly from the current picture of amyloid growth and uncover a general driving force, originating from confinement, which, together with biological quality control mechanisms, helps proteins remain soluble and therefore functional in nature. PMID:21876182

  10. Brain pathologies in extreme old age.

    PubMed

    Neltner, Janna H; Abner, Erin L; Jicha, Gregory A; Schmitt, Frederick A; Patel, Ela; Poon, Leonard W; Marla, Gearing; Green, Robert C; Davey, Adam; Johnson, Mary Ann; Jazwinski, S Michal; Kim, Sangkyu; Davis, Daron; Woodard, John L; Kryscio, Richard J; Van Eldik, Linda J; Nelson, Peter T

    2016-01-01

    With an emphasis on evolving concepts in the field, we evaluated neuropathologic data from very old research volunteers whose brain autopsies were performed at the University of Kentucky Alzheimer's Disease Center, incorporating data from the Georgia Centenarian Study (n = 49 cases included), Nun Study (n = 17), and University of Kentucky Alzheimer's Disease Center (n = 11) cohorts. Average age of death was 102.0 (range: 98-107) years overall. Alzheimer's disease pathology was not universal (62% with "moderate" or "frequent" neuritic amyloid plaque densities), whereas frontotemporal lobar degeneration was absent. By contrast, some hippocampal neurofibrillary tangles (including primary age-related tauopathy) were observed in every case. Lewy body pathology was seen in 16.9% of subjects and hippocampal sclerosis of aging in 20.8%. We describe anatomic distributions of pigment-laden macrophages, expanded Virchow-Robin spaces, and arteriolosclerosis among Georgia Centenarians. Moderate or severe arteriolosclerosis pathology, throughout the brain, was associated with both hippocampal sclerosis of aging pathology and an ABCC9 gene variant. These results provide fresh insights into the complex cerebral multimorbidity, and a novel genetic risk factor, at the far end of the human aging spectrum. PMID:26597697

  11. All-atom Simulation of Amyloid Aggregates

    NASA Astrophysics Data System (ADS)

    Berhanu, Workalemahu M.; Alred, Erik J.; Bernhardt, Nathan A.; Hansmann, Ulrich H. E.

    Molecular simulations are now commonly used to complement experiments in the investigation of amyloid formation and their role in human diseases. While various simulations based on enhanced sampling techniques are used in amyloid formation simulations, this article will focus on those using standard atomistic simulations to evaluate the stability of fibril models. Such studies explore the limitations that arise from the choice of force field or polymorphism; and explore the stability of in vivo and in vitro forms of Aβ fibril aggregates, and the role of heterologous seeding as a link between different amyloid diseases.

  12. Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes.

    PubMed

    Tang, Weihao; Tam, Joshua H K; Seah, Claudia; Chiu, Justin; Tyrer, Andrea; Cregan, Sean P; Meakin, Susan O; Pasternak, Stephen H

    2015-01-01

    Alzheimer's disease (AD) is characterized by the deposition of Beta-Amyloid (Aβ) peptides in the brain. Aβ peptides are generated by cleavage of the Amyloid Precursor Protein (APP) by the β - and γ - secretase enzymes. Although this process is tightly linked to the internalization of cell surface APP, the compartments responsible are not well defined. We have found that APP can be rapidly internalized from the cell surface to lysosomes, bypassing early and late endosomes. Here we show by confocal microscopy and electron microscopy that this pathway is mediated by macropinocytosis. APP internalization is enhanced by antibody binding/crosslinking of APP suggesting that APP may function as a receptor. Furthermore, a dominant negative mutant of Arf6 blocks direct transport of APP to lysosomes, but does not affect classical endocytosis to endosomes. Arf6 expression increases through the hippocampus with the development of Alzheimer's disease, being expressed mostly in the CA1 and CA2 regions in normal individuals but spreading through the CA3 and CA4 regions in individuals with pathologically diagnosed AD. Disruption of lysosomal transport of APP reduces both Aβ40 and Aβ42 production by more than 30 %. Our findings suggest that the lysosome is an important site for Aβ production and that altering APP trafficking represents a viable strategy to reduce Aβ production. PMID:26170135

  13. Nutraceuticals and amyloid neurodegenerative diseases: a focus on natural phenols.

    PubMed

    Rigacci, Stefania; Stefani, Massimo

    2015-01-01

    A common molecular feature of amyloid neurodegenerative diseases is the unfolding/misfolding of specific proteins/peptides which consequently become prone to aggregate into toxic assemblies and deposits that are the key histopathological trait of these pathologies. Apart from the rare early-onset familiar forms, these neurodegenerative diseases are age-associated disorders whose symptoms appear in aged people after long incubation periods. This makes the therapeutic approach particularly compelling and boosts the search for both early diagnostic tools and preventive approaches. In this last respect, natural compounds commonly present in foods and beverages are considered promising molecules, at least on the bench side. The so-called 'nutraceutical approach' suggests life-long healthy diets, particularly focusing on food molecules that are candidates to enter clinical trials as such or following a targeted molecular engineering. Natural phenols abundant in 'healthy' foods such as extra virgin olive oil, red wine, green tea, red berries and spices, appear particularly promising. PMID:25418871

  14. Apple Procyanidins Suppress Amyloid β-Protein Aggregation

    PubMed Central

    Toda, Toshihiko; Sunagawa, Tadahiro; Kanda, Tomomasa; Tagashira, Motoyuki; Shirasawa, Takuji; Shimizu, Takahiko

    2011-01-01

    Procyanidins (PCs) are major components of the apple polyphenols (APs). We previously reported that treatment with PC extended the mean lifespan of Caenorhabditis elegans (Sunagawa et al., 2011). In order to estimate the neuroprotective effects of PC, we investigated the antiaggregative activity of PC on amyloid β-protein (Aβ) aggregation, which is a pathological hallmark of Alzheimer's disease. We herein report that PC significantly suppressed Aβ42 aggregation and dissociated Aβ42 aggregates in a dose-dependent manner, indicating that PC is a potent suppressor of Aβ aggregation. Furthermore, PC significantly inhibited Aβ42 neurotoxicity and stimulated proliferation in PC-12 cells. These results suggested that the PC and AP acted as neuroprotective factors against toxic Aβ aggregates. PMID:21826271

  15. Identification of Human Islet Amyloid Polypeptide as a BACE2 Substrate.

    PubMed

    Rulifson, Ingrid C; Cao, Ping; Miao, Li; Kopecky, David; Huang, Linda; White, Ryan D; Samayoa, Kim; Gardner, Jonitha; Wu, Xiaosu; Chen, Kui; Tsuruda, Trace; Homann, Oliver; Baribault, Helene; Yamane, Harvey; Carlson, Tim; Wiltzius, Jed; Li, Yang

    2016-01-01

    Pancreatic amyloid formation by islet amyloid polypeptide (IAPP) is a hallmark pathological feature of type 2 diabetes. IAPP is stored in the secretory granules of pancreatic beta-cells and co-secreted with insulin to maintain glucose homeostasis. IAPP is innocuous under homeostatic conditions but imbalances in production or processing of IAPP may result in homodimer formation leading to the rapid production of cytotoxic oligomers and amyloid fibrils. The consequence is beta-cell dysfunction and the accumulation of proteinaceous plaques in and around pancreatic islets. Beta-site APP-cleaving enzyme 2, BACE2, is an aspartyl protease commonly associated with BACE1, a related homolog responsible for amyloid processing in the brain and strongly implicated in Alzheimer's disease. Herein, we identify two distinct sites of the mature human IAPP sequence that are susceptible to BACE2-mediated proteolytic activity. The result of proteolysis is modulation of human IAPP fibrillation and human IAPP protein degradation. These results suggest a potential therapeutic role for BACE2 in type 2 diabetes-associated hyperamylinaemia. PMID:26840340

  16. Tau protein kinase I is essential for amyloid beta-protein-induced neurotoxicity.

    PubMed Central

    Takashima, A; Noguchi, K; Sato, K; Hoshino, T; Imahori, K

    1993-01-01

    Pathological changes of Alzheimer disease are characterized by cerebral cortical atrophy as a result of degeneration and loss of neurons. Typical histological lesions include numerous senile plaques composed of deposits of amyloid beta-protein and neurofibrillary tangles consisting predominantly of ubiquitin and highly phosphorylated tau proteins. Previously, tau protein kinase I (TPK I) was purified and its cDNA was cloned. To examine the biological role of this enzyme in neurons, we have studied the induction of its kinase activity in primary cultures of embryonic rat hippocampal neurons. Treatment of cultures with amyloid beta-protein significantly increased TPK I activity and induced the appearance of tau proteins recognized by the Alz-50 monoclonal antibody. In addition, though amyloid beta-protein was neurotoxic, either cycloheximide or actinomycin D prevented neuronal death. Death was also prevented by TPK I antisense oligonucleotides but not by sense oligonucleotides. These observations suggest that rat hippocampal neurons undergo programmed cell death in response to amyloid beta-protein and that TPK I is a key enzyme in this process. Images Fig. 1 Fig. 2 Fig. 3 Fig. 5 PMID:8356085

  17. Screening for amyloid aggregation by Semi-Denaturing Detergent-Agarose Gel Electrophoresis.

    PubMed

    Halfmann, Randal; Lindquist, Susan

    2008-01-01

    Amyloid aggregation is associated with numerous protein misfolding pathologies and underlies the infectious properties of prions, which are conformationally self-templating proteins that are thought to have beneficial roles in lower organisms. Amyloids have been notoriously difficult to study due to their insolubility and structural heterogeneity. However, resolution of amyloid polymers based on size and detergent insolubility has been made possible by Semi-Denaturing Detergent-Agarose Gel Electrophoresis (SDD-AGE). This technique is finding widespread use for the detection and characterization of amyloid conformational variants. Here, we demonstrate an adaptation of this technique that facilitates its use in large-scale applications, such as screens for novel prions and other amyloidogenic proteins. The new SDD-AGE method uses capillary transfer for greater reliability and ease of use, and allows any sized gel to be accomodated. Thus, a large number of samples, prepared from cells or purified proteins, can be processed simultaneously for the presence of SDS-insoluble conformers of tagged proteins. PMID:19066511

  18. Identification of Human Islet Amyloid Polypeptide as a BACE2 Substrate

    PubMed Central

    Rulifson, Ingrid C.; Cao, Ping; Miao, Li; Kopecky, David; Huang, Linda; White, Ryan D.; Samayoa, Kim; Gardner, Jonitha; Wu, Xiaosu; Chen, Kui; Tsuruda, Trace; Homann, Oliver; Baribault, Helene; Yamane, Harvey; Carlson, Tim; Wiltzius, Jed; Li, Yang

    2016-01-01

    Pancreatic amyloid formation by islet amyloid polypeptide (IAPP) is a hallmark pathological feature of type 2 diabetes. IAPP is stored in the secretory granules of pancreatic beta-cells and co-secreted with insulin to maintain glucose homeostasis. IAPP is innocuous under homeostatic conditions but imbalances in production or processing of IAPP may result in homodimer formation leading to the rapid production of cytotoxic oligomers and amyloid fibrils. The consequence is beta-cell dysfunction and the accumulation of proteinaceous plaques in and around pancreatic islets. Beta-site APP-cleaving enzyme 2, BACE2, is an aspartyl protease commonly associated with BACE1, a related homolog responsible for amyloid processing in the brain and strongly implicated in Alzheimer’s disease. Herein, we identify two distinct sites of the mature human IAPP sequence that are susceptible to BACE2-mediated proteolytic activity. The result of proteolysis is modulation of human IAPP fibrillation and human IAPP protein degradation. These results suggest a potential therapeutic role for BACE2 in type 2 diabetes-associated hyperamylinaemia. PMID:26840340

  19. Amyloid Properties of the Mouse Egg Zona Pellucida

    PubMed Central

    Egge, Nathan; Muthusubramanian, Archana; Cornwall, Gail A.

    2015-01-01

    The zona pellucida (ZP) surrounding the oocyte is an extracellular fibrillar matrix that plays critical roles during fertilization including species-specific gamete recognition and protection from polyspermy. The mouse ZP is composed of three proteins, ZP1, ZP2, and ZP3, all of which have a ZP polymerization domain that directs protein fibril formation and assembly into the three-dimensional ZP matrix. Egg coats surrounding oocytes in nonmammalian vertebrates and in invertebrates are also fibrillar matrices and are composed of ZP domain-containing proteins suggesting the basic structure and function of the ZP/egg coat is highly conserved. However, sequence similarity between ZP domains is low across species and thus the mechanism for the conservation of ZP/egg coat structure and its function is not known. Using approaches classically used to identify amyloid including conformation-dependent antibodies and dyes, X-ray diffraction, and negative stain electron microscopy, our studies suggest the mouse ZP is a functional amyloid. Amyloids are cross-β sheet fibrillar structures that, while typically associated with neurodegenerative and prion diseases in mammals, can also carry out functional roles in normal cells without resulting pathology. An analysis of the ZP domain from mouse ZP3 and ZP3 homologs from five additional taxa using the algorithm AmylPred 2 to identify amyloidogenic sites, revealed in all taxa a remarkable conservation of regions that were predicted to form amyloid. This included a conserved amyloidogenic region that localized to a stretch of hydrophobic amino acids previously shown in mouse ZP3 to be essential for fibril assembly. Similarly, a domain in the yeast protein α-agglutinin/Sag 1p, that possesses ZP domain-like features and which is essential for mating, also had sites that were predicted to be amyloidogenic including a hydrophobic stretch that appeared analogous to the critical site in mouse ZP3. Together, these studies suggest that

  20. A Cu-amyloid β complex activating Fenton chemistry in Alzheimer's disease: Learning with multiple first-principles simulations

    NASA Astrophysics Data System (ADS)

    La Penna, Giovanni; Hureau, Christelle; Faller, Peter

    2014-10-01

    Amyloid β peptides form complexes with copper, both in vitro and in vivo, relatively soluble in water as oligomers and active as catalysts for oxidation of organic substrates by hydrogen peroxide, a species always present in cells and in their aerobic environment. All these species are present in the synapse, thus making a connection between the amyloid cascade hypothesis and the oxidative damages by reactive oxygen species in neurons, when pathological dishomeostasis of amyloid peptides and metal ions occur. In order to understand the structural features of these toxic complexes, we built several models of Cu-Aβ peptides in monomeric and dimeric forms and we found, performing multiple first-principles molecular dynamics simulations, that Cu-induced dimers are more active than monomers in converting hydrogen peroxide into aggressive hydroxyl radicals.

  1. A Chemical Screening Approach Reveals that Indole Flourescence is Quenched by Pre-Fibrillar But Not Fibrillar Amyloid

    PubMed Central

    Reinke, Ashley A.; Seh, Han Yiau; Gestwicki, Jason E.

    2009-01-01

    Aggregated amyloid-β (Aβ) peptide is implicated in the pathology of Alzheimer’s disease. In vitro and in vivo, these aggregates are found in a variety of morphologies, including globular oligomers and linear fibrils, which possess distinct biological activities. However, known chemical probes, including the dyes thioflavin T and Congo Red, appear to lack selectivity for specific amyloid structures. To identify molecules that might differentiate between these architectures, we employed a fluorescence-based interaction assay to screen a collection of 68 known Aβ ligands against pre-formed oligomers and fibrils. In these studies, we found that the fluorescence of five indole-based compounds was selectively quenched (~15%) in the presence of oligomers, but remained unchanged after addition of fibrils. These results suggest that indoles might be complementary to existing chemical probes for studying amyloid formation in vitro. PMID:19640715

  2. Amyloid angiopathy and lobar cerebral haemorrhage.

    PubMed Central

    Ishii, N; Nishihara, Y; Horie, A

    1984-01-01

    Seven cases of lobar cerebral haemorrhage due to amyloid angiopathy were found among 60 necropsy cases of intracerebral haemorrhage. Clinically five patients were demented and two had hypertension. Immediately after the onset of stroke there was a high incidence of headache and vomiting, followed by nuchal rigidity. Amyloid angiopathy was most prominent in the cerebral cortex and the leptomeninges. Senile plaques were noted in all cases. One should suspect that a haemorrhage may be due to amyloid angiopathy, when lobar cerebral haemorrhage occurs in an aged, normotensive patient with or without dementia. Surgical evacuation of the haematoma is inadvisable, because of the diffuse nature of amyloid angiopathy, high recurrence rate and less tendency to cause brain stem compression. Images PMID:6502178

  3. Biofilm Inhibitors that Target Amyloid Proteins

    PubMed Central

    Romero, Diego; Sanabria-Valentín, Edgardo; Vlamakis, Hera; Kolter, Roberto

    2012-01-01

    Summary Bacteria establish stable communities, known as biofilms, that are resistant to antimicrobials. Biofilm robustness is due to the presence of an extracellular matrix, which for several species - among them Bacillus subtilis - includes amyloid-like protein fibers. In this work, we show that B. subtilis biofilms can be a simple and reliable tool for screening of molecules with anti-amyloid activity. We identified two molecules, AA-861 and parthenolide, which efficiently inhibited biofilms by preventing the formation of amyloid-like fibers. We found that parthenolide also disrupted pre-established biofilms. These molecules also impeded the formation of biofilms of other bacterial species that secrete amyloid proteins, such as Bacillus cereus and Escherichia coli. Furthermore, the identified molecules decreased the conversion of the yeast protein New1 to the prion state in a heterologous host, indicating the broad range of activity of the molecules. PMID:23352144

  4. Polymorphism of Amyloid Fibrils In Vivo.

    PubMed

    Annamalai, Karthikeyan; Gührs, Karl-Heinz; Koehler, Rolf; Schmidt, Matthias; Michel, Henri; Loos, Cornelia; Gaffney, Patricia M; Sigurdson, Christina J; Hegenbart, Ute; Schönland, Stefan; Fändrich, Marcus

    2016-04-01

    Polymorphism is a wide-spread feature of amyloid-like fibrils formed in vitro, but it has so far remained unclear whether the fibrils formed within a patient are also affected by this phenomenon. In this study we show that the amyloid fibrils within a diseased individual can vary considerably in their three-dimensional architecture. We demonstrate this heterogeneity with amyloid fibrils deposited within different organs, formed from sequentially non-homologous polypeptide chains and affecting human or animals. Irrespective of amyloid type or source, we found in vivo fibrils to be polymorphic. These data imply that the chemical principles of fibril assembly that lead to such polymorphism are fundamentally conserved in vivo and in vitro. PMID:26954430

  5. Amyloid Polymorphism: Structural Basis and Neurobiological Relevance

    PubMed Central

    Tycko, Robert

    2015-01-01

    Summary Our understanding of the molecular structures of amyloid fibrils that are associated with neurodegenerative diseases, of mechanisms by which disease-associated peptides and proteins aggregate into fibrils, and of structural properties of aggregation intermediates has advanced considerably in recent years. Detailed molecular structural models for certain fibrils and aggregation intermediates are now available. It is now well established that amyloid fibrils are generally polymorphic at the molecular level, with a given peptide or protein being capable of forming a variety of distinct, self-propagating fibril structures. Recent results from structural studies and from studies involving cell cultures, transgenic animals, and human tissue provide initial evidence that molecular structural variations in amyloid fibrils and related aggregates may correlate with or even produce variations in disease development. This article reviews our current knowledge of the structural and mechanistic aspects of amyloid formation, as well as current evidence for the biological relevance of structural variations. PMID:25950632

  6. 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.

  7. Organotypic vibrosections from whole brain adult Alzheimer mice (overexpressing amyloid-precursor-protein with the Swedish-Dutch-Iowa mutations) as a model to study clearance of beta-amyloid plaques

    PubMed Central

    Humpel, Christian

    2015-01-01

    Alzheimer's disease is a severe neurodegenerative disorder of the brain, pathologically characterized by extracellular beta-amyloid plaques, intraneuronal Tau inclusions, inflammation, reactive glial cells, vascular pathology and neuronal cell death. The degradation and clearance of beta-amyloid plaques is an interesting therapeutic approach, and the proteases neprilysin (NEP), insulysin and matrix metalloproteinases (MMP) are of particular interest. The aim of this project was to establish and characterize a simple in vitro model to study the degrading effects of these proteases. Organoytpic brain vibrosections (120 μm thick) were sectioned from adult (9 month old) wildtype and transgenic mice (expressing amyloid precursor protein (APP) harboring the Swedish K670N/M671L, Dutch E693Q, and Iowa D694N mutations; APP_SDI) and cultured for 2 weeks. Plaques were stained by immunohistochemistry for beta-amyloid and Thioflavin S. Our data show that plaques were evident in 2 week old cultures from 9 month old transgenic mice. These plaques were surrounded by reactive GFAP+ astroglia and Iba1+ microglia. Incubation of fresh slices for 2 weeks with 1–0.1–0.01 μg/ml of NEP, insulysin, MMP-2, or MMP-9 showed that NEP, insulysin, and MMP-9 markedly degraded beta-amyloid plaques but only at the highest concentration. Our data provide for the first time a potent and powerful living brain vibrosection model containing a high number of plaques, which allows to rapidly and simply study the degradation and clearance of beta-amyloid plaques in vitro. PMID:25914642

  8. Clinical Utility of Amyloid PET Imaging in the Differential Diagnosis of Atypical Dementias and Its Impact on Caregivers.

    PubMed

    Bensaïdane, Mohamed Reda; Beauregard, Jean-Mathieu; Poulin, Stéphane; Buteau, François-Alexandre; Guimond, Jean; Bergeron, David; Verret, Louis; Fortin, Marie-Pierre; Houde, Michèle; Bouchard, Rémi W; Soucy, Jean-Paul; Laforce, Robert

    2016-04-18

    Recent studies have supported a role for amyloid positron emission tomography (PET) imaging in distinguishing Alzheimer's disease (AD) pathology from other pathological protein accumulations leading to dementia. We investigated the clinical utility of amyloid PET in the differential diagnosis of atypical dementia cases and its impact on caregivers. Using the amyloid tracer 18F-NAV4694, we prospectively scanned 28 patients (mean age 59.3 y, s.d. 5.8; mean MMSE 21.4, s.d. 6.0) with an atypical dementia syndrome. Following a comprehensive diagnostic workup (i.e., history taking, neurological examination, blood tests, neuropsychological evaluation, MRI, and FDG-PET), no certain diagnosis could be arrived at. Amyloid PET was then conducted and classified as positive or negative. Attending physicians were asked to evaluate whether this result led to a change in diagnosis or altered management. They also reported their degree of confidence in the diagnosis. Caregivers were met after disclosure of amyloid PET results and completed a questionnaire/interview to assess the impact of the scan. Our cohort was evenly divided between positive (14/28) and negative (14/28) 18F-NAV4694 cases. Amyloid PET resulted in a diagnostic change in 9/28 cases (32.1%: 17.8% changed from AD to non-AD, 14.3% from non-AD to AD). There was a 44% increase in diagnostic confidence. Altered management occurred in 71.4% (20/28) of cases. Knowledge of amyloid status improved caregivers' outcomes in all domains (anxiety, depression, disease perception, future anticipation, and quality of life). This study suggests a useful additive role for amyloid PET in atypical cases with an unclear diagnosis beyond the extensive workup of a tertiary memory clinic. Amyloid PET increased diagnostic confidence and led to clinically significant alterations in management. The information gained from that test was well received by caregivers and encouraged spending quality time with their loved ones. PMID:27104896

  9. Suspected non-AD pathology in mild cognitive impairment.

    PubMed

    Wisse, Laura E M; Butala, Nirali; Das, Sandhitsu R; Davatzikos, Christos; Dickerson, Bradford C; Vaishnavi, Sanjeev N; Yushkevich, Paul A; Wolk, David A

    2015-12-01

    We aim to better characterize mild cognitive impairment (MCI) patients with suspected non-Alzheimer's disease (AD) pathology (SNAP) based on their longitudinal outcome, cognition, biofluid, and neuroimaging profile. MCI participants (n = 361) from ADNI-GO/2 were designated "amyloid positive" with abnormal amyloid-beta 42 levels (AMY+) and "neurodegeneration positive" (NEU+) with abnormal hippocampal volume or hypometabolism using fluorodeoxyglucose-positron emission tomography. SNAP was compared with the other MCI groups and with AMY- controls. AMY-NEU+/SNAP, 16.6%, were older than the NEU- groups but not AMY- controls. They had a lower conversion rate to AD after 24 months than AMY+NEU+ MCI participants. SNAP-MCI participants had similar amyloid-beta 42 levels, florbetapir and tau levels, but larger white matter hyperintensity volumes than AMY- controls and AMY-NEU- MCI participants. SNAP participants performed worse on all memory domains and on other cognitive domains, than AMY-NEU- participants but less so than AMY+NEU+ participants. Subthreshold levels of cerebral amyloidosis are unlikely to play a role in SNAP-MCI, but pathologies involving the hippocampus and cerebrovascular disease may underlie the neurodegeneration and cognitive impairment in this group. PMID:26422359

  10. Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology.

    PubMed

    Akter, Rehana; Cao, Ping; Noor, Harris; Ridgway, Zachary; Tu, Ling-Hsien; Wang, Hui; Wong, Amy G; Zhang, Xiaoxue; Abedini, Andisheh; Schmidt, Ann Marie; Raleigh, Daniel P

    2016-01-01

    The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy. PMID:26649319

  11. Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology

    PubMed Central

    Akter, Rehana; Cao, Ping; Noor, Harris; Ridgway, Zachary; Tu, Ling-Hsien; Wang, Hui; Wong, Amy G.; Zhang, Xiaoxue; Abedini, Andisheh; Schmidt, Ann Marie; Raleigh, Daniel P.

    2016-01-01

    The hormone islet amyloid polypeptide (IAPP, or amylin) plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy. PMID:26649319

  12. 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

  13. 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. PMID:26673736

  14. Amyloid Plaques in PSAPP Mice Bind Less Metal than Plaques in Human Alzheimer’s Disease

    PubMed Central

    Leskovjan, Andreana C.; Lanzirotti, Antonio; Miller, Lisa M.

    2009-01-01

    Amyloid beta (Aβ) is the primary component of Alzheimer’s disease (AD) plaques, a key pathological feature of the disease. Metal ions of zinc (Zn), copper (Cu), iron (Fe), and calcium (Ca) are elevated in human amyloid plaques and are thought to be involved in neurodegeneration. Transgenic mouse models of AD also exhibit amyloid plaques, but fail to exhibit the high degree of neurodegeneration observed in humans. In this study, we imaged the Zn, Cu, Fe, and Ca ion distribution in the PSAPP transgenic mouse model representing end-stage AD (N = 6) using synchrotron X-ray fluorescence (XRF) microprobe. In order to account for differences in density in the plaques, the relative protein content was imaged with synchrotron Fourier transform infrared microspectroscopy (FTIRM) on the same samples. FTIRM results revealed a 61% increase in protein content in the plaques compared to the surrounding tissue. After normalizing to protein density, we found that the PSAPP plaques contained only a 29% increase in Zn and there was actually less Cu, Fe, and Ca in the plaque compared to the surrounding tissue. Since metal-binding to Aβ is thought to induce redox chemistry that is toxic to neurons, the reduced metal-binding in PSAPP mice is consistent with the lack of neurodegeneration in these animals. These findings were in stark contrast to the high metal ion content observed in human AD plaques, further implicating the role of metal ions in human AD pathology. PMID:19481608

  15. Amyloid Plaques in PSAPP Mice Bind Less Metal than Plaques in Human Alzheimer's Disease

    SciTech Connect

    Leskovjan, A.; Lanzirotti, A; Miller, L

    2009-01-01

    Amyloid beta (A{Beta}) is the primary component of Alzheimer's disease (AD) plaques, a key pathological feature of the disease. Metal ions of zinc (Zn), copper (Cu), iron (Fe), and calcium (Ca) are elevated in human amyloid plaques and are thought to be involved in neurodegeneration. Transgenic mouse models of AD also exhibit amyloid plaques, but fail to exhibit the high degree of neurodegeneration observed in humans. In this study, we imaged the Zn, Cu, Fe, and Ca ion distribution in the PSAPP transgenic mouse model representing end-stage AD (N = 6) using synchrotron X-ray fluorescence (XRF) microprobe. In order to account for differences in density in the plaques, the relative protein content was imaged with synchrotron Fourier transform infrared microspectroscopy (FTIRM) on the same samples. FTIRM results revealed a 61% increase in protein content in the plaques compared to the surrounding tissue. After normalizing to protein density, we found that the PSAPP plaques contained only a 29% increase in Zn and there was actually less Cu, Fe, and Ca in the plaque compared to the surrounding tissue. Since metal binding to A{beta} is thought to induce redox chemistry that is toxic to neurons, the reduced metal binding in PSAPP mice is consistent with the lack of neurodegeneration in these animals. These findings were in stark contrast to the high metal ion content observed in human AD plaques, further implicating the role of metal ions in human AD pathology.

  16. 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. PMID:26954017

  17. 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

  18. Development of magnetic resonance imaging based detection methods for beta amyloids via sialic acid-functionalized magnetic nanoparticles

    NASA Astrophysics Data System (ADS)

    Kouyoumdjian, Hovig

    The development of a non-invasive method for the detection of Alzheimer's disease is of high current interest, which can be critical in early diagnosis and in guiding preventive treatment of the disease. The aggregates of beta amyloids are a pathological hallmark of Alzheimer's disease. Carbohydrates such as sialic acid terminated gangliosides have been shown to play significant roles in initiation of amyloid aggregation. Herein, we report a biomimetic approach using sialic acid coated iron oxide superparamagnetic nanoparticles for in vitro detection in addition to the assessment of the in vivo mouse-BBB (Blood brain barrier) crossing of the BSA (bovine serum albumin)-modified ones. The sialic acid functionalized dextran nanoparticles were shown to bind with beta amyloids through several techniques including ELISA (enzyme linked immunosorbent assay), MRI (magnetic resonance imaging), TEM (transmission electron microscopy), gel electrophoresis and tyrosine fluorescence assay. The superparamagnetic nature of the nanoparticles allowed easy detection of the beta amyloids in mouse brains in both in vitro and ex vivo model by magnetic resonance imaging. Furthermore, the sialic acid nanoparticles greatly reduced beta amyloid induced cytotoxicity to SH-SY5Y neuroblastoma cells, highlighting the potential of the glyconanoparticles for detection and imaging of beta amyloids. Sialic acid functionalized BSA (bovine serum albumin) nanoparticles also showed significant binding to beta amyloids, through ELISA and ex vivo mouse brain MRI experiments. Alternatively, the BBB crossing was demonstrated by several techniques such as confocal microscopy, endocytosis, exocytosis assays and were affirmed by nanoparticles transcytosis assays through bEnd.3 endothelial cells. Finally, the BBB crossing was confirmed by analyzing the MRI signal of nanoparticle-injected CD-1 mice.

  19. 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.

  20. 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

  1. The Role of the 14–20 Domain of the Islet Amyloid Polypeptide in Amyloid Formation

    PubMed Central

    Gilead, Sharon; Gazit, Ehud

    2008-01-01

    The molecular mechanism of amyloid formation by the islet amyloid polypeptide (IAPP) has been intensively studied since its identification in the late 1980s. The IAPP(20–29) region is considered to be the central amyloidogenic module of the polypeptide. This assumption is mainly based on the amyloidogenic properties of the region and on the large sequence diversity within this region between the human and mouse IAPP, as the mouse IAPP does not form amyloids. A few years ago, another region within IAPP was identified that seems to be at least as important as IAPP(20–29) in facilitation of molecular recognition that leads to amyloid formation. Here, we reinforce our and others' previous findings by analyzing supporting evidence from the recent literature. Moreover, we provide new proofs to our hypothesis by comparing between the amyloidogenic properties of the two regions derived from the IAPP of cats, which is also known to form amyloid fibrils. PMID:18566678

  2. Islet amyloid polypeptide-induced membrane leakage involves uptake of lipids by forming amyloid fibers.

    PubMed

    Sparr, Emma; Engel, Maarten F M; Sakharov, Dmitri V; Sprong, Mariette; Jacobs, Jet; de Kruijff, Ben; Höppener, Jo W M; Killian, J Antoinette

    2004-11-01

    Fibril formation of islet amyloid polypeptide (IAPP) is associated with cell death of the insulin-producing pancreatic beta-cells in patients with Type 2 Diabetes Mellitus. A likely cause for the cytotoxicity of human IAPP is that it destroys the barrier properties of the cell membrane. Here, we show by fluorescence confocal microscopy on lipid vesicles that the process of hIAPP amyloid formation is accompanied by a loss of barrier function, whereby lipids are extracted from the membrane and taken up in the forming amyloid deposits. No membrane interaction was observed when preformed fibrils were used. It is proposed that lipid uptake from the cell membrane is responsible for amyloid-induced membrane damage and that this represents a general mechanism underlying the cytotoxicity of amyloid forming proteins. PMID:15527771

  3. Abnormal gephyrin immunoreactivity associated with Alzheimer disease pathologic changes.

    PubMed

    Hales, Chadwick M; Rees, Howard; Seyfried, Nicholas T; Dammer, Eric B; Duong, Duc M; Gearing, Marla; Montine, Thomas J; Troncoso, Juan C; Thambisetty, Madhav; Levey, Allan I; Lah, James J; Wingo, Thomas S

    2013-11-01

    Many neurodegenerative disorders involve the abnormal accumulation of proteins. In addition to the pathologic hallmarks of neurofibrillary tangles and β-amyloid plaques in Alzheimer disease (AD), here we show that abnormal accumulations of gephyrin, an inhibitory receptor-anchoring protein, are highly correlated with the neuropathologic diagnosis of AD in 17 AD versus 14 control cases. Furthermore, gephyrin accumulations were specific for AD and not seen in normal controls or other neurodegenerative diseases including Parkinson disease, corticobasal degeneration, and frontotemporal degeneration. Gephyrin accumulations in AD overlapped with β-amyloid plaques and, more rarely, neurofibrillary tangles. Biochemical and proteomic studies of AD and control brain samples suggested alterations in gephyrin solubility and reveal elevated levels of gephyrin lower-molecular-weight species in the AD insoluble fraction. Because gephyrin is involved in synaptic organization and synaptic dysfunction is an early event in AD, these findings point to its possible role in the pathogenesis of AD. PMID:24128675

  4. Quantitative characterization of brain β-amyloid using a joint PiB/FDG PET image histogram

    NASA Astrophysics Data System (ADS)

    Camp, Jon J.; Hanson, Dennis P.; Holmes, David R.; Kemp, Bradley J.; Senjem, Matthew L.; Murray, Melissa E.; Dickson, Dennis W.; Parisi, Joseph; Petersen, Ronald C.; Lowe, Val J.; Robb, Richard A.

    2014-03-01

    A complex analysis performed by spatial registration of PiB and MRI patient images in order to localize the PiB signal to specific cortical brain regions has been proven effective in identifying imaging characteristics associated with underlying Alzheimer's Disease (AD) and Lewy Body Disease (LBD) pathology. This paper presents an original method of image analysis and stratification of amyloid-related brain disease based on the global spatial correlation of PiB PET images with 18F-FDG PET images (without MR images) to categorize the PiB signal arising from the cortex. Rigid registration of PiB and 18F-FDG images is relatively straightforward, and in registration the 18F-FDG signal serves to identify the cortical region in which the PiB signal is relevant. Cortical grey matter demonstrates the highest levels of amyloid accumulation and therefore the greatest PiB signal related to amyloid pathology. The highest intensity voxels in the 18F-FDG image are attributed to the cortical grey matter. The correlation of the highest intensity PiB voxels with the highest 18F-FDG values indicates the presence of β-amyloid protein in the cortex in disease states, while correlation of the highest intensity PiB voxels with mid-range 18F-FDG values indicates only nonspecific binding in the white matter.

  5. Conformational Switching and Nanoscale Assembly of Human Prion Protein into Polymorphic Amyloids via Structurally Labile Oligomers.

    PubMed

    Dalal, Vijit; Arya, Shruti; Bhattacharya, Mily; Mukhopadhyay, Samrat

    2015-12-29

    Conformational switching of the prion protein (PrP) from an α-helical normal cellular form (PrP(C)) to an aggregation-prone and self-propagating β-rich scrapie form (PrP(Sc)) underlies the molecular basis of pathogenesis in prion diseases. Anionic lipids play a critical role in the misfolding and conformational conversion of the membrane-anchored PrP into the amyloidogenic pathological form. In this work, we have used a diverse array of techniques to interrogate the early intermediates during amyloid formation from recombinant human PrP in the presence of a membrane mimetic anionic detergent such as sodium dodecyl sulfate. We have been able to detect and characterize two distinct types of interconvertible oligomers. Our results demonstrate that highly ordered large β-oligomers represent benign off-pathway intermediates that lack the ability to mature into amyloid fibrils. On the contrary, structurally labile small oligomers are capable of switching to an ordered amyloid-state that exhibits profound toxicity to mammalian cells. Our fluorescence resonance energy transfer measurements revealed that the partially disordered PrP serves as precursors to small amyloid-competent oligomers. These on-pathway oligomers are eventually sequestered into higher order supramolecular assemblies that conformationally mature into polymorphic amyloids possessing varied nanoscale morphology as evident by the atomic force microscopy imaging. The nanoscale diversity of fibril architecture is attributed to the heterogeneous ensemble of early obligatory oligomers and offers a plausible explanation for the existence of multiple prion strains in vivo. PMID:26645611

  6. Functional Amyloid Signaling via the Inflammasome, Necrosome, and Signalosome: New Therapeutic Targets in Heart Failure

    PubMed Central

    Parry, Traci L.; Melehani, Jason H.; Ranek, Mark J.; Willis, Monte S.

    2015-01-01

    As the most common cause of death and disability, globally, heart disease remains an incompletely understood enigma. A growing number of cardiac diseases are being characterized by the presence of misfolded proteins underlying their pathophysiology, including cardiac amyloidosis and dilated cardiomyopathy (DCM). At least nine precursor proteins have been implicated in the development of cardiac amyloidosis, most commonly caused by multiple myeloma light chain disease and disease-causing mutant or wildtype transthyretin (TTR). Similarly, aggregates with PSEN1 and COFILIN-2 have been identified in up to one-third of idiopathic DCM cases studied, indicating the potential predominance of misfolded proteins in heart failure. In this review, we present recent evidence linking misfolded proteins mechanistically with heart failure and present multiple lines of new therapeutic approaches that target the prevention of misfolded proteins in cardiac TTR amyloid disease. These include multiple small molecule pharmacological chaperones now in clinical trials designed specifically to support TTR folding by rational design, such as tafamidis, and chaperones previously developed for other purposes, such as doxycycline and tauroursodeoxycholic acid. Last, we present newly discovered non-pathological “functional” amyloid structures, such as the inflammasome and necrosome signaling complexes, which can be activated directly by amyloid. These may represent future targets to successfully attenuate amyloid-induced proteotoxicity in heart failure, as the inflammasome, for example, is being therapeutically inhibited experimentally in autoimmune disease. Together, these studies demonstrate multiple novel points in which new therapies may be used to primarily prevent misfolded proteins or to inhibit their downstream amyloid-mediated effectors, such as the inflammasome, to prevent proteotoxicity in heart failure. PMID:26664897

  7. Functional Amyloid Signaling via the Inflammasome, Necrosome, and Signalosome: New Therapeutic Targets in Heart Failure.

    PubMed

    Parry, Traci L; Melehani, Jason H; Ranek, Mark J; Willis, Monte S

    2015-01-01

    As the most common cause of death and disability, globally, heart disease remains an incompletely understood enigma. A growing number of cardiac diseases are being characterized by the presence of misfolded proteins underlying their pathophysiology, including cardiac amyloidosis and dilated cardiomyopathy (DCM). At least nine precursor proteins have been implicated in the development of cardiac amyloidosis, most commonly caused by multiple myeloma light chain disease and disease-causing mutant or wildtype transthyretin (TTR). Similarly, aggregates with PSEN1 and COFILIN-2 have been identified in up to one-third of idiopathic DCM cases studied, indicating the potential predominance of misfolded proteins in heart failure. In this review, we present recent evidence linking misfolded proteins mechanistically with heart failure and present multiple lines of new therapeutic approaches that target the prevention of misfolded proteins in cardiac TTR amyloid disease. These include multiple small molecule pharmacological chaperones now in clinical trials designed specifically to support TTR folding by rational design, such as tafamidis, and chaperones previously developed for other purposes, such as doxycycline and tauroursodeoxycholic acid. Last, we present newly discovered non-pathological "functional" amyloid structures, such as the inflammasome and necrosome signaling complexes, which can be activated directly by amyloid. These may represent future targets to successfully attenuate amyloid-induced proteotoxicity in heart failure, as the inflammasome, for example, is being therapeutically inhibited experimentally in autoimmune disease. Together, these studies demonstrate multiple novel points in which new therapies may be used to primarily prevent misfolded proteins or to inhibit their downstream amyloid-mediated effectors, such as the inflammasome, to prevent proteotoxicity in heart failure. PMID:26664897

  8. Contemporary treatment of amyloid heart disease.

    PubMed

    Palecek, Tomas; Fikrle, Michal; Nemecek, Eduard; Bauerova, Lenka; Kuchynka, Petr; Louch, William E; Spicka, Ivan; Rysava, Romana

    2015-01-01

    The amyloidoses represent a group of diseases characterized by extracellular deposition of abnormal protein, amyloid, which is formed by insoluble extracellular fibrils in β-pleated sheets. Although cardiac involvement may occur in all types of amyloidoses, clinically relevant amyloid cardiomyopathy is a typical feature of AL amyloidosis and transthyretin-related amyloidoses. Congestive heart failure represents the commonest manifestation of amyloid heart disease. Noninvasive imaging techniques, especially echocardiography and cardiac magnetic resonance, play a major role in the diagnosis of amyloid cardiomyopathy; however, histological confirmation and exact typing of amyloid deposits is necessary whether in extracardiac location or directly in the myocardium. Early diagnosis of amyloid heart disease is of utmost importance as the presence and especially the severity of cardiac involvement generally drives the prognosis of affected subjects and plays a major role in determining the intensity of specific treatment, namely in AL amyloidosis. The management of patients with amyloid heart disease is complex. Loop diuretics together with aldosterone antagonists represent the basis for influencing signs of congestion. In AL amyloidosis, high-dose chemotherapy followed by autologous stem cell transplantation is generally considered to be a front-line treatment option, if the disease is diagnosed at its early stage. The combination of mephalan with dexamethasone has been the standard therapy for severely affected individuals; however, the combinations with several novel agents including immunomodulatory drugs and bortezomibe have been tested in clinical trials with promising results. New therapeutic substances with the potential to slow or even stop the progression of transthyretin-related amyloidosis are also extensively studied. PMID:25483951

  9. Deletion of the γ-secretase subunits Aph1B/C impairs memory and worsens the deficits of knock-in mice modeling the Alzheimer-like familial Danish dementia

    PubMed Central

    Biundo, Fabrizio; Ishiwari, Keita; Del Prete, Dolores; D'Adamio, Luciano

    2016-01-01

    Mutations in BRI2/ITM2b genes cause Familial British and Danish Dementias (FBD and FDD), which are pathogenically similar to Familial Alzheimer Disease (FAD). BRI2 inhibits processing of Amyloid precursor protein (APP), a protein involved in FAD pathogenesis. Accumulation of a carboxyl-terminal APP metabolite –β-CTF- causes memory deficits in a knock-in mouse model of FDD, called FDDKI. We have investigated further the pathogenic function of β-CTF studying the effect of Aph1B/C deletion on FDDKI mice. This strategy is based on the evidence that deletion of Aph1B/C proteins, which are components of the γ-secretase that cleaves β-CTF, results in stabilization of β-CTF and a reduction of Aβ. We found that both the FDD mutation and the Aph1B/C deficiency mildly interfered with spatial long term memory, spatial working/short-term memory and long-term contextual fear memory. In addition, the Aph1BC deficiency induced deficits in long-term cued fear memory. Moreover, the two mutations have additive adverse effects as they compromise the accuracy of spatial long-term memory and induce spatial memory retention deficits in young mice. Overall, the data are consistent with a role for β-CTF in the genesis of memory deficits. PMID:26942869

  10. Rifampicin is a candidate preventive medicine against amyloid-β and tau oligomers.

    PubMed

    Umeda, Tomohiro; Ono, Kenjiro; Sakai, Ayumi; Yamashita, Minato; Mizuguchi, Mineyuki; Klein, William L; Yamada, Masahito; Mori, Hiroshi; Tomiyama, Takami

    2016-05-01

    Amyloid-β, tau, and α-synuclein, or more specifically their soluble oligomers, are the aetiologic molecules in Alzheimer's disease, tauopathies, and α-synucleinopathies, respectively. These proteins have been shown to interact to accelerate each other's pathology. Clinical studies of amyloid-β-targeting therapies in Alzheimer's disease have revealed that the treatments after disease onset have little benefit on patient cognition. These findings prompted us to explore a preventive medicine which is orally available, has few adverse effects, and is effective at reducing neurotoxic oligomers with a broad spectrum. We initially tested five candidate compounds: rifampicin, curcumin, epigallocatechin-3-gallate, myricetin, and scyllo-inositol, in cells expressing amyloid precursor protein (APP) with the Osaka (E693Δ) mutation, which promotes amyloid-β oligomerization. Among these compounds, rifampicin, a well-known antibiotic, showed the strongest activities against the accumulation and toxicity (i.e. cytochrome c release from mitochondria) of intracellular amyloid-β oligomers. Under cell-free conditions, rifampicin inhibited oligomer formation of amyloid-β, tau, and α-synuclein, indicating its broad spectrum. The inhibitory effects of rifampicin against amyloid-β and tau oligomers were evaluated in APPOSK mice (amyloid-β oligomer model), Tg2576 mice (Alzheimer's disease model), and tau609 mice (tauopathy model). When orally administered to 17-month-old APPOSK mice at 0.5 and 1 mg/day for 1 month, rifampicin reduced the accumulation of amyloid-β oligomers as well as tau hyperphosphorylation, synapse loss, and microglial activation in a dose-dependent manner. In the Morris water maze, rifampicin at 1 mg/day improved memory of the mice to a level similar to that in non-transgenic littermates. Rifampicin also inhibited cytochrome c release from the mitochondria and caspase 3 activation in the hippocampus. In 13-month-old Tg2576 mice, oral rifampicin at 0.5 mg

  11. Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer's disease.

    PubMed

    Fan, Zhen; Okello, Aren A; Brooks, David J; Edison, Paul

    2015-12-01

    Amyloid deposition, tangle formation, neuroinflammation and neuronal dysfunction are pathological processes involved in Alzheimer's disease. However, the relative role of these processes in driving disease progression is still unclear. The aim of this positron emission tomography study was to: (i) investigate longitudinal changes of microglial activation, amyloid and glucose metabolism; and (ii) assess the temporospatial relationship between these three processes in Alzheimer's disease. A group of eight patients with a diagnosis of Alzheimer's disease (66 ± 4.8 years) and 14 healthy controls (65 ± 5.5 years) underwent T1 and T2 magnetic resonance imaging, along with (11)C-(R)-PK11195, (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography scans for microglial activation, amyloid deposition and glucose metabolism. All patients were followed-up with repeated magnetic resonance imaging and three positron emission tomography scans after 16 months. Parametric maps were interrogated using region of interest analysis, Statistical Parametric Mapping, and between-group correlation analysis at voxel-level using Biological Parametric Mapping. At baseline, patients with Alzheimer's disease showed significantly increased microglial activation compared to the control subjects. During follow-up, for the first time, we found that while there is a progressive reduction of glucose metabolism, there was a longitudinal increase of microglial activation in the majority of the patients with Alzheimer's disease. Voxel-wise correlation analysis revealed that microglial activation in patients with Alzheimer's disease was positively correlated with amyloid deposition and inversely correlated with regional cerebral metabolic rate at voxel level over time. Even though one of the limitations of this study is the lack of longitudinal follow-up of healthy control subjects, this study demonstrates that there is persistent neuroinflammation throughout the Alzheimer

  12. Amyloid-degrading ability of nattokinase from Bacillus subtilis natto.

    PubMed

    Hsu, Ruei-Lin; Lee, Kung-Ta; Wang, Jung-Hao; Lee, Lily Y-L; Chen, Rita P-Y

    2009-01-28

    More than 20 unrelated proteins can form amyloid fibrils in vivo which are related to various diseases, such as Alzheimer's disease, prion disease, and systematic amyloidosis. Amyloid fibrils are an ordered protein aggregate with a lamellar cross-beta structure. Enhancing amyloid clearance is one of the targets of the therapy of these amyloid-related diseases. Although there is debate on whether the toxicity is due to amyloids or their precursors, research on the degradation of amyloids may help prevent or alleviate these diseases. In this study, we explored the amyloid-degrading ability of nattokinase, a fibrinolytic subtilisin-like serine protease, and determined the optimal conditions for amyloid hydrolysis. This ability is shared by proteinase K and subtilisin Carlsberg, but not by trypsin or plasmin. PMID:19117402

  13. A brief overview of amyloids and Alzheimer’s disease

    PubMed Central

    Ow, Sian-Yang; Dunstan, Dave E

    2014-01-01

    Amyloid fibrils are self-assembled fibrous protein aggregates that are associated with a number of presently incurable diseases such as Alzheimer’s and Parkinson’s disease. Millions of people worldwide suffer from amyloid diseases. This review summarizes the unique cross-β structure of amyloid fibrils, morphological variations, the kinetics of amyloid fibril formation, and the cytotoxic effects of these fibrils and oligomers. Alzheimer’s disease is also explored as an example of an amyloid disease to show the various approaches to treat these amyloid diseases. Finally, this review investigates the nanotechnological and biological applications of amyloid fibrils; as well as a summary of the typical biological pathways involved in the disposal of amyloid fibrils and their precursors. PMID:25042050

  14. Physical and structural basis for polymorphism in amyloid fibrils

    PubMed Central

    Tycko, Robert

    2014-01-01

    As our understanding of the molecular structures of amyloid fibrils has matured over the past 15 years, it has become clear that, while amyloid fibrils do have well-defined molecular structures, their molecular structures are not uniquely determined by the amino acid sequences of their constituent peptides and proteins. Self-propagating molecular-level polymorphism is a common phenomenon. This article reviews current information about amyloid fibril structures, variations in molecular structures that underlie amyloid polymorphism, and physical considerations that explain the development and persistence of amyloid polymorphism. Much of this information has been obtained through solid state nuclear magnetic resonance measurements. The biological significance of amyloid polymorphism is also discussed briefly. Although this article focuses primarily on studies of fibrils formed by amyloid-β peptides, the same principles apply to many amyloid-forming peptides and proteins. PMID:25179159

  15. Rapid Generation of Amyloid from Native Proteins In vitro

    PubMed Central

    Dorta-Estremera, Stephanie M; Li, Jingjing; Cao, Wei

    2013-01-01

    Proteins carry out crucial tasks in organisms by exerting functions elicited from their specific three dimensional folds. Although the native structures of polypeptides fulfill many purposes, it is now recognized that most proteins can adopt an alternative assembly of beta-sheet rich amyloid. Insoluble amyloid fibrils are initially associated with multiple human ailments, but they are increasingly shown as functional players participating in various important cellular processes. In addition, amyloid deposited in patient tissues contains nonproteinaceous components, such as nucleic acids and glycosaminoglycans (GAGs). These cofactors can facilitate the formation of amyloid, resulting in the generation of different types of insoluble precipitates. By taking advantage of our understanding how proteins misfold via an intermediate stage of soluble amyloid precursor, we have devised a method to convert native proteins to amyloid fibrils in vitro. This approach allows one to prepare amyloid in large quantities, examine the properties of amyloid generated from specific proteins, and evaluate the structural changes accompanying the conversion. PMID:24335677

  16. Cell Adhesion on Amyloid Fibrils Lacking Integrin Recognition Motif.

    PubMed

    Jacob, Reeba S; George, Edna; Singh, Pradeep K; Salot, Shimul; Anoop, Arunagiri; Jha, Narendra Nath; Sen, Shamik; Maji, Samir K

    2016-03-01

    Amyloids are highly ordered, cross-β-sheet-rich protein/peptide aggregates associated with both human diseases and native functions. Given the well established ability of amyloids in interacting with cell membranes, we hypothesize that amyloids can serve as universal cell-adhesive substrates. Here, we show that, similar to the extracellular matrix protein collagen, amyloids of various proteins/peptides support attachment and spreading of cells via robust stimulation of integrin expression and formation of integrin-based focal adhesions. Additionally, amyloid fibrils are also capable of immobilizing non-adherent red blood cells through charge-based interactions. Together, our results indicate that both active and passive mechanisms contribute to adhesion on amyloid fibrils. The present data may delineate the functional aspect of cell adhesion on amyloids by various organisms and its involvement in human diseases. Our results also raise the exciting possibility that cell adhesivity might be a generic property of amyloids. PMID:26742841

  17. Post-Mortem evaluation of amyloid-dopamine terminal positron emission tomography dementia classifications.

    PubMed

    Albin, Roger L; Fisher-Hubbard, Amanda; Shanmugasundaram, Krithika; Koeppe, Robert A; Burke, James F; Camelo-Piragua, Sandra; Lieberman, Andrew P; Giordani, Bruno; Frey, Kirk A

    2015-11-01

    Clinical classification of early dementia and mild cognitive impairment (MCI) is imprecise. We reported previously that molecular imaging classification of early dementia and MCI with dual amyloid and dopamine terminal positron emission tomography differs significantly from expert clinical classification. We now report pathological diagnoses in a substantial subset of our previously imaged subjects. Among 36 subjects coming to autopsy, imaging classifications and pathological diagnosis were concordant in 33 cases (κ = 0.85). This approach enhanced specificity of Alzheimer's disease diagnosis. The strong concordance of imaging-based classifications and pathological diagnoses suggests that this imaging approach will be useful in establishing more accurate and convenient classification biomarkers for dementia research. PMID:26183692

  18. Immunotherapy for the treatment of Alzheimer’s disease: amyloid-β or tau, which is the right target?

    PubMed Central

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

    2014-01-01

    Alzheimer’s disease (AD) is characterized by the presence of amyloid plaques composed mainly of amyloid-β (Aβ) protein. Overproduction or slow clearance of Aβ initiates a cascade of pathologic events that may lead to formation of neurofibrillary tangles, neuronal cell death, and dementia. Although immunotherapy in animal models has been demonstrated to be successful at removing plaques or prefibrillar forms of Aβ, clinical trials have yielded disappointing results. The lack of substantial cognitive improvement obtained by targeting Aβ raises the question of whether or not this is the correct target. Another important pathologic process in the AD brain is tau aggregation, which seems to become independent once initiated. Recent studies targeting tau in AD mouse models have displayed evidence of cognitive improvement, providing a novel therapeutic approach for the treatment of AD. In this review, we describe new advances in immunotherapy targeting Aβ peptide and tau protein, as well as future directions. PMID:27471697

  19. Appropriate Use Criteria for Amyloid PET

    PubMed Central

    Johnson, Keith A.; Minoshima, Satoshi; Bohnen, Nicolaas I.; Donohoe, Kevin J.; Foster, Norman L.; Herscovitch, Peter; Karlawish, Jason H.; Rowe, Christopher C.; Carrillo, Maria C.; Hartley, Dean M.; Hedrick, Saima; Mitchell, Kristi; Pappas, Virginia; Thies, William H.

    2013-01-01

    Positron Emission Tomography (PET) of brain amyloid-beta is a technology that is becoming more available, but its clinical utility in medical practice requires careful definition. In order to provide guidance to dementia care practitioners, patients and caregivers, the Alzheimer Association and the Society of Nuclear Medicine and Molecular Imaging convened the Amyloid Imaging Taskforce (AIT). The AIT considered a broad range of specific clinical scenarios in which amyloid PET could potentially be appropriately used. Peer-reviewed, published literature was searched to ascertain available evidence relevant to these scenarios, and the AIT developed a consensus of expert opinion. While empirical evidence of impact on clinical outcomes is not yet available, a set of specific Appropriate Use Criteria (AUC) were agreed upon that define the types of patients and clinical circumstances in which amyloid PET could be used. Both appropriate and inappropriate uses were considered and formulated, and are reported and discussed here. Because both dementia care and amyloid PET technology are in active development, these AUC will require periodic reassessment. Future research directions are also outlined, including diagnostic utility and patient-centered outcomes. PMID:23360977

  20. Shear flow promotes amyloid-{beta} fibrilization.

    PubMed

    Dunstan, Dave E; Hamilton-Brown, Paul; Asimakis, Peter; Ducker, William; Bertolini, Joseph

    2009-12-01

    The rate of formation of amyloid fibrils in an aqueous solution of amyloid-beta (Abeta) is greatly increased when the solution is sheared. When Abeta solution is stirred with a magnetic stirrer bar at 37 degrees C, a rapid increase in thioflavin T fluorescence is observed. Atomic Force Microscopy (AFM) images show the formation of aggregates, the growth of fibrils and the intertwining of the fibrils with time. Circular dichroism (CD) spectroscopy of samples taken after stirring shows a transition from random coil to alpha-helix to beta-sheet secondary structure over 20 h at 37 degrees C. The fluorescence, AFM and CD measurements are all consistent with the formation of amyloid fibrils. Quiescent, non-stirred solutions incubated at 37 degrees C showed no evidence of amyloid formation over a period of 3 days. Couette flow was found to accelerate the formation of amyloid fibrils demonstrating that the primary effect of stirring is not mixing but shearing. Only very small shear forces are applied to individual molecules in our experiments. Simple calculation suggests that the force is too small to support a hypothesis that shearing promotes partial unfolding of the protein as is observed. PMID:19850675

  1. Functional Amyloids in the Mouse Sperm Acrosome

    PubMed Central

    Guyonnet, Benoit; Egge, Nathan

    2014-01-01

    The acrosomal matrix (AM) is an insoluble structure within the sperm acrosome that serves as a scaffold controlling the release of AM-associated proteins during the sperm acrosome reaction. The AM also interacts with the zona pellucida (ZP) that surrounds the oocyte, suggesting a remarkable stability that allows its survival despite being surrounded by proteolytic and hydrolytic enzymes released during the acrosome reaction. To date, the mechanism responsible for the stability of the AM is not known. Our studies demonstrate that amyloids are present within the sperm AM and contribute to the formation of an SDS- and formic-acid-resistant core. The AM core contained several known amyloidogenic proteins, as well as many proteins predicted to form amyloid, including several ZP binding proteins, suggesting a functional role for the amyloid core in sperm-ZP interactions. While stable at pH 3, at pH 7, the sperm AM rapidly destabilized. The pH-dependent dispersion of the AM correlated with a change in amyloid structure leading to a loss of mature forms and a gain of immature forms, suggesting that the reversal of amyloid is integral to AM dispersion. PMID:24797071

  2. Heparan Sulfate Proteoglycans Are Important for Islet Amyloid Formation and Islet Amyloid Polypeptide-induced Apoptosis*

    PubMed Central

    Oskarsson, Marie E.; Singh, Kailash; Wang, Jian; Vlodavsky, Israel; Li, Jin-ping; Westermark, Gunilla T.

    2015-01-01

    Deposition of β cell toxic islet amyloid is a cardinal finding in type 2 diabetes. In addition to the main amyloid component islet amyloid polypeptide (IAPP), heparan sulfate proteoglycan is constantly present in the amyloid deposit. Heparan sulfate (HS) side chains bind to IAPP, inducing conformational changes of the IAPP structure and an acceleration of fibril formation. We generated a double-transgenic mouse strain (hpa-hIAPP) that overexpresses human heparanase and human IAPP but is deficient of endogenous mouse IAPP. Culture of hpa-hIAPP islets in 20 mm glucose resulted in less amyloid formation compared with the amyloid load developed in cultured islets isolated from littermates expressing human IAPP only. A similar reduction of amyloid was achieved when human islets were cultured in the presence of heparin fragments. Furthermore, we used CHO cells and the mutant CHO pgsD-677 cell line (deficient in HS synthesis) to explore the effect of cellular HS on IAPP-induced cytotoxicity. Seeding of IAPP aggregation on CHO cells resulted in caspase-3 activation and apoptosis that could be prevented by inhibition of caspase-8. No IAPP-induced apoptosis was seen in HS-deficient CHO pgsD-677 cells. These results suggest that β cell death caused by extracellular IAPP requires membrane-bound HS. The interaction between HS and IAPP or the subsequent effects represent a possible therapeutic target whose blockage can lead to a prolonged survival of β cells. PMID:25922077

  3. Bapineuzumab Alters Aβ Composition: Implications for the Amyloid Cascade Hypothesis and Anti-Amyloid Immunotherapy

    PubMed Central

    Roher, Alex E.; Cribbs, David H.; Kim, Ronald C.; Maarouf, Chera L.; Whiteside, Charisse M.; Kokjohn, Tyler A.; Daugs, Ian D.; Head, Elizabeth; Liebsack, Carolyn; Serrano, Geidy; Belden, Christine; Sabbagh, Marwan N.; Beach, Thomas G.

    2013-01-01

    The characteristic neuropathological changes associated with Alzheimer’s disease (AD) and other lines of evidence support the amyloid cascade hypothesis. Viewing amyloid deposits as the prime instigator of dementia has now led to clinical trials of multiple strategies to remove or prevent their formation. We performed neuropathological and biochemical assessments of 3 subjects treated with bapineuzumab infusions. Histological analyses were conducted to quantify amyloid plaque densities, Braak stages and the extent of cerebral amyloid angiopathy (CAA). Amyloid-β (Aβ) species in frontal and temporal lobe samples were quantified by ELISA. Western blots of amyloid-β precursor protein (AβPP) and its C-terminal (CT) fragments as well as tau species were performed. Bapineuzumab-treated (Bapi-AD) subjects were compared to non-immunized age-matched subjects with AD (NI-AD) and non-demented control (NDC) cases. Our study revealed that Bapi-AD subjects exhibited overall amyloid plaque densities similar to those of NI-AD cases. In addition, CAA was moderate to severe in NI-AD and Bapi-AD patients. Although histologically-demonstrable leptomeningeal, cerebrovascular and neuroparenchymal-amyloid densities all appeared unaffected by treatment, Aβ peptide profiles were significantly altered in Bapi-AD subjects. There was a trend for reduction in total Aβ42 levels as well as an increase in Aβ40 which led to a corresponding significant decrease in Aβ42:Aβ40 ratio in comparison to NI-AD subjects. There were no differences in the levels of AβPP, CT99 and CT83 or tau species between Bapi-AD and NI-AD subjects. The remarkable alteration in Aβ profiles reveals a dynamic amyloid production in which removal and depositional processes were apparently perturbed by bapineuzumab therapy. Despite the alteration in biochemical composition, all 3 immunized subjects exhibited continued cognitive decline. PMID:23555764

  4. Structure of amyloid oligomers and their mechanisms of toxicities: Targeting amyloid oligomers using novel therapeutic approaches.

    PubMed

    Salahuddin, Parveen; Fatima, Munazza Tamkeen; Abdelhameed, Ali Saber; Nusrat, Saima; Khan, Rizwan Hasan

    2016-05-23

    Protein misfolding is one of the leading causes of amyloidoses. Protein misfolding occurs from changes in environmental conditions and host of other factors, including errors in post-translational modifications, increase in the rate of degradation, error in trafficking, loss of binding partners and oxidative damage. Misfolding gives rise to the formation of partially unfolded or misfolded intermediates, which have exposed hydrophobic residues and interact with complementary intermediates to form oligomers and consequently protofibrils and fibrils. The amyloid fibrils accumulate as amyloid deposits in the brain and central nervous system in Alzheimer's disease (AD), Prion disease and Parkinson's disease (PD). Initial studies have shown that amyloid fibrils were the main culprit behind toxicity that cause neurodegenerative diseases. However, attention shifted to the cytotoxicity of amyloid fibril precursors, notably amyloid oligomers, which are the major cause of toxicity. The mechanism of toxicity triggered by amyloid oligomers remains elusive. In this review, we have focused on the current knowledge of the structures of different aggregated states, including amyloid fibril, protofibrils, annular aggregates and oligomers. Based on the studies on the mechanism of toxicities, we hypothesize two major possible mechanisms of toxicities instigated by oligomers of Aβ (amyloid beta), PrP (prion protein) (106-126), and α-Syn (alpha-synuclein) including direct formation of ion channels and neuron membrane disruption by the increase in membrane conductance or leakage in the presence of small globulomers to large prefibrillar assemblies. Finally, we have discussed various novel innovative approaches that target amyloid oligomers in Alzheimer's diseases, Prion disease and Parkinson's disease. PMID:26974374

  5. Rhynchophylline Protects Against the Amyloid β-Induced Increase of Spontaneous Discharges in the Hippocampal CA1 Region of Rats.

    PubMed

    Shao, Hui; Mi, Ze; Ji, Wei-gang; Zhang, Cheng-huan; Zhang, Teng; Ren, Shuan-cheng; Zhu, Zhi-ru

    2015-11-01

    Accumulated soluble amyloid β (Aβ)-induced aberrant neuronal network activity has been recognized as a key causative factor leading to cognitive deficits which are the most outstanding characteristic of Alzheimer's disease (AD). As an important structure associated with learning and memory, the hippocampus is one of the brain regions that are impaired very early in AD, and the hippocampal CA1 region is selectively vulnerable to soluble Aβ oligomers. Our recent study showed that soluble Aβ1-42 oligomers induced hyperactivity and perturbed the firing patterns in hippocampal neurons. Rhynchophylline (RIN) is an important active tetracyclic oxindole alkaloid isolated from Uncaria rhynchophylla which is a traditional Chinese medicine and often used to treat central nervous system illnesses such as hypertension, convulsions, tremor, stroke etc. Previous evidence showed that RIN possessed neuroprotective effects of improving the cognitive function of mice with Alzheimer-like symptoms. In the present study, we aimed to investigate the protective effect of RIN against soluble Aβ1-42 oligomers-induced hippocampal hyperactivity. The results showed that (1) the mean frequency of spontaneous discharge was increased by the local application of 3 μM soluble Aβ1-42 oligomers; (2) 30 μM RIN did not exert any obvious effects on basal physiological discharges; and (3) treatment with RIN effectively inhibited the soluble Aβ1-42 oligomers-induced enhancement of spontaneous discharge, in a concentration-dependent manner with an IC50 = 9.0 μM. These in vivo electrophysiological results indicate that RIN can remold the spontaneous discharges disturbed by Aβ and counteract the deleterious effect of Aβ1-42 on neural circuit. The experimental findings provide further evidence to affirm the potential of RIN as a worthy candidate for further development into a therapeutic agent for AD. PMID:26441223

  6. Apolipoprotein C-II Adopts Distinct Structures in Complex with Micellar and Submicellar Forms of the Amyloid-Inhibiting Lipid-Mimetic Dodecylphosphocholine.

    PubMed

    Ryan, Timothy M; Griffin, Michael D W; McGillivray, Duncan J; Knott, Robert B; Wood, Kathleen; Masters, Colin L; Kirby, Nigel; Curtain, Cyril C

    2016-01-01

    The formation of amyloid deposits is a common feature of a broad range of diseases, including atherosclerosis, Alzheimer's disease, and Parkinson's disease. The basis and role of amyloid deposition in the pathogenesis of these diseases is still being defined, however an interesting feature of amyloidogenic proteins is that the majority of the pathologically associated proteins are involved in lipid homeostasis, be it in lipid transport, incorporation into membranes, or the regulation of lipid pathways. Thus, amyloid-forming proteins commonly bind lipids, and lipids are generally involved in the proper folding of these proteins. However, understanding of the basis for these lipid-related aspects of amyloidogenesis is lacking. Thus, we have used the apolipoprotein C-II amyloid model system in conjunction with x-ray and neutron scattering analyses to address this problem. Apolipoprotein C-II is a well-studied model system of systemic amyloid fibril formation, with a clear and well-defined pathway for fibril formation, where the effects of lipid interaction are characterized, particularly for the lipid mimetic dodecylphosphocholine. We show that the micellar state of an inhibitory lipid can have a very significant effect on protein conformation, with micelles stabilizing a particular α-helical structure, whereas submicellar lipids stabilize a very different dimeric, α-helical structure. These results indicate that lipids may have an important role in the development and progression of amyloid-related diseases. PMID:26745412

  7. The pathological and biochemical identification of possible seed‐lesions of transmitted transthyretin amyloidosis after domino liver transplantation

    PubMed Central

    Yoshinaga, Tsuneaki; Sekijima, Yoshiki; Kametani, Fuyuki; Miyashita, Kana; Hachiya, Naomi; Tanaka, Tomohiro; Kokudo, Norihiro; Higuchi, Keiichi; Ikeda, Shu‐ichi

    2016-01-01

    Abstract The most serious issue in domino liver transplantation (DLT) using liver grafts from patients with transthyretin (TTR)‐related familial amyloid polyneuropathy (FAP) is the development of iatrogenic transmitted amyloidosis (de novo amyloidosis) in DLT‐recipients. However, little is known regarding the mechanisms of the initial stage of amyloid formation in these recipients. We detected initial lesions (possible seed‐lesions) of this iatrogenic amyloidosis in two recipients following liver grafting from FAP patients. Patient 1 underwent DLT at age 65 from an FAP patient with a Val30Met TTR variant and patient 2 received DLT from an FAP patient with a Val30Leu TTR variant at age 32. Patient 2 was started on diflunisal administration from 4 years after DLT. While neither patient had symptoms of FAP, small amyloid deposits were detected on the gastroduodenal mucosae 14 months and 12 years after DLT in patient 1 and patient 2, respectively. The amyloid was analyzed using a laser microdissection system and tandem mass spectrometry. Biochemical analysis indicated that the amyloid was composed mostly of variant TTR produced from the transplanted liver in both patients. In patient 1, wild‐type TTR amyloid was detectable in the duodenal mucosa obtained 2 years after DLT. This is the first study to successfully capture the pathological and biochemical features of initial‐stage amyloid lesions in DLT recipients. The findings clearly indicate that amyloid deposition can start by deposition of variant TTR followed by deposition of wild‐type TTR, and blocking of amyloid seed formation from variant TTR may be a key to prevent or delay the development of DLT‐associated amyloidosis. PMID:27499917

  8. Fibrillar dimer formation of islet amyloid polypeptides

    NASA Astrophysics Data System (ADS)

    Chiu, Chi-cheng; de Pablo, Juan J.

    2015-09-01

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 - 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 - 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  9. Fibrillar dimer formation of islet amyloid polypeptides

    SciTech Connect

    Chiu, Chi-cheng; de Pablo, Juan J.

    2015-05-08

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 – 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 – 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  10. Neuropsychological Effects of Cerebral Amyloid Angiopathy.

    PubMed

    Schrag, Matthew; Kirshner, Howard

    2016-08-01

    Cerebral amyloid angiopathy is a condition of the cerebral arterioles and to a lesser extent capillaries and veins, wherein beta-amyloid is deposited. In arterioles, this preferentially targets vascular smooth muscle cells and in the later stages undermines the stability of the vessel. This condition is frequently comorbid with Alzheimer's disease and its role in cognitive impairment and dementia is a topic of considerable recent research. This article reviews recent literature which confirms that CAA independently contributes to cognitive impairment by potentiating the neurodegeneration of Alzheimer's disease, by predisposing to microhemorrhagic and microischemic injury to the brain parenchyma, and by interfering with the autoregulation of CNS blood flow. In this review, we discuss the clinical presentation of cerebral amyloid angiopathy, with a focus on the neuropsychological manifestations of this vasculopathy. PMID:27357378

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

    PubMed

    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. PMID:25613018

  12. 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.

  13. Pharmacological removal of serum amyloid P component from intracerebral plaques and cerebrovascular Aβ amyloid deposits in vivo

    PubMed Central

    Millar, David J.; Richard-Londt, Angela

    2016-01-01

    Human amyloid deposits always contain the normal plasma protein serum amyloid P component (SAP), owing to its avid but reversible binding to all amyloid fibrils, including the amyloid β (Aβ) fibrils in the cerebral parenchyma plaques and cerebrovascular amyloid deposits of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). SAP promotes amyloid fibril formation in vitro, contributes to persistence of amyloid in vivo and is also itself directly toxic to cerebral neurons. We therefore developed (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), a drug that removes SAP from the blood, and thereby also from the cerebrospinal fluid (CSF), in patients with AD. Here we report that, after introduction of transgenic human SAP expression in the TASTPM double transgenic mouse model of AD, all the amyloid deposits contained human SAP. Depletion of circulating human SAP by CPHPC administration in these mice removed all detectable human SAP from both the intracerebral and cerebrovascular amyloid. The demonstration that removal of SAP from the blood and CSF also removes it from these amyloid deposits crucially validates the strategy of the forthcoming ‘Depletion of serum amyloid P component in Alzheimer's disease (DESPIAD)’ clinical trial of CPHPC. The results also strongly support clinical testing of CPHPC in patients with CAA. PMID:26842068

  14. Early detection of cryptic memory and glucose uptake deficits in pre-pathological APP mice

    PubMed Central

    Beglopoulos, V.; Tulloch, J.; Roe, A. D.; Daumas, S.; Ferrington, L.; Watson, R.; Fan, Z.; Hyman, B. T.; Kelly, P. A. T.; Bard, F.; Morris, R. G. M.

    2016-01-01

    Earlier diagnosis and treatment of Alzheimer's disease would greatly benefit from the identification of biomarkers at the prodromal stage. Using a prominent animal model of aspects of the disease, we here show using clinically relevant methodologies that very young, pre-pathological PDAPP mice, which overexpress mutant human amyloid precursor protein in the brain, exhibit two cryptic deficits that are normally undetected using standard methods of assessment. Despite learning a spatial memory task normally and displaying normal brain glucose uptake, they display faster forgetting after a long delay following performance to a criterion, together with a strong impairment of brain glucose uptake at the time of attempted memory retrieval. Preliminary observations suggest that these deficits, likely caused by an impairment in systems consolidation, could be rescued by immunotherapy with an anti-β-amyloid antibody. Our data suggest a biomarker strategy for the early detection of β-amyloid-related abnormalities. PMID:27249364

  15. Early detection of cryptic memory and glucose uptake deficits in pre-pathological APP mice.

    PubMed

    Beglopoulos, V; Tulloch, J; Roe, A D; Daumas, S; Ferrington, L; Watson, R; Fan, Z; Hyman, B T; Kelly, P A T; Bard, F; Morris, R G M

    2016-01-01

    Earlier diagnosis and treatment of Alzheimer's disease would greatly benefit from the identification of biomarkers at the prodromal stage. Using a prominent animal model of aspects of the disease, we here show using clinically relevant methodologies that very young, pre-pathological PDAPP mice, which overexpress mutant human amyloid precursor protein in the brain, exhibit two cryptic deficits that are normally undetected using standard methods of assessment. Despite learning a spatial memory task normally and displaying normal brain glucose uptake, they display faster forgetting after a long delay following performance to a criterion, together with a strong impairment of brain glucose uptake at the time of attempted memory retrieval. Preliminary observations suggest that these deficits, likely caused by an impairment in systems consolidation, could be rescued by immunotherapy with an anti-β-amyloid antibody. Our data suggest a biomarker strategy for the early detection of β-amyloid-related abnormalities. PMID:27249364

  16. Compressive deformation of ultralong amyloid fibrils

    NASA Astrophysics Data System (ADS)

    Paparcone, Raffaella; Cranford, Steven; Buehler, Markus J.

    2010-12-01

    Involved in various neurodegenerative diseases, amyloid fibrils and plaques feature a hierarchical structure, ranging from the atomistic to the micrometer scale. At the atomistic level, a dense and organized hydrogen bond network is resembled in a beta-sheet rich secondary structure, which drives a remarkable stiffness in the range of 10-20GPa, larger than many other biological nanofibrils, a result confirmed by both experiment and theory. However, the understanding of how these exceptional mechanical properties transfer from the atomistic to the nanoscale remains unknown. Here we report a multiscale analysis that, from the atomistic-level structure of a single fibril, extends to the mesoscale level, reaching size scales of hundreds of nanometers. We use parameters directly derived from full atomistic simulations of A β (1-40) amyloid fibrils to parameterize a mesoscopic coarse-grained model, which is used to reproduce the elastic properties of amyloid fibrils. We then apply our mesoscopic model in an analysis of the buckling behavior of amyloid fibrils with different lengths and report a comparison with predictions from continuum beam theory. An important implication of our results is a severe reduction of the effective modulus due to buckling, an effect that could be important to interpret experimental results of ultra-long amyloid fibrils. Our model represents a powerful tool to mechanically characterize molecular structures on the order of hundreds of nanometers to micrometers on the basis of the underlying atomistic behavior. The work provides insight into structural and mechanical properties of amyloid fibrils and may enable further analysis of larger-scale assemblies such as amyloidogenic bundles or plaques as found in disease states.

  17. Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta

    PubMed Central

    Pigino, G.; Morfini, G.; Atagi, Y.; Deshpande, A.; Yu, C.; Jungbauer, L.; LaDu, M.; Busciglio, J.; Brady, S.

    2009-01-01

    The pathological mechanism by which Aβ causes neuronal dysfunction and death remains largely unknown. Deficiencies in fast axonal transport (FAT) were suggested to play a crucial role in neuronal dysfunction and loss for a diverse set of dying back neuropathologies including Alzheimer's disease (AD), but the molecular basis for pathological changes in FAT were undetermined. Recent findings indicate that soluble intracellular oligomeric Aβ (oAβ) species may play a critical role in AD pathology. Real-time analysis of vesicle mobility in isolated axoplasms perfused with oAβ showed bidirectional axonal transport inhibition as a consequence of endogenous casein kinase 2 (CK2) activation. Conversely, neither unaggregated amyloid beta nor fibrillar amyloid beta affected FAT. Inhibition of FAT by oAβ was prevented by two specific pharmacological inhibitors of CK2, as well as by competition with a CK2 substrate peptide. Furthermore, perfusion of axoplasms with active CK2 mimics the inhibitory effects of oAβ on FAT. Both oAβ and CK2 treatment of axoplasm led to increased phosphorylation of kinesin-1 light chains and subsequent release of kinesin from its cargoes. Therefore pharmacological modulation of CK2 activity may represent a promising target for therapeutic intervention in AD. PMID:19321417

  18. Expression of the alternative oxidase mitigates beta-amyloid production and toxicity in model systems.

    PubMed

    El-Khoury, Riyad; Kaulio, Eveliina; Lassila, Katariina A; Crowther, Damian C; Jacobs, Howard T; Rustin, Pierre

    2016-07-01

    Mitochondrial dysfunction has been widely associated with the pathology of Alzheimer's disease, but there is no consensus on whether it is a cause or consequence of disease, nor on the precise mechanism(s). We addressed these issues by testing the effects of expressing the alternative oxidase AOX from Ciona intestinalis, in different models of AD pathology. AOX can restore respiratory electron flow when the cytochrome segment of the mitochondrial respiratory chain is inhibited, supporting ATP synthesis, maintaining cellular redox homeostasis and mitigating excess superoxide production at respiratory complexes I and III. In human HEK293-derived cells, AOX expression decreased the production of beta-amyloid peptide resulting from antimycin inhibition of respiratory complex III. Because hydrogen peroxide was neither a direct product nor substrate of AOX, the ability of AOX to mimic antioxidants in this assay must be indirect. In addition, AOX expression was able to partially alleviate the short lifespan of Drosophila models neuronally expressing human beta-amyloid peptides, whilst abrogating the induction of markers of oxidative stress. Our findings support the idea of respiratory chain dysfunction and excess ROS production as both an early step and as a pathologically meaningful target in Alzheimer's disease pathogenesis, supporting the concept of a mitochondrial vicious cycle underlying the disease. PMID:27094492

  19. Tau aggregation and its interplay with amyloid-β.

    PubMed

    Nisbet, Rebecca M; Polanco, Juan-Carlos; Ittner, Lars M; Götz, Jürgen

    2015-02-01

    Neurofibrillary tangles and amyloid plaques constitute the hallmark brain lesions of Alzheimer's disease (AD) patients. Tangles are composed of fibrillar aggregates of the microtubule-associated protein tau, and plaques comprise fibrillar forms of a proteolytic cleavage product, amyloid-β (Aβ). Although plaques and tangles are the end-stage lesions in AD, small oligomers of Aβ and tau are now receiving increased attention as they are shown to correlate best with neurotoxicity. One key question of debate, however, is which of these pathologies appears first and hence is upstream in the pathocascade. Studies suggest that there is an intense crosstalk between the two molecules and, based on work in animal models, there is increasing evidence that Aβ, at least in part, exerts its toxicity via tau, with the Src kinase Fyn playing a crucial role in this process. In other experimental paradigms, Aβ and tau have been found to exert both separate and synergistic modes of toxicity. The challenge, however, is to integrate these different scenarios into a coherent picture. Furthermore, the ability of therapeutic interventions targeting just one of these molecules, to successfully neutralize the toxicity of the other, needs to be ascertained to improve current therapeutic strategies, such as immunotherapy, for the treatment of AD. Although this article is not intended to provide a comprehensive review of the currently pursued therapeutic strategies, we will discuss what has been achieved by immunotherapy and, in particular, how the inherent limitations of this approach can possibly be overcome by novel strategies that involve single-chain antibodies. PMID:25492702

  20. [Treatment of familial amyloid polyneuropathy].

    PubMed

    Adams, David; Samuel, Didier; Slama, Michel

    2012-09-01

    The treatment of familial amyloid polyneuropathies (FAP) is complex and requires a neurological and cardiological multidisciplinary coverage. It includes specific treatments to control the progression of the systemic amyloidogenesis, the symptomatic treatment of the peripheral and autonomic neuropathy (digestive, urinary, sexual, postural hypotension) and the treatment of organs severely involved by amyloidosis (heart, eyes, kidneys). First line specific treatment of met30 TTR-FAP is liver transplantation (LT) which allows to suppress the main source of mutant TTR, to stop the progression of the neuropathy in 70 % of cases at long-term (with an experience of 18 years) and to double the median survival. In case of severe renal or cardiac insufficiency, a double transplant kidney-liver or heart-liver can be discussed. The tafamidis (in temporary authorization of use in France) is a stabilizing medicine of the tetrameric TTR which showed in very early stages of met30 TTR-FAP short-term capacities to stop the progress of the peripheral neuropathy in 60 % of the cases versus 38 % with placebo. It should be proposed in case of contraindication of TH (age>70 years [20 % of the cases]), of very early stages (very low NIS-LL score), or for the period of wait of LT. Other innovative medicines issued from biopharmaceutical companies have been developed to block the hepatic production of both mutant and wild TTR which are noxious in the late forms NAH (>50 years old) (RNAi [RNA interference] therapeutics, AntiSens oligonucleotids), for removing the amyloid deposits (monoclonal antibody anti-SAP), or to slow down the formation of deposits of TTR and amyloidosis (combination of doxycycline-TUDCA). Clinical trials should be first addressed to the patients with a late onset of FAP or non-met30 TTR-FAP who are less responding to LT and patients with contraindications in the LT. Initial cardiac assessment and periodic cardiac investigations are important for the FAP according to the

  1. Mild cognitive impairment with suspected nonamyloid pathology (SNAP)

    PubMed Central

    Caroli, Anna; Prestia, Annapaola; Galluzzi, Samantha; Ferrari, Clarissa; van der Flier, Wiesje M.; Ossenkoppele, Rik; Van Berckel, Bart; Barkhof, Frederik; Teunissen, Charlotte; Wall, Anders E.; Carter, Stephen F.; Schöll, Michael; Choo, Il Han; Grimmer, Timo; Redolfi, Alberto; Nordberg, Agneta; Scheltens, Philip; Drzezga, Alexander

    2015-01-01

    Objectives: The aim of this study was to investigate predictors of progressive cognitive deterioration in patients with suspected non–Alzheimer disease pathology (SNAP) and mild cognitive impairment (MCI). Methods: We measured markers of amyloid pathology (CSF β-amyloid 42) and neurodegeneration (hippocampal volume on MRI and cortical metabolism on [18F]-fluorodeoxyglucose–PET) in 201 patients with MCI clinically followed for up to 6 years to detect progressive cognitive deterioration. We categorized patients with MCI as A+/A− and N+/N− based on presence/absence of amyloid pathology and neurodegeneration. SNAPs were A−N+ cases. Results: The proportion of progressors was 11% (8/41), 34% (14/41), 56% (19/34), and 71% (60/85) in A−N−, A+N−, SNAP, and A+N+, respectively; the proportion of APOE ε4 carriers was 29%, 70%, 31%, and 71%, respectively, with the SNAP group featuring a significantly different proportion than both A+N− and A+N+ groups (p ≤ 0.005). Hypometabolism in SNAP patients was comparable to A+N+ patients (p = 0.154), while hippocampal atrophy was more severe in SNAP patients (p = 0.002). Compared with A−N−, SNAP and A+N+ patients had significant risk of progressive cognitive deterioration (hazard ratio = 2.7 and 3.8, p = 0.016 and p < 0.001), while A+N− patients did not (hazard ratio = 1.13, p = 0.771). In A+N− and A+N+ groups, none of the biomarkers predicted time to progression. In the SNAP group, lower time to progression was correlated with greater hypometabolism (r = 0.42, p = 0.073). Conclusions: Our findings support the notion that patients with SNAP MCI feature a specific risk progression profile. PMID:25568301

  2. [Familial amyloid polyneuropathies: therapeutic issues].

    PubMed

    Adams, David; Cauquil, Cécile; Théaudin, Marie

    2012-10-01

    Patients with familial amyloidpolyneuropathies (FAP) require multidisciplinary neurologic and cardiologic management, including specific treatments to control the progression of systemic amyloidogenesis, symptomatic treatment of peripheral and autonomic neuropathies, and management of severe organ involvement (heart, eyes, kidneys). The first-line specific treatment of choice for met30 TTR-FAP is liver transplantation (LT) which suppresses the main source of mutant TTR, halts the progression of neuropathy in 70% of cases, and doubles the median survival time. Dual kidney-liver or heart-liver transplantation may be appropriate for patients with severe renal or cardiac failure. Tafamidis (Vyndaqel(R), Pfizer), a novel stabilizer of tetrameric TTR, has shown short-term effectiveness in slowing the progression of peripheral neuropathy in very early stages of met30 TTR-FAP This drug should thus be proposed for stage 1 symptomatic polyneuropathy. Other innovative medicines (RNA interference, antisense oligonucleotides) have been developed to block hepatic production of both mutant and wildtype TTR (noxious in late-onset forms of NAH after age 50 years), and to remove amyloid deposits (monoclonal anti-SAP). Clinical trials should first include patients with late-onset FAP or non-met30 TTR-FAP who are less responsive to LT7 and patients in whom Vyndaqel(R) is ineffective or inappropriate. Initial and periodic cardiac assessment is necessary, as cardiac impairment is inevitable and largely responsible for mortality. Symptomatic treatment is crucial to improve these patients' quality of life. Familial screening for carriers of the TTR gene mutation and regular clinical examination are essential to detect disease onset and to start specific therapy in a timely manner. PMID:23815018

  3. Amyloid growth: combining experiment and kinetic theory

    NASA Astrophysics Data System (ADS)

    Knowles, Tuomas; Cohen, Samuel; Vendruscolo, Michele; Dobson, Christopher

    2012-02-01

    The conversion of proteins from their soluble forms into fibrillar amyloid nanostructures is a general type of behaviour encountered for many different proteins in the context of disease as well as for the generation of a select class of functional materials in nature. This talk focuses on the problem of defining the rates of the individual molecular level processes involved in the overall conversion reaction. A master equation approach is discussedootnotetextCohen et al, J Chem Phys 2011, 135, 065106 ootnotetextKnowles et al, Science, 2009, 326, 1533-1537 and used in combination with kinetic measurements to yield mechanistic insights into the amyloid growth phenomenon.

  4. Amyloids or prions? That is the question

    PubMed Central

    Sabate, Raimon; Rousseau, Frederic; Schymkowitz, Joost; Batlle, Cristina; Ventura, Salvador

    2015-01-01

    ABSTRACT Despite major efforts devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the amino acid sequence. In recent years, experimental data on yeast prion domains allow to start at least partially decrypting the sequence requirements of prion formation. These experiments illustrate the need for intrinsically disordered sequence regions enriched with a particularly high proportion of glutamine and asparagine. Bioinformatic analysis suggests that these regions strike a balance between sufficient amyloid nucleation propensity on the one hand and disorder on the other, which ensures availability of the amyloid prone regions but entropically prevents unwanted nucleation and facilitates brittleness required for propagation. PMID:26039159

  5. Quenched Hydrogen Exchange NMR of Amyloid Fibrils.

    PubMed

    Alexandrescu, Andrei T

    2016-01-01

    Amyloid fibrils are associated with a number of human diseases. These aggregatively misfolded intermolecular β-sheet assemblies constitute some of the most challenging targets in structural biology because to their complexity, size, and insolubility. Here, protocols and controls are described for experiments designed to study hydrogen-bonding in amyloid fibrils indirectly, by transferring information about amide proton occupancy in the fibrils to the dimethyl sulfoxide-denatured state. Since the denatured state is amenable to solution NMR spectroscopy, the method can provide residue-level-resolution data on hydrogen exchange for the monomers that make up the fibrils. PMID:26453215

  6. LCAT deficiency does not impair amyloid metabolism in APP/PS1 mice[S

    PubMed Central

    Stukas, Sophie; Freeman, Lita; Lee, Michael; Wilkinson, Anna; Ossoli, Alice; Vaisman, Boris; Demosky, Stephen; Chan, Jeniffer; Hirsch-Reinshagen, Veronica; Remaley, Alan T.; Wellington, Cheryl L.

    2014-01-01

    A key step in plasma HDL maturation from discoidal to spherical particles is the esterification of cholesterol to cholesteryl ester, which is catalyzed by LCAT. HDL-like lipoproteins in cerebrospinal fluid (CSF) are also spherical, whereas nascent lipoprotein particles secreted from astrocytes are discoidal, suggesting that LCAT may play a similar role in the CNS. In plasma, apoA-I is the main LCAT activator, while in the CNS, it is believed to be apoE. apoE is directly involved in the pathological progression of Alzheimer’s disease, including facilitating β-amyloid (Aβ) clearance from the brain, a function that requires its lipidation by ABCA1. However, whether apoE particle maturation by LCAT is also required for Aβ clearance is unknown. Here we characterized the impact of LCAT deficiency on CNS lipoprotein metabolism and amyloid pathology. Deletion of LCAT from APP/PS1 mice resulted in a pronounced decrease of apoA-I in plasma that was paralleled by decreased apoA-I levels in CSF and brain tissue, whereas apoE levels were unaffected. Furthermore, LCAT deficiency did not increase Aβ or amyloid in APP/PS1 LCAT−/− mice. Finally, LCAT expression and plasma activity were unaffected by age or the onset of Alzheimer’s-like pathology in APP/PS1 mice. Taken together, these results suggest that apoE-containing discoidal HDLs do not require LCAT-dependent maturation to mediate efficient Aβ clearance. PMID:24950691

  7. Enhanced antidepressant efficacy of sigma1 receptor agonists in rats after chronic intracerebroventricular infusion of beta-amyloid-(1-40) protein.

    PubMed

    Urani, Alexandre; Romieu, Pascal; Roman, François J; Yamada, Kiyofumi; Noda, Yukihiro; Kamei, Hiroyuki; Manh Tran, Hung; Nagai, Taku; Nabeshima, Toshitaka; Maurice, Tangui

    2004-02-20

    Treatment of depressive symptoms in patients suffering from neurodegenerative disorders remains a challenging issue, since few available antidepressants present an adequate efficacy during pathological aging. Previous reports suggested that selective sigma(1) receptor agonists might constitute putative candidates. We here examined the pharmacological efficacy of igmesine and (+)-SKF-10,047 and the sigma(1) receptor-related neuroactive steroid dehydroepiandrosterone sulfate, in rats infused intracerebroventricularly during 14 days with the beta-amyloid-(1-40) protein and then submitted to the conditioned fear stress test. Igmesine and (+)-SKF-10,047 significantly reduced the stress-induced motor suppression at 30 and 6 mg/kg, respectively, in beta-amyloid-(40-1)-treated control rats. Active doses were decreased, to 10 and 3 mg/kg, respectively, in beta-amyloid-(1-40)-treated animals. The dehydroepiandrosterone sulfate effect was also facilitated, both in dose (10 vs. 30 mg/kg) and intensity, in beta-amyloid-(1-40)-treated rats. Neurosteroid levels were measured in several brain structures after beta-amyloid infusion, in basal and stress conditions. Progesterone levels, both under basal and stress-induced conditions, were decreased in the hippocampus and cortex of beta-amyloid-(1-40)-treated rats. The levels in pregnenolone, dehydroepiandrosterone and their sulfate esters appeared less affected by the beta-amyloid infusion. The sigma(1) receptor agonist efficacy is known to be inversely correlated to brain progesterone levels, synthesized mainly by neurons that are mainly affected by the beta-amyloid toxicity. The present study suggests that sigma(1) receptor agonists, due to their enhanced efficacy in a nontransgenic animal model, may alleviate Alzheimer's disease-associated depressive symptoms. PMID:14975704

  8. Detection of amyloid plaques targeted by USPIO-Aβ1-42 in Alzheimer's disease transgenic mice using magnetic resonance microimaging.

    PubMed

    Yang, Jing; Wadghiri, Youssef Zaim; Hoang, Dung Minh; Tsui, Wai; Sun, Yanjie; Chung, Erika; Li, Yongsheng; Wang, Andrew; de Leon, Mony; Wisniewski, Thomas

    2011-04-15

    Amyloid plaques are one of the pathological hallmarks of Alzheimer's disease (AD). The visualization of amyloid plaques in the brain is important to monitor AD progression and to evaluate the efficacy of therapeutic interventions. Our group has developed several contrast agents to detect amyloid plaques in vivo using magnetic resonance microimaging (μMRI) in AD transgenic mice, where we used intra-carotid mannitol to enhance blood-brain barrier (BBB) permeability. In the present study, we used ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, chemically coupled with Aβ1-42 peptide to detect amyloid deposition along with mannitol for in vivo μMRI by femoral intravenous injection. A 3D gradient multi-echo sequence was used for imaging with a 100μm isotropic resolution. The amyloid plaques detected by T2*-weighted μMRI were confirmed with matched histological sections. Furthermore, two different quantitative analyses were used. The region of interest-based quantitative measurement of T2* values showed contrast-injected APP/PS1 mice had significantly reduced T2* values compared to wild-type mice. In addition, the scans were examined with voxel-based morphometry (VBM) using statistical parametric mapping (SPM) for comparison of contrast-injected AD transgenic and wild-type mice. The regional differences seen in VBM comparing USPIO-Aβ1-42 injected APP/PS1 and wild-type mice correlated with the amyloid plaque distribution histologically, contrasting with no differences between the two groups of mice without contrast agent injection in regions of the brain with amyloid deposition. Our results demonstrated that both approaches were able to identify the differences between AD transgenic mice and wild-type mice, after injected with USPIO-Aβ1-42. The feasibility of using less invasive intravenous femoral injections for amyloid plaque detection in AD transgenic mice facilitates using this method for longitudinal studies in the pathogenesis of AD. PMID

  9. Handheld computing in pathology

    PubMed Central

    Park, Seung; Parwani, Anil; Satyanarayanan, Mahadev; Pantanowitz, Liron

    2012-01-01

    Handheld computing has had many applications in medicine, but relatively few in pathology. Most reported uses of handhelds in pathology have been limited to experimental endeavors in telemedicine or education. With recent advances in handheld hardware and software, along with concurrent advances in whole-slide imaging (WSI), new opportunities and challenges have presented themselves. This review addresses the current state of handheld hardware and software, provides a history of handheld devices in medicine focusing on pathology, and presents future use cases for such handhelds in pathology. PMID:22616027

  10. Alopecia in Systemic Amyloidosis: Trichoscopic-Pathologic Correlation

    PubMed Central

    Miteva, Mariya; Wei, Erin; Milikowski, Clara; Tosti, Antonella

    2015-01-01

    Alopecia in systemic amyloidosis is very rare and has been described as individual cases of diffuse nonscarring alopecia and a case of alopecia universalis. We report the trichoscopic findings in alopecia associated with systemic amyloidosis. The most prominent feature was a salmon colored halo (0.3-1 mm in diameter) surrounding the follicular ostia. Other features included broken hairs and black dots. The salmon colored halo correlated on pathology with the perifollicular deposition of amyloid. The horizontal sections showed that the sebaceous glands were preserved which supports the nonscarring pattern of the alopecia. PMID:26903748

  11. Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly.

    PubMed

    Westwood, Sarah; Leoni, Emanuela; Hye, Abdul; Lynham, Steven; Khondoker, Mizanur R; Ashton, Nicholas J; Kiddle, Steven J; Baird, Alison L; Sainz-Fuertes, Ricardo; Leung, Rufina; Graf, John; Hehir, Cristina Tan; Baker, David; Cereda, Cristina; Bazenet, Chantal; Ward, Malcolm; Thambisetty, Madhav; Lovestone, Simon

    2016-03-29

    Increasingly, clinical trials for Alzheimer's disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aβ measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p <  0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q <  0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature. PMID:27031486

  12. Amyloid-clearing proteins and their epigenetic regulation as a therapeutic target in Alzheimer’s disease

    PubMed Central

    Nalivaeva, Natalia N.; Belyaev, Nikolai D.; Kerridge, Caroline; Turner, Anthony J.

    2014-01-01

    Abnormal elevation of amyloid β-peptide (Aβ) levels in the brain is the primary trigger for neuronal cell death specific to Alzheimer’s disease (AD). It is now evident that Aβ levels in the brain are manipulable due to a dynamic equilibrium between its production from the amyloid precursor protein (APP) and removal by amyloid clearance proteins. Clearance can be either enzymic or non-enzymic (binding/transport proteins). Intriguingly several of the main amyloid-degrading enzymes (ADEs) are members of the M13 peptidase family (neprilysin (NEP), NEP2 and the endothelin converting enzymes (ECE-1 and -2)). A distinct metallopeptidase, insulin-degrading enzyme (IDE), also contributes to Aβ degradation in the brain. The ADE family currently embraces more than 20 members, both membrane-bound and soluble, and of differing cellular locations. NEP plays an important role in brain function terminating neuropeptide signals. Its decrease in specific brain areas with age or after hypoxia, ischaemia or stroke contribute significantly to the development of AD pathology. The recently discovered mechanism of epigenetic regulation of NEP (and other genes) by the APP intracellular domain (AICD) and its dependence on the cell type and APP isoform expression suggest possibilities for selective manipulation of NEP gene expression in neuronal cells. We have also observed that another amyloid-clearing protein, namely transthyretin (TTR), is also regulated in the neuronal cell by a mechanism similar to NEP. Dependence of amyloid clearance proteins on histone deacetylases and the ability of HDAC inhibitors to up-regulate their expression in the brain opens new avenues for developing preventive strategies in AD. PMID:25278875

  13. Amyloid Arthropathy of the Hip Joint Associated with Multiple Myeloma: A Case Report

    PubMed Central

    Chun, Young Soo; Rhyu, Kee Hyung; Park, Yong Koo; Ryu, Kyung Nam; Park, Ji Seon; Liang, Huo; Jung, Gwang Young; Shin, Won Ju

    2016-01-01

    Amyloidosis is a disease characterized by the deposition of non-soluble fibrous protein in multiple tissues with a number of possible causes. This protein deposition can occur in any tissue, yet is most commonly seen in kidneys, heart, and gastrointestinal tracts. However, invasion to bone tissues is not often reported. The deposition of amyloid proteins in bone tissues may result in joint pain and pathological fractures; it is important to elucidate the causes and detect early to determine prognosis and treat optimally. In the present case report, with relevant literature review, the authors report a case of total hip arthroplasty in an amyloidosis patient. PMID:27536655

  14. Migration of blood cells to β-amyloid plaques in Alzheimer’s disease

    PubMed Central

    Hohsfield, Lindsay A.; Humpel, Christian

    2015-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disease that leads to the progressive deterioration of cognitive and memory functions. The deposition of extracellular beta-amyloid (Aβ) senile plaques and intracellular tau neurofibrillary tangles are considered the cardinal pathological hallmarks of AD, however, accumulating evidence indicates that immune cells may also play an important role in disease pathogenesis. Among these immune cells, blood-derived cells and their infiltration into the CNS towards Aβ plaques have been implicated in therapeutic strategies against AD. Here, we review the current literature on blood cell migration into the AD brain and the important players involved in this selective migration towards Aβ plaques. PMID:25752742

  15. Amyloid Arthropathy of the Hip Joint Associated with Multiple Myeloma: A Case Report.

    PubMed

    Cho, Yoon Je; Chun, Young Soo; Rhyu, Kee Hyung; Park, Yong Koo; Ryu, Kyung Nam; Park, Ji Seon; Liang, Huo; Jung, Gwang Young; Shin, Won Ju

    2016-06-01

    Amyloidosis is a disease characterized by the deposition of non-soluble fibrous protein in multiple tissues with a number of possible causes. This protein deposition can occur in any tissue, yet is most commonly seen in kidneys, heart, and gastrointestinal tracts. However, invasion to bone tissues is not often reported. The deposition of amyloid proteins in bone tissues may result in joint pain and pathological fractures; it is important to elucidate the causes and detect early to determine prognosis and treat optimally. In the present case report, with relevant literature review, the authors report a case of total hip arthroplasty in an amyloidosis patient. PMID:27536655

  16. 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

  17. Amyloid fibril formation by macrophage migration inhibitory factor

    SciTech Connect

    Lashuel, Hilal A. . E-mail: hilal.lashuel@epfl.ch; Aljabari, Bayan; Sigurdsson, Einar M.; Metz, Christine N.; Leng Lin; Callaway, David J.E.; Bucala, Richard

    2005-12-16

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

  18. Immunohistochemical characterization of amyloid proteins in sural nerves and clinical associations in amyloid neuropathy.

    PubMed Central

    Li, K.; Kyle, R. A.; Dyck, P. J.

    1992-01-01

    To test whether immunohistochemical characterization of proteins in amyloid deposits in biopsied sural nerves gives reliable and useful diagnostic information using commercially available reagents, biopsy specimens of sural nerves from 38 patients with amyloid neuropathy were studied. Transthyretin (TTR) was detected in the amyloid deposits of 11 nerves, lambda light chains (LC) in 8 nerves, kappa LC in 7 nerves, and both lambda and kappa LC in 3 nerves. In 9 nerves, the amyloid deposits were too small to allow adequate immunohistochemical characterization of amyloid proteins in serial sections. Evidence that immunohistochemical characterization was correct came from: 1) evaluation of kin, 2) search for monoclonal proteins in the plasma, and 3) sequencing of the gene abnormalities in TTR+ cases. In 9 of 11 TTR+ cases, in which DNA could be obtained, sequencing of the gene showed that each of the 9 cases was heterozygous for a gene mutation; 7 had previously described mutations and 2 undescribed mutations. Therefore, in the nine sporadic cases without plasma monoclonal light chains, the immunohistochemical characterization correctly identified the protein in amyloid as transthyretin. Likewise, there was a high concordance between immunoglobulin light chains in plasma and light chains in amyloid in primary amyloidosis. Evaluation of the type, distribution, and severity of the neurologic symptoms and deficits showed: 1) the sensorimotor and autonomic neuropathy of amyloidosis characteristically affects proximal as well as distal limbs, and 2) the type of amyloidosis probably cannot be determined from the characteristics or severity of the neuropathy alone or from the location or size of amyloid deposits in nerve. Images Figure 1 PMID:1321563

  19. Amyloid-β peptides act as allosteric modulators of cholinergic signalling through formation of soluble BAβACs

    PubMed Central

    Kumar, Rajnish; Nordberg, Agneta

    2016-01-01

    amyloid-β interacts readily in an apolipoprotein-facilitated manner with butyrylcholinesterase, forming highly stable and soluble complexes, BAβACs, which can be separated in their native states by sucrose density gradient technique. Enzymological analyses further evinced that amyloid-β concentration dependently increased the acetylcholine-hydrolyzing capacity of cholinesterases. In silico biomolecular analysis further deciphered the allosteric amino acid fingerprint of the amyloid-β-cholinesterase molecular interaction in formation of BAβACs. In the case of butyrylcholinesterase, the results indicated that amyloid-β interacts with a putative activation site at the mouth of its catalytic tunnel, most likely leading to increased acetylcholine influx into the catalytic site, and thereby increasing the intrinsic catalytic rate of butyrylcholinesterase. In conclusion, at least one of the native physiological functions of amyloid-β is allosteric modulation of the intrinsic catalytic efficiency of cholinesterases, and thereby regulation of synaptic and extrasynaptic cholinergic signalling. High apolipoprotein-E may pathologically alter the biodynamics of this amyloid-β function. PMID:26525916

  20. Amyloid Plaque-Associated Oxidative Degradation of Uniformly Radiolabeled Arachidonic Acid.

    PubMed

    Furman, Ran; Murray, Ian V J; Schall, Hayley E; Liu, Qiwei; Ghiwot, Yonatan; Axelsen, Paul H

    2016-03-16

    Oxidative stress is a frequently observed feature of Alzheimer's disease, but its pathological significance is not understood. To explore the relationship between oxidative stress and amyloid plaques, uniformly radiolabeled arachidonate was introduced into transgenic mouse models of Alzheimer's disease via intracerebroventricular injection. Uniform labeling with carbon-14 is used here for the first time, and made possible meaningful quantification of arachidonate oxidative degradation products. The injected arachidonate entered a fatty acid pool that was subject to oxidative degradation in both transgenic and wild-type animals. However, the extent of its degradation was markedly greater in the hippocampus of transgenic animals where amyloid plaques were abundant. In human Alzheimer's brain, plaque-associated proteins were post-translationally modified by hydroxynonenal, a well-known oxidative degradation product of arachidonate. These results suggest that several recurring themes in Alzheimer's pathogenesis, amyloid β proteins, transition metal ions, oxidative stress, and apolipoprotein isoforms, may be involved in a common mechanism that has the potential to explain both neuronal loss and fibril formation in this disease. PMID:26800372

  1. Ketones block amyloid entry and improve cognition in an Alzheimer's model.

    PubMed

    Yin, Jun Xiang; Maalouf, Marwan; Han, Pengcheng; Zhao, Minglei; Gao, Ming; Dharshaun, Turner; Ryan, Christopher; Whitelegge, Julian; Wu, Jie; Eisenberg, David; Reiman, Eric M; Schweizer, Felix E; Shi, Jiong

    2016-03-01

    Sporadic Alzheimer's disease (AD) is responsible for 60%-80% of dementia cases, and the most opportune time for preventive intervention is in the earliest stage of its preclinical phase. As traditional mitochondrial energy substrates, ketone bodies (ketones, for short), beta-hydroxybutyrate, and acetoacetate, have been reported to provide symptomatic improvement and disease-modifying activity in epilepsy and neurodegenerative disorders. Recently, ketones are thought as more than just metabolites and also as endogenous factors protecting against AD. In this study, we discovered a novel neuroprotective mechanism of ketones in which they blocked amyloid-β 42, a pathologic hallmark protein of AD, entry into neurons. The suppression of intracellular amyloid-β 42 accumulation rescued mitochondrial complex I activity, reduced oxidative stress, and improved synaptic plasticity. Most importantly, we show that peripheral administration of ketones significantly reduced amyloid burden and greatly improved learning and memory ability in a symptomatic mouse model of AD. These observations provide us insights to understand and to establish a novel therapeutic use of ketones in AD prevention. PMID:26923399

  2. Dietary (-)-epicatechin as a potent inhibitor of βγ-secretase amyloid precursor protein processing.

    PubMed

    Cox, Carla J; Choudhry, Fahd; Peacey, Eleanor; Perkinton, Michael S; Richardson, Jill C; Howlett, David R; Lichtenthaler, Stefan F; Francis, Paul T; Williams, Robert J

    2015-01-01

    Flavonoids, a group of dietary polyphenols have been shown to possess cognitive health benefits. Epidemiologic evidence suggests that they could play a role in risk reduction in dementia. Amyloid precursor protein processing and the subsequent generation of amyloid beta (Aβ) are central to the pathogenesis of Alzheimer's disease, as soluble, oligomeric Aβ is thought to be the toxic species driving disease progression. We undertook an in vitro screen to identify flavonoids with bioactivity at βγ-mediated amyloid precursor protein processing, which lead to identification of a number of flavonoids bioactive at 100 nM. Because of known bioavailability, we investigated the catechin family further and identified epigallocatechin and (-)-epicatechin as potent (nanomolar) inhibitors of amyloidogenic processing. Supporting this finding, we have shown reduced Aβ pathology and Aβ levels following short term, a 21-day oral delivery of (-)-epicatechin in 7-month-old TASTPM mice. Further, in vitro mechanistic studies suggest this is likely because of indirect BACE1 inhibition. Taken together, our results suggest that orally delivered (-)-epicatechin may be a potential prophylactic for Alzheimer's disease. PMID:25316600

  3. Role of amyloid peptides in vascular dysfunction and platelet dysregulation in Alzheimer’s disease

    PubMed Central

    Canobbio, Ilaria; Abubaker, Aisha Alsheikh; Visconte, Caterina; Torti, Mauro; Pula, Giordano

    2015-01-01

    Alzheimer’s disease (AD) is the most common neurodegenerative cause of dementia in the elderly. AD is accompanied by the accumulation of amyloid peptides in the brain parenchyma and in the cerebral vessels. The sporadic form of AD accounts for about 95% of all cases. It is characterized by a late onset, typically after the age of 65, with a complex and still poorly understood aetiology. Several observations point towards a central role of cerebrovascular dysfunction in the onset of sporadic AD (SAD). According to the “vascular hypothesis”, AD may be initiated by vascular dysfunctions that precede and promote the neurodegenerative process. In accordance to this, AD patients show increased hemorrhagic or ischemic stroke risks. It is now clear that multiple bidirectional connections exist between AD and cerebrovascular disease, and in this new scenario, the effect of amyloid peptides on vascular cells and blood platelets appear to be central to AD. In this review, we analyze the effect of amyloid peptides on vascular function and platelet activation and its contribution to the cerebrovascular pathology associated with AD and the progression of this disease. PMID:25784858

  4. Mechanisms and Kinetics of Amyloid Aggregation Investigated by a Phenomenological Coarse-Grained Model

    NASA Astrophysics Data System (ADS)

    Magno, Andrea; Pellarin, Riccardo; Caflisch, Amedeo

    Amyloid fibrils are ordered polypeptide aggregates that have been implicated in several neurodegenerative pathologies, such as Alzheimer's, Parkinson's, Huntington's, and prion diseases, [1, 2] and, more recently, also in biological functionalities. [3, 4, 5] These findings have paved the way for a wide range of experimental and computational studies aimed at understanding the details of the fibril-formation mechanism. Computer simulations using low-resolution models, which employ a simplified representation of protein geometry and energetics, have provided insights into the basic physical principles underlying protein aggregation in general [6, 7, 8] and ordered amyloid aggregation. [9, 10, 11, 12, 13, 14, 15] For example, Dokholyan and coworkers have used the Discrete Molecular Dynamics method [16, 17] to shed light on the mechanisms of protein oligomerization [18] and the conformational changes that take place in proteins before the aggregation onset. [19, 20] One challenging observation, which is difficult to observe by computer simulations, is the wide range of aggregation scenarios emerging from a variety of biophysical measurements. [21, 22] Atomistic models have been employed to study the conformational space of amyloidogenic polypeptides in the monomeric state, [23, 24, 25] the very initial steps of amyloid formation, [26, 27, 28, 29, 30, 31, 32] and the structural stability of fibril models. [33, 34, 35) However, all-atom simulations of the kinetics of fibril formation are beyond what can be done with modern computers.

  5. Blood metabolite markers of neocortical amyloid-β burden: discovery and enrichment using candidate proteins.

    PubMed

    Voyle, N; Kim, M; Proitsi, P; Ashton, N J; Baird, A L; Bazenet, C; Hye, A; Westwood, S; Chung, R; Ward, M; Rabinovici, G D; Lovestone, S; Breen, G; Legido-Quigley, C; Dobson, R J B; Kiddle, S J

    2016-01-01

    We believe this is the first study to investigate associations between blood metabolites and neocortical amyloid burden (NAB) in the search for a blood-based biomarker for Alzheimer's disease (AD). Further, we present the first multi-modal analysis of blood markers in this field. We used blood plasma samples from 91 subjects enrolled in the University of California, San Francisco Alzheimer's Disease Research Centre. Non-targeted metabolomic analysis was used to look for associations with NAB using both single and multiple metabolic feature models. Five metabolic features identified subjects with high NAB, with 72% accuracy. We were able to putatively identify four metabolites from this panel and improve the model further by adding fibrinogen gamma chain protein measures (accuracy=79%). One of the five metabolic features was studied in the Alzheimer's Disease Neuroimaging Initiative cohort, but results were inconclusive. If replicated in larger, independent studies, these metabolic features and proteins could form the basis of a blood test with potential for enrichment of amyloid pathology in anti-amyloid trials. PMID:26812040

  6. Amyloid beta protein levels in cerebrospinal fluid are elevated in early-onset Alzheimer's disease.

    PubMed

    Nakamura, T; Shoji, M; Harigaya, Y; Watanabe, M; Hosoda, K; Cheung, T T; Shaffer, L M; Golde, T E; Younkin, L H; Younkin, S G

    1994-12-01

    The 4-kd amyloid beta protein (A beta) deposited as amyloid in Alzheimer's disease (AD) is produced and released by normal proteolytic processing of the amyloid beta protein precursor (beta APP) and is readily detected in cerebrospinal fluid (CSF). Here, we present the levels of A beta in CSF from a total of 95 subjects, including 38 patients with AD, 14 with early-onset AD and 24 with late-onset AD, 25 normal control subjects, and 32 patients with other neurological diseases. The level of A beta decreased with normal aging, and there was a significant elevation in the level of A beta in the CSF of early-onset AD patients (4.14 +/- 1.37 pmol/ml, p < 0.01). Neither Mini-Mental State nor Functional Assessment Staging were correlated with the amount of A beta in the CSF. The A beta/secreted form of beta APP ratio was elevated, but the level of alpha 1-antichymotrypsin in the CSF did not correlate with the level of CSF A beta in early-onset AD patients. Thus, the level of A beta in the CSF is elevated in early-onset AD patients and is suggested to be correlated with the pathology in the brain that characterizes AD. PMID:7998778

  7. Synergic interaction between amyloid precursor protein and neural cell adhesion molecule promotes neurite outgrowth

    PubMed Central

    Chen, Keping; Lu, Huixia; Gao, Tianli; Xue, Xiulei; Wang, Chunling; Miao, Fengqin

    2016-01-01

    Alzheimer's disease (AD) is one of the most common neurodegenerative diseases worldwide. The main features of AD are the pathological changes of density and distribution of intracellular neurofibrillary tangles (NFT) and extracellular amyloid plaques. The processing of amyloid beta precursor protein (APP) to β-amyloid peptide (Aβ) is one of the critical events in the pathogenesis of AD. In this study, we evaluated the role of the interaction of neural cell adhesion molecule (NCAM) and APP in neurite outgrowth using two different experimental systems: PC12E2 cells and hippocampal neurons that were isolated from wild type, APP knock-in and APP knock-out mice. PC12E2 cells or hippocampal neurons were co-cultured with NCAM-negative or NCAM-positive fibroblasts L929 cells. We found that APP promoted neurite outgrowth of PC12E2 cells and hippocampal neurons in either the presence or absence of NCAM. Secreted APP can rescue the neurite outgrowth in hippocampal neurons from APP knock-out mice. The interaction of APP and NCAM had synergic effect in promoting neurite outgrowth in both PC12E2 cells and hippocampal neurons. Our results suggested that the interaction of APP with NCAM played an important role in AD development and therefore could be a potential therapeutic target for AD treatment. PMID:26883101

  8. Senile plaques and cerebral amyloid angiopathy in an aged California sea lion (Zalophus californianus).

    PubMed

    Takahashi, Erika; Kuribayashi, Hiroyuki; Chambers, James Kenn; Imamura, Emi; Une, Yumi

    2014-09-01

    Senile plaques (SPs) and cerebral amyloid angiopathy (CAA) consisting of β-amyloid (Aβ) are major features in the brain of Alzheimer's disease (AD) patients and elderly humans and animals. In this study, we report the finding of SPs and CAA in an aged sea lion (30 years), which is the first demonstration of AD-related pathological changes in a marine animal. Histologically, SPs were observed at the cerebral cortex, most frequently at the frontal lobe, with two morphologically different types: the small round type and the large granular type. Only the small round SPs were positive for Congo red staining. The SPs were equally immunoreactive to Aβ40 and Aβ42 and were mainly composed of Aβ with an N-terminal pyroglutamate residue at position 3. Amyloid depositions at vessel walls were noted at the meninges and within the parenchyma. Interestingly, double immunofluorescence staining for Aβ40 and Aβ42 showed that the two subtypes were deposited segmentally in different parts of the vessel walls. The lesions observed in the sea lion suggest that Aβ deposition is widely present in various animal species, including marine mammals; however, the peculiar deposits similar to cotton wool plaques and the specific pattern of CAA are characteristic features of this animal. PMID:24779910

  9. Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril

    PubMed Central

    Wälti, Marielle Aulikki; Ravotti, Francesco; Arai, Hiromi; Glabe, Charles G.; Wall, Joseph S.; Böckmann, Anja; Güntert, Peter; Meier, Beat H.; Riek, Roland

    2016-01-01

    Amyloid-β (Aβ) is present in humans as a 39- to 42-amino acid residue metabolic product of the amyloid precursor protein. Although the two predominant forms, Aβ(1–40) and Aβ(1–42), differ in only two residues, they display different biophysical, biological, and clinical behavior. Aβ(1–42) is the more neurotoxic species, aggregates much faster, and dominates in senile plaque of Alzheimer’s disease (AD) patients. Although small Aβ oligomers are believed to be the neurotoxic species, Aβ amyloid fibrils are, because of their presence in plaques, a pathological hallmark of AD and appear to play an important role in disease progression through cell-to-cell transmissibility. Here, we solved the 3D structure of a disease-relevant Aβ(1–42) fibril polymorph, combining data from solid-state NMR spectroscopy and mass-per-length measurements from EM. The 3D structure is composed of two molecules per fibril layer, with residues 15–42 forming a double-horseshoe–like cross–β-sheet entity with maximally buried hydrophobic side chains. Residues 1–14 are partially ordered and in a β-strand conformation, but do not display unambiguous distance restraints to the remainder of the core structure. PMID:27469165

  10. Atomic-resolution structure of a disease-relevant Aβ(1-42) amyloid fibril.

    PubMed

    Wälti, Marielle Aulikki; Ravotti, Francesco; Arai, Hiromi; Glabe, Charles G; Wall, Joseph S; Böckmann, Anja; Güntert, Peter; Meier, Beat H; Riek, Roland

    2016-08-23

    Amyloid-β (Aβ) is present in humans as a 39- to 42-amino acid residue metabolic product of the amyloid precursor protein. Although the two predominant forms, Aβ(1-40) and Aβ(1-42), differ in only two residues, they display different biophysical, biological, and clinical behavior. Aβ(1-42) is the more neurotoxic species, aggregates much faster, and dominates in senile plaque of Alzheimer's disease (AD) patients. Although small Aβ oligomers are believed to be the neurotoxic species, Aβ amyloid fibrils are, because of their presence in plaques, a pathological hallmark of AD and appear to play an important role in disease progression through cell-to-cell transmissibility. Here, we solved the 3D structure of a disease-relevant Aβ(1-42) fibril polymorph, combining data from solid-state NMR spectroscopy and mass-per-length measurements from EM. The 3D structure is composed of two molecules per fibril layer, with residues 15-42 forming a double-horseshoe-like cross-β-sheet entity with maximally buried hydrophobic side chains. Residues 1-14 are partially ordered and in a β-strand conformation, but do not display unambiguous distance restraints to the remainder of the core structure. PMID:27469165

  11. Analysis of the length distribution of amyloid fibrils by centrifugal sedimentation.

    PubMed

    Arosio, Paolo; Cedervall, Tommy; Knowles, Tuomas P J; Linse, Sara

    2016-07-01

    The aggregation of normally soluble peptides and proteins into amyloid fibrils is a process associated with a wide range of pathological conditions, including Alzheimer's and Parkinson's diseases. It has become apparent that aggregates of different sizes possess markedly different biological effects, with aggregates of lower relative molecular weight being associated with stronger neurotoxicity. Yet, although many approaches exist to measure the total mass concentration of aggregates, the ability to probe the length distribution of growing aggregates in solution has remained more elusive. In this work, we applied a differential centrifugation technique to measure the sedimentation coefficients of amyloid fibrils produced during the aggregation process of the amyloid β (M1-42) peptide (Aβ42). The centrifugal method has the advantage of providing structural information on the fibril distribution directly in solution and affording a short analysis time with respect to alternative imaging and analytical centrifugation approaches. We show that under quiescent conditions interactions between Aβ42 fibrils lead to lateral association and to the formation of entangled clusters. By contrast, aggregation under shaking generates a population of filaments characterized by shorter lengths. The results, which have been validated by cryogenic transmission electron microscopy (cryo-TEM) analysis, highlight the important role that fibril-fibril assembly can play in the deposition of aggregation-prone peptides. PMID:27033008

  12. Requirement of aggregation propensity of Alzheimer amyloid peptides for neuronal cell surface binding

    PubMed Central

    Bateman, David A; McLaurin, JoAnne; Chakrabartty, Avijit

    2007-01-01

    Background Aggregation of the amyloid peptides, Aβ40 and Aβ42, is known to be involved in the pathology of Alzheimer's disease (AD). Here we investigate the relationship between peptide aggregation and cell surface binding of three forms of Aβ (Aβ40, Aβ42, and an Aβ mutant). Results Using confocal microscopy and flow cytometry with fluorescently labelled Aβ, we demonstrate a correlation between the aggregation propensity of the Alzheimer amyloid peptides and their neuronal cell surface association. We find that the highly aggregation prone Aβ42 associates with the surface of neuronal cells within one hour, while the less aggregation prone Aβ40 associates over 24 hours. We show that a double mutation in Aβ42 that reduces its aggregation propensity also reduces its association with the cell surface. Furthermore, we find that a cell line that is resistant to Aβ cytotoxicity, the non-neuronal human lymphoma cell line U937, does not bind either Aβ40 or Aβ42. Conclusion Taken together, our findings reveal that amyloid peptide aggregation propensity is an essential determinant of neuronal cell surface association. We anticipate that our approach, involving Aβ imaging in live cells, will be highly useful for evaluating the efficacy of therapeutic drugs that prevent toxic Aβ association with neuronal cells. PMID:17475015

  13. Radiographic pathology for technologists

    SciTech Connect

    Mace, J.D.; Kowalczyk, N.

    1988-01-01

    This book explains the fundamentals of disease mechanisms and relates this to the practice of radiologic science. Each chapter begins with a discussion of normal anatomy and physiology, then covers pathology and demonstrates how the pathology appears on film. Imaging modalities such as computed tomography, MRI, and ultrasound are also discussed. Clinical case studies are included.

  14. Opportunities in Speech Pathology.

    ERIC Educational Resources Information Center

    Newman, Parley W.

    The importance of speech is discussed and speech pathology is described. Types of communication disorders considered are articulation disorders, aphasia, facial deformity, hearing loss, stuttering, delayed speech, voice disorders, and cerebral palsy; examples of five disorders are given. Speech pathology is investigated from these aspects: the…

  15. Nanoparticles and amyloid systems: A fatal encounter?

    NASA Astrophysics Data System (ADS)

    Abel, Bernd

    2014-10-01

    Nanoparticles (NPs) are used in many products of our daily life, however, there has been concern that they may also be harmful to human health. Recently NPs thave been found to accelerate the fibrillation kinetics of amyloid systems. In the past this has been preliminarily attributed to a nucleation effect. Nanoparticle surfaces and interfaces appear to limit the degrees of freedom of amyloid systems (i.e., peptides and proteins) due to a phase space constraint such that rapid cross-beta structures are formed faster than without interface interactions and in turn fibril formation is enhanced significantly. Here we explore if lipid bilayers in the form of liposomes (140nm) also accelerate fibril formation for amyloid systems. We have investigated a fragment NNFGAIL of the Human islet amyloid polypeptide (hIAPP) in contact with 1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC) liposomes in aqueous solution. We found that the lipid bilayer vesicles do accelerate fibril formation in time-resolved off-line detected atomic force microscopy experiments. Characteristic Thioflavine-T fluorescence on the same structures verify that the structures consist of aggregated peptides in a typical cross-β-structure arrangement.

  16. Serum amyloid P inhibits dermal wound healing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The repair of open wounds depends on granulation tissue formation and contraction, which is primarily mediated by myofibroblasts. A subset of myofibroblasts originates from bone-marrow-derived monocytes which differentiate into fibroblast-like cells called fibrocytes. Serum amyloid P (SAP) inhibits ...

  17. Bap: A New Type of Functional Amyloid.

    PubMed

    Di Martino, Patrick

    2016-09-01

    Bacteria can build a biofilm matrix scaffold from exopolysaccharides or proteins, and DNA. In a recent report, Taglialegna and colleagues show that pathogenic Staphylococcus aureus produces a protein scaffold based on amyloid assembly of fragments from the biofilm-associated protein. Amyloidogenesis occurs in response to environmental signals. PMID:27451288

  18. Fibrillar Amyloid Plaque Formation Precedes Microglial Activation

    PubMed Central

    Steinbach, Sonja; Blazquez-Llorca, Lidia; Herms, Jochen

    2015-01-01

    In Alzheimer’s disease (AD), hallmark β-amyloid deposits are characterized by the presence of activated microglia around them. Despite an extensive characterization of the relation of amyloid plaques with microglia, little is known about the initiation of this interaction. In this study, the detailed investigation of very small plaques in brain slices in AD transgenic mice of the line APP-PS1(dE9) revealed different levels of microglia recruitment. Analysing plaques with a diameter of up to 10 μm we find that only the half are associated with clear morphologically activated microglia. Utilizing in vivo imaging of new appearing amyloid plaques in double-transgenic APP-PS1(dE9)xCX3CR1+/- mice further characterized the dynamic of morphological microglia activation. We observed no correlation of morphological microglia activation and plaque volume or plaque lifetime. Taken together, our results demonstrate a very prominent variation in size as well as in lifetime of new plaques relative to the state of microglia reaction. These observations might question the existing view that amyloid deposits by themselves are sufficient to attract and activate microglia in vivo. PMID:25799372

  19. Nanoparticles and amyloid systems: A fatal encounter?

    SciTech Connect

    Abel, Bernd

    2014-10-06

    Nanoparticles (NPs) are used in many products of our daily life, however, there has been concern that they may also be harmful to human health. Recently NPs have been found to accelerate the fibrillation kinetics of amyloid systems. In the past this has been preliminarily attributed to a nucleation effect. Nanoparticle surfaces and interfaces appear to limit the degrees of freedom of amyloid systems (i.e., peptides and proteins) due to a phase space constraint such that rapid cross-beta structures are formed faster than without interface interactions and in turn fibril formation is enhanced significantly. Here we explore if lipid bilayers in the form of liposomes (140nm) also accelerate fibril formation for amyloid systems. We have investigated a fragment NNFGAIL of the Human islet amyloid polypeptide (hIAPP) in contact with 1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC) liposomes in aqueous solution. We found that the lipid bilayer vesicles do accelerate fibril formation in time-resolved off-line detected atomic force microscopy experiments. Characteristic Thioflavine-T fluorescence on the same structures verify that the structures consist of aggregated peptides in a typical cross-β-structure arrangement.

  20. Activation of the Amyloid Cascade in Apolipoprotein E4 Transgenic Mice Induces Lysosomal Activation and Neurodegeneration Resulting in Marked Cognitive Deficits

    PubMed Central

    Belinson, Haim; Lev, Dimitri; Masliah, Eliezer

    2008-01-01

    The allele E4 of apolipoprotein E (apoE4), the most prevalent genetic risk factor for Alzheimer's disease, is associated histopathologically with elevated levels of brain amyloid. This led to the suggestion that the pathological effects of apoE4 are mediated by cross-talk interactions with amyloid β peptide (Aβ), which accentuate the pathological effects of the amyloid cascade. The mechanisms underlying the Aβ-mediated pathological effects of apoE4 are unknown. We have shown recently that inhibition of the Aβ-degrading enzyme neprilysin in brains of wild-type apoE3 and apoE4 mice results in rapid and similar elevations in their total brain Aβ levels. However, the nucleation and aggregation of Aβ in these mice were markedly affected by the apoE genotype and were specifically enhanced in the apoE4 mice. We presently used the neprilysin inhibition paradigm to analyze the neuropathological and cognitive effects that are induced by apoE4 after activation of the amyloid cascade. This revealed that apoE4 stimulates isoform specifically the degeneration of hippocampal CA1 neurons and of entorhinal and septal neurons, which is accompanied by the accumulation of intracellular Aβ and apoE and with lysosomal activation. Furthermore, these neuropathological effects are associated isoform specifically with the occurrence of pronounced cognitive deficits in the ApoE4 mice. These findings provide the first in vivo evidence regarding the cellular mechanisms underlying the pathological cross talk between apoE4 and Aβ, as well as a novel model system of neurodegeneration in vivo that is uniquely suitable for studying the early stages of the amyloid cascade and the effects thereon of apoE4. PMID:18448646

  1. Adenoviral expression of murine serum amyloid A proteins to study amyloid fibrillogenesis.

    PubMed

    Kindy, M S; King, A R; Yu, J; Gerardot, C; Whitley, J; de Beer, F C

    1998-06-15

    Serum amyloid A (SAA) proteins are one of the most inducible acute-phase reactants and are precursors of secondary amyloidosis. In the mouse, SAA1 and SAA2 are induced in approximately equal quantities in response to amyloid induction models. These two isotypes differ in only 9 of 103 amino acid residues; however, only SAA2 is selectively deposited into amyloid fibrils. SAA expression in the CE/J mouse species is an exception in that gene duplication did not occur and the CE/J variant is a hybrid molecule sharing features of SAA1 and SAA2. However, even though it is more closely related to SAA2 it is not deposited as amyloid fibrils. We have developed an adenoviral vector system to overexpress SAA proteins in cell culture to determine the ability of these proteins to form amyloid fibrils, and to study the structural features in relation to amyloid formation. Both the SAA2 and CE/J SAA proteins were synthesized in large quantities and purified to homogeneity. Electron microscopic analysis of the SAA proteins revealed that the SAA2 protein was capable of forming amyloid fibrils, whereas the CE/J SAA was incapable. Radiolabelled SAAs were associated with normal or acute-phase high-density lipoproteins (HDLs); we examined them for their clearance from the circulation. In normal mice, SAA2 had a half-life of 70 min and CE/J SAA had a half-life of 120 min; however, in amyloid mice 50% of the SAA2 cleared in 55 min, compared with 135 min for the CE/J protein. When the SAA proteins were associated with acute-phase HDLs, SAA2 clearance was decreased to 60 min in normal mice compared with 30 min in amyloidogenic mice. Both normal and acute-phase HDLs were capable of depositing SAA2 into preformed amyloid fibrils, whereas the CE/J protein did not become associated with amyloid fibrils. This established approach opens the doors for large-scale SAA production and for the examination of specific amino acids involved in the fibrillogenic capability of the SAA2 molecule in vitro

  2. The neuritic plaque facilitates pathological conversion of tau in an Alzheimer's disease mouse model

    PubMed Central

    Li, Tong; Braunstein, Kerstin E.; Zhang, Juhong; Lau, Ashley; Sibener, Leslie; Deeble, Christopher; Wong, Philip C.

    2016-01-01

    A central question in Alzheimer's Disease (AD) is whether the neuritic plaque is necessary and sufficient for the development of tau pathology. Hyperphosphorylation of tau is found within dystrophic neurites surrounding β-amyloid deposits in AD mouse models but the pathological conversion of tau is absent. Likewise, expression of a human tau repeat domain in mice is insufficient to drive the pathological conversion of tau. Here we developed an Aβ-amyloidosis mouse model that expresses the human tau repeat domain and show that in these mice, the neuritic plaque facilitates the pathological conversion of wild-type tau. We show that this tau fragment seeds the neuritic plaque-dependent pathological conversion of wild-type tau that spreads from the cortex and hippocampus to the brain stem. These results establish that in addition to the neuritic plaque, a second determinant is required to drive the conversion of wild-type tau. PMID:27373369

  3. Aβ(1–40) forms five distinct amyloid structures whose β-sheet contents and fibril stabilities are correlated

    PubMed Central

    Kodali, Ravindra; Williams, Angela D.; Chemuru, Saketh; Wetzel, Ronald

    2010-01-01

    The ability of a single polypeptide sequence to grow into multiple stable amyloid fibrils sets these aggregates apart from most native globular proteins. The existence of multiple amyloid forms is the basis for strain effects in yeast prion biology, and may also contribute to variations in Alzheimer’s disease pathology. However, the structural basis for amyloid polymorphism is poorly understood. We report here five structurally distinct fibrillar aggregates of the Alzheimer’s plaque peptide Aβ(1–40), as well as a non-fibrillar aggregate induced by Zn+2. Each of these conformational forms exhibits a unique profile of physical properties, and all the fibrillar forms “breed true” in elongation reactions at a common set of growth conditions. Consistent with their defining cross-β structure, we find that in this series the amyloid fibrils containing more extensive β-sheet exhibit greater stability. At the same time, side chain packing outside of the β-sheet regions also contributes to stability, and to stability differences between polymorphic forms. Stability comparison is facilitated by the unique feature that the free energy of the monomer (equivalent to the unfolded state in a protein folding reaction) does not vary, and hence can be ignored, in the comparison of ΔG° of elongation values for each polymorphic fibril obtained at a single set of conditions. PMID:20600131

  4. β2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH

    PubMed Central

    Goodchild, Sophia C.; Sheynis, Tania; Thompson, Rebecca; Tipping, Kevin W.; Xue, Wei-Feng; Ranson, Neil A.; Beales, Paul A.; Hewitt, Eric W.; Radford, Sheena E.

    2014-01-01

    Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of β2-microglobulin (β2m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which β2m-lipid interactions occur have not been investigated previously. Here we examine membrane damage resulting from the interaction of β2m monomers and fibrils with lipid bilayers. Using dye release, tryptophan fluorescence quenching and fluorescence confocal microscopy assays we investigate the effect of anionic lipid composition and pH on the susceptibility of liposomes to fibril-induced membrane damage. We show that β2m fibril-induced membrane disruption is modulated by anionic lipid composition and is enhanced by acidic pH. Most strikingly, the greatest degree of membrane disruption is observed for liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH, conditions likely to reflect those encountered in the endocytic pathway. The results suggest that the interaction between β2m fibrils and membranes of endosomal origin may play a role in the molecular mechanism of β2m amyloid-associated osteoarticular tissue destruction in DRA. PMID:25100247

  5. Development of (99m)Tc-Labeled Pyridyl Benzofuran Derivatives To Detect Pancreatic Amylin in Islet Amyloid Model Mice.

    PubMed

    Yoshimura, Masashi; Ono, Masahiro; Watanabe, Hiroyuki; Kimura, Hiroyuki; Saji, Hideo

    2016-06-15

    While islet amyloid deposition comprising amylin is one of pathological hallmarks of type 2 diabetes mellitus (T2DM), no useful amylin-imaging probe has been reported. In this study, we evaluated two (99m)Tc-labeled pyridyl benzofuran derivatives as novel amylin-imaging probes using the newly established islet amyloid model mouse. Binding experiments in vitro demonstrated that [(99m)Tc]1 displayed a higher affinity for amylin aggregates than [(99m)Tc]2. Autoradiographic studies using human pancreas sections with T2DM revealed that [(99m)Tc]1 clearly labeled islet amyloid in T2DM pancreatic sections, while [(99m)Tc]2 did not. Although the initial uptake of [(99m)Tc]1 by the normal mouse pancreas was low (0.74%ID/g at 2 min post-injection), [(99m)Tc]1 showed higher retention in the model mouse pancreas than that of the normal mouse, and exhibited strong binding to amylin aggregates in the living pancreas of the model mice. These results suggest that [(99m)Tc]1 is a potential imaging probe targeting islet amyloids in the T2DM pancreas. PMID:27219875

  6. Drosophila Melanogaster as a Model System for Studies of Islet Amyloid Polypeptide Aggregation

    PubMed Central

    Schultz, Sebastian Wolfgang; Nilsson, K. Peter R.; Westermark, Gunilla Torstensdotter

    2011-01-01

    Background Recent research supports that aggregation of islet amyloid polypeptide (IAPP) leads to cell death and this makes islet amyloid a plausible cause for the reduction of beta cell mass, demonstrated in patients with type 2 diabetes. IAPP is produced by the beta cells as a prohormone, and proIAPP is processed into IAPP by the prohormone convertases PC1/3 and PC2 in the secretory granules. Little is known about the pathogenesis for islet amyloid and which intracellular mechanisms are involved in amyloidogenesis and induction of cell death. Methodology/Principal Findings We have established expression of human proIAPP (hproIAPP), human IAPP (hIAPP) and the non-amyloidogenic mouse IAPP (mIAPP) in Drosophila melanogaster, and compared survival of flies with the expression driven to different cell populations. Only flies expressing hproIAPP in neurons driven by the Gal4 driver elavC155,Gal4 showed a reduction in lifespan whereas neither expression of hIAPP or mIAPP influenced survival. Both hIAPP and hproIAPP expression caused formation of aggregates in CNS and fat body region, and these aggregates were both stained by the dyes Congo red and pFTAA, both known to detect amyloid. Also, the morphology of the highly organized protein granules that developed in the fat body of the head in hIAPP and hproIAPP expressing flies was characterized, and determined to consist of 15.8 nm thick pentagonal rod-like structures. Conclusions/Significance These findings point to a potential for Drosophila melanogaster to serve as a model system for studies of hproIAPP and hIAPP expression with subsequent aggregation and developed pathology. PMID:21695120

  7. Small Liposomes Accelerate the Fibrillation of Amyloid β (1–40)*

    PubMed Central

    Terakawa, Mayu S.; Yagi, Hisashi; Adachi, Masayuki; Lee, Young-Ho; Goto, Yuji

    2015-01-01

    The deposition of amyloid β (Aβ) peptides is a pathological hallmark of Alzheimer disease. Aβ peptides were previously considered to interact specifically with ganglioside-containing membranes. Several studies have suggested that Aβ peptides also bind to phosphatidylcholine membranes, which lead to deformation of membranes and fibrillation of Aβ. Moreover, the role of membrane curvature, one type of deformation produced by binding of proteins to a membrane, in the binding and fibrillation of Aβ remains unclear. To clearly understand the relationship between the binding, consequent membrane deformation, and fibrillation of Aβ, we examined the amyloid fibrillation of Aβ-(1–40) in the presence of liposomes of various sizes. Membrane curvature increased with a decrease in the size of the liposomes. We used liposomes made of 1,2-dioleoyl-sn-glycero-3-phosphocholine to eliminate electrostatic effects. The results obtained showed that liposomes of smaller sizes (≤50 nm) significantly accelerated the nucleation step, thereby shortening the lag time of fibrillation. On the other hand, liposomes of larger sizes decreased the amount of fibrils but did not notably affect the lag time. The morphologies of fibrils, which were monitored by total internal reflection fluorescence microscopy, atomic force microscopy, and transmission electron microscopy, revealed that the length of Aβ-(1–40) fibrils became shorter and the amount of amorphous aggregates became larger as liposomes increased in size. These results suggest that the curvature of membranes coupled with an increase in water-accessible hydrophobic regions is important for binding and concentrating Aβ monomers, leading to amyloid nucleation. Furthermore, amyloid fibrillation on membranes may compete with non-productive binding to produce amorphous aggregates. PMID:25406316

  8. Introduction of yeast artificial chromosomes containing mutant human amyloid precursor protein genes into transgenic mice

    SciTech Connect

    Call, L.M.; Lamb, B.T.; Boese, K.F.

    1994-09-01

    Several hypothetical mechanisms have been proposed for the generation and deposition of the amyloid beta (A{beta}) peptide in Alzheimer`s disease (AD). These include overexpression of the amyloid precursor protein (APP) gene, as suggested by Down Syndrome (DS, trisomy 21), and mutation of APP, as suggested by mutations associated with the presence of disease/amyloid deposition in some cases of familial AD (FAD). Although numerous in vitro studies have lead to certain insights into the molecular basis for amyloid deposition, the mechanisms(s) of amyloidogenesis in vivo remains poorly defined. To examine the effect of FAD mutations on amyloidogenesis in an animal model, we have focused on producing APP YAC transgenic mice containing the human APP gene with FAD mutations. These APP YAC transgenics are being produced by introduction of a 650 kb APP YAC through lipid-mediated transfection of ES cells. This strategy has two principal advantages: the APP genomic sequences contain transcriptional regulatory elements required for proper spatial and temporal expression and contain appropriate splice donor and acceptor sites needed to generate the entire spectrum of alternatively spliced APP transcripts. As a first step, we cloned the genomic regions surrounding APP exons 16 and 17 from an APP YAC sublibrary. Both the Swedish and the 717 mutations were then introduced into exons 16 and 17, respectively, by PCR mutagenesis, and subsequently transferred into the 650 kb APP YAC by a two step gene replacement in yeast. The mutant YACs have been introduced into ES cells, and we have determined that these cells are expressing human mutant APP mRNA and protein. These cells are being used to generate transgenic mice. This paradigm should provide the appropriate test of whether a mutant APP gene is capable of producing AD-like pathology in a mouse model.

  9. Mutations in or near the transmembrane domain alter PMEL amyloid formation from functional to pathogenic.

    PubMed

    Watt, Brenda; Tenza, Danièle; Lemmon, Mark A; Kerje, Susanne; Raposo, Graça; Andersson, Leif; Marks, Michael S

    2011-09-01

    PMEL is a pigment cell-specific protein that forms physiological amyloid fibrils upon which melanins ultimately deposit in the lumen of the pigment organelle, the melanosome. Whereas hypomorphic PMEL mutations in several species result in a mild pigment dilution that is inherited in a recessive manner, PMEL alleles found in the Dominant white (DW) chicken and Silver horse (HoSi)--which bear mutations that alter the PMEL transmembrane domain (TMD) and that are thus outside the amyloid core--are associated with a striking loss of pigmentation that is inherited in a dominant fashion. Here we show that the DW and HoSi mutations alter PMEL TMD oligomerization and/or association with membranes, with consequent formation of aberrantly packed fibrils. The aberrant fibrils are associated with a loss of pigmentation in cultured melanocytes, suggesting that they inhibit melanin production and/or melanosome integrity. A secondary mutation in the Smoky chicken, which reverts the dominant DW phenotype, prevents the accumulation of PMEL in fibrillogenic compartments and thus averts DW-associated pigment loss; a secondary mutation found in the Dun chicken likely dampens a HoSi-like dominant mutation in a similar manner. We propose that the DW and HoSi mutations alter the normally benign amyloid to a pathogenic form that antagonizes melanosome function, and that the secondary mutations found in the Smoky and Dun chickens revert or dampen pathogenicity by functioning as null alleles, thus preventing the formation of aberrant fibrils. We speculate that PMEL mutations can model the conversion between physiological and pathological amyloid. PMID:21949659

  10. An azobenzene photoswitch sheds light on turn nucleation in amyloid-β self-assembly.

    PubMed

    Doran, Todd M; Anderson, Elizabeth A; Latchney, Sarah E; Opanashuk, Lisa A; Nilsson, Bradley L

    2012-03-21

    Amyloid-β (Aβ) self-assembly into cross-β amyloid fibrils is implicated in a causative role in Alzheimer's disease pathology. Uncertainties persist regarding the mechanisms of amyloid self-assembly and the role of metastable prefibrillar aggregates. Aβ fibrils feature a sheet-turn-sheet motif in the constituent β-strands; as such, turn nucleation has been proposed as a rate-limiting step in the self-assembly pathway. Herein, we report the use of an azobenzene β-hairpin mimetic to study the role turn nucleation plays on Aβ self-assembly. [3-(3-Aminomethyl)phenylazo]phenylacetic acid (AMPP) was incorporated into the putative turn region of Aβ42 to elicit temporal control over Aβ42 turn nucleation; it was hypothesized that self-assembly would be favored in the cis-AMPP conformation if β-hairpin formation occurs during Aβ self-assembly and that the trans-AMPP conformer would display attenuated fibrillization propensity. It was unexpectedly observed that the trans-AMPP Aβ42 conformer forms fibrillar constructs that are similar in almost all characteristics, including cytotoxicity, to wild-type Aβ42. Conversely, the cis-AMPP Aβ42 congeners formed nonfibrillar, amorphous aggregates that exhibited no cytotoxicity. Additionally, cis-trans photoisomerization resulted in rapid formation of native-like amyloid fibrils and trans-cis conversion in the fibril state reduced the population of native-like fibrils. Thus, temporal photocontrol over Aβ turn conformation provides significant insight into Aβ self-assembly. Specifically, Aβ mutants that adopt stable β-turns form aggregate structures that are unable to enter folding pathways leading to cross-β fibrils and cytotoxic prefibrillar intermediates. PMID:22860190

  11. An In Vivo Evaluation of Cerebral Cortical Amyloid with [18F]Flutemetamol Using Positron Emission Tomography Compared with Parietal Biopsy Samples in Living Normal Pressure Hydrocephalus Patients

    PubMed Central

    Wong, Dean F.; Moghekar, Abhay R.; Rigamonti, Daniele; Brašić, James R.; Rousset, Olivier; Willis, William; Buckley, Chris; Smith, Adrian; Gok, Beril; Sherwin, Paul; Grachev, Igor D.

    2014-01-01

    specificity of 100 % with pathology reads staining for amyloid plaque with Bielschowsky and thioflavin S and overall pathology read. The results of the blinded reader agreement for [18F] flutemetamol PET showed full agreement among three readers. Conclusions PET imaging of NPH patients following the administration of [18F]flutemetamol injection was highly correlated with the presence of fibrillar amyloid β in subsequent cortical biopsy samples in this small sample. Administration of [18F]flutemetamol injection was well tolerated. PMID:22878921

  12. The Anti-Prion Antibody 15B3 Detects Toxic Amyloid-β Oligomers.

    PubMed

    Stravalaci, Matteo; Tapella, Laura; Beeg, Marten; Rossi, Alessandro; Joshi, Pooja; Pizzi, Erika; Mazzanti, Michele; Balducci, Claudia; Forloni, Gianluigi; Biasini, Emiliano; Salmona, Mario; Diomede, Luisa; Chiesa, Roberto; Gobbi, Marco

    2016-07-01

    15B3 is a monoclonal IgM antibody that selectively detects pathological aggregates of the prion protein (PrP). We report the unexpected finding that 15B3 also recognizes oligomeric but not monomeric forms of amyloid-β (Aβ)42, an aggregating peptide implicated in the pathogenesis of Alzheimer's disease (AD). The 15B3 antibody: i) inhibits the binding of synthetic Aβ42 oligomers to recombinant PrP and neuronal membranes; ii) prevents oligomer-induced membrane depolarization; iii) antagonizes the inhibitory effects of oligomers on the physiological pharyngeal contractions of the nematode Caenorhabditis elegans; and iv) counteracts the memory deficits induced by intracerebroventricular injection of Aβ42 oligomers in mice. Thus this antibody binds to pathologically relevant forms of Aβ, and offers a potential research, diagnostic, and therapeutic tool for AD. PMID:27392850

  13. What amyloid ligands can tell us about molecular polymorphism and disease.

    PubMed

    LeVine, Harry; Walker, Lary C

    2016-06-01

    Brain-penetrant positron emission tomography imaging ligands selective for amyloid pathology in living subjects have sparked a revolution in presymptomatic biomarkers for Alzheimer's disease progression. As additional chemical structures were investigated, the heterogeneity of ligand-binding sites became apparent, as did discrepancies in binding of some ligands between human disease and animal models. These differences and their implications have received little attention. This review discusses the impact of different ligand-binding sites and misfolded protein conformational polymorphism on the interpretation of imaging data acquired with different ligands. Investigation of the differences in binding in animal models may identify pathologic processes informing improvements to these models for more faithful recapitulation of this uniquely human disease. The differential selectivity for binding of particular ligands to different conformational states could potentially be harnessed to better define disease progression and improve the prediction of clinical outcomes. PMID:27143437

  14. Memory decline shows stronger associations with estimated spatial patterns of amyloid deposition progression than total amyloid burden.

    PubMed

    Yotter, Rachel A; Doshi, Jimit; Clark, Vanessa; Sojkova, Jitka; Zhou, Yun; Wong, Dean F; Ferrucci, Luigi; Resnick, Susan M; Davatzikos, Christos

    2013-12-01

    The development of amyloid imaging compounds has allowed in vivo imaging of amyloid deposition. In this study, we examined the spatial patterns of amyloid deposition throughout the brain using Pittsburgh Compound Blue ((11)C-PiB) positron emission tomography data from the Baltimore Longitudinal Study of Aging. We used a new methodology that allowed us to approximate spatial patterns of the temporal progression of amyloid plaque deposition from cross-sectional data. Our results are consistent with patterns of progression known from autopsy studies, with frontal and precuneus regions affected early and occipital and sensorimotor cortices affected later in disease progression--here, disease progression means lower-to-higher total amyloid burden. Furthermore, we divided participants into subgroups based on longitudinal change in memory performance, and demonstrated significantly different spatial patterns of the estimated progression of amyloid deposition between these subgroups. Our results indicate that the spatial pattern of amyloid deposition is related to cognitive performance and may be more informative than a biomarker reflecting total amyloid burden, the use of which is the current practice. This finding has broad implications for our understanding of the relationship between cognitive decline/resilience and amyloid deposition, as well as for the use of amyloid imaging as a biomarker in research and clinical applications. PMID:23859610

  15. Tau and Amyloid-β Cerebrospinal Fluid Biomarkers have Differential Relationships with Cognition in Mild Cognitive Impairment.

    PubMed

    Malpas, Charles B; Saling, Michael M; Velakoulis, Dennis; Desmond, Patricia; O'Brien, Terence J

    2015-01-01

    Alzheimer's disease (AD) is characterized by two primary pathologies: tau-related neurofibrillary tangles and the extracellular accumulation of amyloid-β (Aβ). The development of these pathologies is topologically distinct early in the disease, with Aβ beginning to accumulate as a diffuse, neocortical pathology, while tau-related pathology begins to form in mesial temporal regions. This study investigated the hypothesis that, by virtue of this distinction, there exist preferential associations between the primary pathologies and aspects of the cognitive phenotype. We investigated the relationship between cerebrospinal fluid (CSF) biomarkers for tau and Aβ pathologies with neurocognitive measures in 191 patients with mild cognitive impairment (MCI). Participants completed cognitive tests of new learning, information processing speed, and working memory. Separate regression models were computed and then followed up with mediation analyses to examine the predictive status of CSF biomarkers. The effect of Aβ on learning was mediated by phospho-tau (p = 0.008). In contrast, Aβ had a direct effect on information processing speed that was not mediated by phospho-tau (p = 0.59). No predictors were significant for working memory. This study provided evidence for a differential relationship of Aβ and phospho-tau pathologies on the neurocognitive phenotype of MCI. This supports the proposition that these primary AD pathologies maximally affect different aspects of cognition, and has potential implications for cognitive assessments and the use of biomarkers in disease-modifyingtherapeutic trials. PMID:26401775

  16. Clinical governance and pathology

    PubMed Central

    Crook, M

    2002-01-01

    This article looks at clinical governance and pathology. Clinical governance should be an important tool in seeking quality improvement within the Natinal Health Service. But how as pathologists should we go about it? PMID:11896066

  17. Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer's disease.

    PubMed

    Sadleir, Katherine R; Kandalepas, Patty C; Buggia-Prévot, Virginie; Nicholson, Daniel A; Thinakaran, Gopal; Vassar, Robert

    2016-08-01

    Alzheimer's disease (AD) is characterized by amyloid plaques composed of the β-amyloid (Aβ) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Aβ generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Aβ may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of Aβ, particularly neurotoxic Aβ42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to Aβ42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations or voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors, kinesin and dynein, and other neuronal proteins were aberrantly localized in peri-plaque dystrophies. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Aβ generation. Our study supports the hypothesis that Aβ induces microtubule disruption in presynaptic dystrophic neurites that surround plaques, thus impairing axonal transport and leading to accumulation of

  18. 1Divergent effect of glycosaminoglycans on the in vitro aggregation of Serum Amyloid A

    PubMed Central

    Aguilera, J. Javier; Zhang, Fuming; Beaudet, Julie M.; Linhardt, Robert J.; Colón, Wilfredo

    2014-01-01

    Serum amyloid A (SAA) is an apolipoprotein involved in poorly understood roles in inflammation. Upon trauma, hepatic expression of SAA rises 1000 times the basal levels. In the case of inflammatory diseases like rheumatoid arthritis, there is a risk for deposition of SAA fibrils in various organs leading to Amyloid A (AA) amyloidosis. Although the amyloid deposits in AA amyloidosis accumulate with the glycosaminoglycan (GAG) heparan sulfate, the role GAGs play in the function and pathology of SAA is an enigma. It has been shown that GAG sulfation is a contributing factor in protein fibrillation and for co-aggregating with a plethora of amyloidogenic proteins. Herein, the effects of heparin, heparan sulfate, hyaluronic acid, chondroitin sulfate A, and heparosan on the oligomerization and aggregation properties of pathogenic mouse SAA1.1 were investigated. Delipidated SAA was used to better understand the interactions between SAA and GAGs without the complicating involvement of lipids. The results revealed—to varying degrees—that all GAGs accelerated SAA1.1 aggregation, but had variable effects on its fibrillation. Heparan sulfate, hyaluronic acid, and heparosan did not affect much the fibrillation of SAA1.1. In contrast, chondroitin sulfate A blocked SAA fibril formation and facilitated the formation of spherical aggregates of various sizes. Interestingly, heparin caused formation of spherical SAA1.1 aggregates of various sizes, vast amounts of thin protofibrils, and few long fibrils of various heights. These results suggest that GAGs may have an intrinsic and divergent influence on the aggregation and fibrillation of HDL-free SAA1.1 in vivo, with functional and pathological implications. PMID:24878279

  19. Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease.

    PubMed

    Shinohara, Mitsuru; Murray, Melissa E; Frank, Ryan D; Shinohara, Motoko; DeTure, Michael; Yamazaki, Yu; Tachibana, Masaya; Atagi, Yuka; Davis, Mary D; Liu, Chia-Chen; Zhao, Na; Painter, Meghan M; Petersen, Ronald C; Fryer, John D; Crook, Julia E; Dickson, Dennis W; Bu, Guojun; Kanekiyo, Takahisa

    2016-08-01

    Cerebral amyloid angiopathy (CAA) often coexists with Alzheimer's disease (AD). APOE4 is a strong genetic risk factor for both AD and CAA. Sex-dependent differences have been shown in AD as well as in cerebrovascular diseases. Therefore, we examined the effects of APOE4, sex, and pathological components on CAA in AD subjects. A total of 428 autopsied brain samples from pathologically confirmed AD cases were analyzed. CAA severity was histologically scored in inferior parietal, middle frontal, motor, superior temporal and visual cortexes. In addition, subgroups with severe CAA (n = 60) or without CAA (n = 39) were subjected to biochemical analysis of amyloid-β (Aβ) and apolipoprotein E (apoE) by ELISA in the temporal cortex. After adjusting for age, Braak neurofibrillary tangle stage and Thal amyloid phase, we found that overall CAA scores were higher in males than females. Furthermore, carrying one or more APOE4 alleles was associated with higher overall CAA scores. Biochemical analysis revealed that the levels of detergent-soluble and detergent-insoluble Aβ40, and insoluble apoE were significantly elevated in individuals with severe CAA or APOE4. The ratio of Aβ40/Aβ42 in insoluble fractions was also increased in the presence of CAA or APOE4, although it was negatively associated with male sex. Levels of insoluble Aβ40 were positively associated with those of insoluble apoE, which were strongly influenced by CAA status. Pertaining to insoluble Aβ42, the levels of apoE correlated regardless of CAA status. Our results indicate that sex and APOE genotypes differentially influence the presence and severity of CAA in AD, likely by affecting interaction and aggregation of Aβ40 and apoE. PMID:27179972

  20. Tau and α-Synuclein Pathology in Amygdala of Parkinsonism-Dementia Complex Patients of Guam

    PubMed Central

    Forman, Mark S.; Schmidt, M. Luise; Kasturi, Sanjay; Perl, Daniel P.; Lee, Virginia M.-Y.; Trojanowski, John Q.

    2002-01-01

    Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disorder of Chamorro residents of Guam and the Mariana Islands, characterized by abundant neuron loss and tau neurofibrillary pathology similar to that observed in Alzheimer’s disease (AD). A variety of neurodegenerative diseases with tau pathology including ALS/PDC also have α-synuclein positive pathology, primarily in the amygdala. We further characterized the tau and α-synuclein pathology in the amygdala of a large series of 30 Chamorros using immunohistochemical and biochemical techniques. Tau pathology was readily detected in both affected and unaffected Chamorros. In contrast, α-synuclein pathology was detected in 37% of patients with PDC but not detected in Chamorros without PDC or AD. The α-synuclein aggregates often co-localized within neurons harboring neurofibrillary tangles suggesting a possible interaction between the two proteins. Tau and α-synuclein pathology within the amygdala is biochemically similar to that observed in AD and synucleinopathies, respectively. Thus, the amygdala may be selectively vulnerable to developing both tau and α-synuclein pathology or tau pathology may predispose it to synuclein aggregation. Furthermore, in PDC, tau and α-synuclein pathology occurs independent of β-amyloid deposition in amygdala thereby implicating the aggregation of these molecules in the severe neurodegeneration frequently observed in this location. PMID:12000724

  1. Dementia in cerebral amyloid angiopathy: a clinicopathological study.

    PubMed

    Yoshimura, M; Yamanouchi, H; Kuzuhara, S; Mori, H; Sugiura, S; Mizutani, T; Shimada, H; Tomonaga, M; Toyokura, Y

    1992-10-01

    Dementia is in addition to cerebral haemorrhage major symptom of cerebral amyloid angiopathy (CAa). In order to explore the pathological basis for dementia in CAa-related conditions, we made a clinicopathological analysis of CAa, with special attention to dementia. Among 150 patients (mean age 78.6 years) with autopsy-proven intracranial haemorrhage in Tokyo Metropolitan Geriatric Medical Center, CAa with cerebral haemorrhage accounted for 8.0% (12 cases), associated with hypertension and metastatic brain tumour. Among 38 patients with lobar haemorrhage, CAa represented the second most common cause (21.1%) of intracranial haemorrhage after hypertension. A total of 20 patients with CAa (mean age 82.5 years) were studies clinically and pathologically. Hypertension was present in 50%. Thirteen had a history of stroke and others had either ill-defined or no strokes. The average number of strokes 2.9. Fifteen patients (75%) had dementia. Based on the clinicopathological grounds for dementia, CAa-related conditions could be divided into three subtypes: "haemorrhagic", "dementia-haemorrhagic" and "dementia" type. Haemorrhagic type (30%, 6 cases) showed multiple recurrent lobar haemorrhages caused by CAa. Hypertension was present in only 1 patient. The incidence of senile plaques and neurofibrillary tangles was generally correlated with age. Only 1 patient had dementia. The dementia-haemorrhagic type (40%, 8 patients) had recurrent strokes with cerebral haemorrhage after preceding dementia. There were two different neuropathological subsets: CAa with atypical senile dementia of Alzheimer type (SDAT) and CAa with diffuse leucoencephalopathy. Patients with CAa with atypical SDAT had multiple cerebral haemorrhages caused by CAa combined with atypical Alzheimer-type pathology. Patients with CAa with diffuse leucoencephalopathy had cerebral haemorrhages in combination with diffuse white matter damage like Binswanger's subcortical vascular encephalopathy (BSVE). The incidence of

  2. Colorectal carcinoma: Pathologic aspects

    PubMed Central

    Fleming, Matthew; Ravula, Sreelakshmi; Tatishchev, Sergei F.

    2012-01-01

    Colorectal carcinoma is one of the most common cancers and one of the leading causes of cancer-related death in the United States. Pathologic examination of biopsy, polypectomy and resection specimens is crucial to appropriate patient managemnt, prognosis assessment and family counseling. Molecular testing plays an increasingly important role in the era of personalized medicine. This review article focuses on the histopathology and molecular pathology of colorectal carcinoma and its precursor lesions, with an emphasis on their clinical relevance. PMID:22943008

  3. Modeling the complex pathology of Alzheimer's disease in Drosophila.

    PubMed

    Fernandez-Funez, Pedro; de Mena, Lorena; Rincon-Limas, Diego E

    2015-12-01

    Alzheimer's disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. AD is mostly a sporadic disorder and its main risk factor is age, but mutations in three genes that promote the accumulation of the amyloid-β (Aβ42) peptide revealed the critical role of amyloid precursor protein (APP) processing in AD. Neurofibrillary tangles enriched in tau are the other pathological hallmark of AD, but the lack of causative tau mutations still puzzles researchers. Here, we describe the contribution of a powerful invertebrate model, the fruit fly Drosophila melanogaster, to uncover the function and pathogenesis of human APP, Aβ42, and tau. APP and tau participate in many complex cellular processes, although their main function is microtubule stabilization and the to-and-fro transport of axonal vesicles. Additionally, expression of secreted Aβ42 induces prominent neuronal death in Drosophila, a critical feature of AD, making this model a popular choice for identifying intrinsic and extrinsic factors mediating Aβ42 neurotoxicity. Overall, Drosophila has made significant contributions to better understand the complex pathology of AD, although additional insight can be expected from combining multiple transgenes, performing genome-wide loss-of-function screens, and testing anti-tau therapies alone or in combination with Aβ42. PMID:26024860

  4. Monocyte-mediated regulation of genes by the amyloid and prion peptides in SH-SY5Y neuroblastoma cells.

    PubMed

    Morte, Beatriz; Martínez, Tamara; Zambrano, Alberto; Pascual, Angel

    2011-05-01

    Alzheimer's disease as well as prion-related encephalopathies are neurodegenerative disorders of the central nervous system, which cause mental deterioration and progressive dementia. Both pathologies appear to be primarily associated with the pathological accumulation and deposit of β-amyloid or prion peptides in the brain, and it has been even suggested that neurotoxicity induced by these peptides would be associated to essentially similar pathogenic mechanisms, in particular to those that follow the activation of microglial cells. To probe whether the neurotoxic effects induced by the β-amyloid and prion peptides are actually mediated by similar glial-associated mechanisms, we have examined the differential expression of genes in SH-SY5Y neuroblastoma cells incubated with conditioned media from β-amyloid or prion-stimulated THP-1 monocytic cells. According to microarray analysis, not many coincidences are observed and only four genes (Hint3, Psph, Daam1 and c-Jun) appear to be commonly upregulated by both peptides. Furthermore, c-Jun appears to be involved in the cell death mediated by both peptides. PMID:21303680

  5. Proliferation in the Alzheimer Hippocampus Is due to Microglia, Not Astroglia, and Occurs at Sites of Amyloid Deposition

    PubMed Central

    Marlatt, Michael W.; Bauer, Jan; Aronica, Eleonora; van Haastert, Elise S.; Hoozemans, Jeroen J. M.; Joels, Marian; Lucassen, Paul J.

    2014-01-01

    Microglia and astrocytes contribute to Alzheimer's disease (AD) etiology and may mediate early neuroinflammatory responses. Despite their possible role in disease progression and despite the fact that they can respond to amyloid deposition in model systems, little is known about whether astro- or microglia can undergo proliferation in AD and whether this is related to the clinical symptoms or to local neuropathological changes. Previously, proliferation was found to be increased in glia-rich regions of the presenile hippocampus. Since their phenotype was unknown, we here used two novel triple-immunohistochemical protocols to study proliferation in astro- or microglia in relation to amyloid pathology. We selected different age-matched cohorts to study whether proliferative changes relate to clinical severity or to neuropathological changes. Proliferating cells were found across the hippocampus but never in mature neurons or astrocytes. Almost all proliferating cells were colabeled with Iba1+, indicating that particularly microglia contribute to proliferation in AD. Proliferating Iba1+ cells was specifically seen within the borders of amyloid plaques, indicative of an active involvement in, or response to, plaque accumulation. Thus, consistent with animal studies, proliferation in the AD hippocampus is due to microglia, occurs in close proximity of plaque pathology, and may contribute to the neuroinflammation common in AD. PMID:25215243

  6. Amyloid persistence in decellularized liver: biochemical and histopathological characterization

    PubMed Central

    Mazza, Giuseppe; Simons, J. Paul; Al-Shawi, Raya; Ellmerich, Stephan; Urbani, Luca; Giorgetti, Sofia; Taylor, Graham W.; Gilbertson, Janet A.; Hall, Andrew R.; Al-Akkad, Walid; Dhar, Dipok; Hawkins, Philip N.; De Coppi, Paolo; Pinzani, Massimo; Bellotti, Vittorio; Mangione, P. Patrizia

    2016-01-01

    Abstract Systemic amyloidoses are a group of debilitating and often fatal diseases in which fibrillar protein aggregates are deposited in the extracellular spaces of a range of tissues. The molecular basis of amyloid formation and tissue localization is still unclear. Although it is likely that the extracellular matrix (ECM) plays an important role in amyloid deposition, this interaction is largely unexplored, mostly because current analytical approaches may alter the delicate and complicated three-dimensional architecture of both ECM and amyloid. We describe here a decellularization procedure for the amyloidotic mouse liver which allows high-resolution visualization of the interactions between amyloid and the constitutive fibers of the extracellular matrix. The primary structure of the fibrillar proteins remains intact and the amyloid fibrils retain their amyloid enhancing factor activity. PMID:26646718

  7. Molecular basis for amyloid fibril formation and stability

    PubMed Central

    Makin, O. Sumner; Atkins, Edward; Sikorski, Pawel; Johansson, Jan; Serpell, Louise C.

    2005-01-01

    The molecular structure of the amyloid fibril has remained elusive because of the difficulty of growing well diffracting crystals. By using a sequence-designed polypeptide, we have produced crystals of an amyloid fiber. These crystals diffract to high resolution (1 Å) by electron and x-ray diffraction, enabling us to determine a detailed structure for amyloid. The structure reveals that the polypeptides form fibrous crystals composed of antiparallel β-sheets in a cross-β arrangement, characteristic of all amyloid fibers, and allows us to determine the side-chain packing within an amyloid fiber. The antiparallel β-sheets are zipped together by means of π-bonding between adjacent phenylalanine rings and salt-bridges between charge pairs (glutamic acid–lysine), thus controlling and stabilizing the structure. These interactions are likely to be important in the formation and stability of other amyloid fibrils. PMID:15630094

  8. Size Effect of Graphene Oxide on Modulating Amyloid Peptide Assembly.

    PubMed

    Wang, Jie; Cao, Yunpeng; Li, Qiang; Liu, Lei; Dong, Mingdong

    2015-06-26

    Protein misfolding and abnormal assembly could lead to aggregates such as oligomer, proto-fibril, mature fibril, and senior amyloid plaques, which are associated with the pathogenesis of many amyloid diseases. These irreversible amyloid aggregates typically form in vivo and researchers have been endeavoring to find new modulators to invert the aggregation propensity in vitro, which could increase understanding in the mechanism of the aggregation of amyloid protein and pave the way to potential clinical treatment. Graphene oxide (GO) was shown to be a good modulator, which could strongly control the amyloidosis of Aβ (33-42). In particular, quartz crystal microbalance (QCM), circular dichroism (CD) spectroscopy, and atomic force microscopy (AFM) measurements revealed the size-dependent manner of GO on modulating the assembly of amyloid peptides, which could be a possible way to regulate the self-assembled nanostructure of amyloid peptide in a predictable manner. PMID:26031933

  9. Atomic View of a Toxic Amyloid Small Oligomer

    SciTech Connect

    Laganowsky, Arthur; Liu, Cong; Sawaya, Michael R.; Whitelegge, Julian P.; Park, Jiyong; Zhao, Minglei; Pensalfini, Anna; Soriaga, Angela B.; Landau, Meytal; Teng, Poh K.; Cascio, Duilio; Glabe, Charles; Eisenberg, David

    2012-04-30

    Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. These amyloid fibrils were long suspected to be the disease agents, but evidence suggests that smaller, often transient and polymorphic oligomers are the toxic entities. Here, we identify a segment of the amyloid-forming protein {alpha}{beta} crystallin, which forms an oligomeric complex exhibiting properties of other amyloid oligomers: {beta}-sheet-rich structure, cytotoxicity, and recognition by an oligomer-specific antibody. The x-ray-derived atomic structure of the oligomer reveals a cylindrical barrel, formed from six antiparallel protein strands, that we term a cylindrin. The cylindrin structure is compatible with a sequence segment from the {beta}-amyloid protein of Alzheimer's disease. Cylindrins offer models for the hitherto elusive structures of amyloid oligomers.

  10. Amyloid persistence in decellularized liver: biochemical and histopathological characterization.

    PubMed

    Mazza, Giuseppe; Simons, J Paul; Al-Shawi, Raya; Ellmerich, Stephan; Urbani, Luca; Giorgetti, Sofia; Taylor, Graham W; Gilbertson, Janet A; Hall, Andrew R; Al-Akkad, Walid; Dhar, Dipok; Hawkins, Philip N; De Coppi, Paolo; Pinzani, Massimo; Bellotti, Vittorio; Mangione, P Patrizia

    2016-01-01

    Systemic amyloidoses are a group of debilitating and often fatal diseases in which fibrillar protein aggregates are deposited in the extracellular spaces of a range of tissues. The molecular basis of amyloid formation and tissue localization is still unclear. Although it is likely that the extracellular matrix (ECM) plays an important role in amyloid deposition, this interaction is largely unexplored, mostly because current analytical approaches may alter the delicate and complicated three-dimensional architecture of both ECM and amyloid. We describe here a decellularization procedure for the amyloidotic mouse liver which allows high-resolution visualization of the interactions between amyloid and the constitutive fibers of the extracellular matrix. The primary structure of the fibrillar proteins remains intact and the amyloid fibrils retain their amyloid enhancing factor activity. PMID:26646718

  11. Detection of Alzheimer's amyloid beta aggregation by capturing molecular trails of individual assemblies

    SciTech Connect

    Vestergaard, Mun'delanji Hamada, Tsutomu; Saito, Masato; Yajima, Yoshifumi; Kudou, Monotori; Tamiya, Eiichi; Takagi, Masahiro

    2008-12-12

    Assembly of Amyloid beta (A{beta}) peptides, in particular A{beta}-42 is central to the formation of the amyloid plaques associated with neuro-pathologies such as Alzheimer's disease (AD). Molecular assembly of individual A{beta}-42 species was observed using a simple fluorescence microscope. From the molecular movements (aka Brownian motion) of the individual peptide assemblies, we calculated a temporal evolution of the hydrodynamic radius (R{sub H}) of the peptide at physiological temperature and pH. The results clearly show a direct relationship between R{sub H} of A{beta}-42 and incubation period, corresponding to the previously reported peptide's aggregation kinetics. The data correlates highly with in solution-based label-free electrochemical detection of the peptide's aggregation, and A{beta}-42 deposited on a solid surface and analysed using atomic force microscopy (AFM). To the best of our knowledge, this is the first analysis and characterisation of A{beta} aggregation based on capturing molecular trails of individual assemblies. The technique enables both real-time observation and a semi-quantitative distribution profile of the various stages of A{beta} assembly, at microM peptide concentration. Our method is a promising candidate for real-time observation and analysis of the effect of other pathologically-relevant molecules such as metal ions on pathways to A{beta} oligomerisation and aggregation. The method is also a promising screening tool for AD therapeutics that target A{beta} assembly.

  12. Protective effect of recombinant soluble neprilysin against β-amyloid induced neurotoxicity.

    PubMed

    Oh, Jae Hoon; Choi, Sunghyun; Shin, Jeehae; Park, Jong-Sang

    2016-09-01

    A few decades ago, researchers found emerging evidence showing that a number of sequential events lead to the pathological cascade of Alzheimer's disease (AD) which is caused by the accumulation of amyloid beta (Aβ), a physiological peptide, in the brain. Therefore, regulation of Aβ represents a crucial treatment approach for AD. Neprilysin (NEP), a membrane metallo-endopeptidase, is a rate-limiting peptidase which is known to degrade the amyloid beta peptide. This study investigated soluble NEP (sNEP) produced by recombinant mammalian cells stably transfected with a non-viral NEP expression vector to demonstrate its protective effect against Aβ peptides in neuronal cells in vitro. Stably transfected HEK 293 cells were used to purify the soluble protein. sNEP and Aβ peptide co-treated hippocampal cells had a decreased level of Aβ peptides shown by an increase in cell viability and decrease in apoptosis measured by the CCK-8 and relative caspase-3 activity ratio assays, respectively. This study shows that stably transfected mammalian cells can produce soluble NEP proteins which could be used to protect against Aβ accumulation in AD and subsequently neuronal toxicity. Additionally, approaches using protein therapy for potential targets could change the pathological cascade of Alzheimer's disease. PMID:27395340

  13. Structural requirements of glycosaminoglycans for facilitating amyloid fibril formation of human serum amyloid A.

    PubMed

    Takase, Hiroka; Tanaka, Masafumi; Yamamoto, Aki; Watanabe, Shiori; Takahashi, Sanae; Nadanaka, Satomi; Kitagawa, Hiroshi; Yamada, Toshiyuki; Mukai, Takahiro

    2016-06-01

    Serum amyloid A (SAA) is a precursor protein of amyloid fibrils. Given that heparan sulfate (HS), a glycosaminoglycan (GAG), is detected in amyloid deposits, it has been suggested that GAG is a key component of amyloid fibril formation. We previously reported that heparin (an analog of HS) facilitates the fibril formation of SAA, but the structural requirements remain unknown. In the present study, we investigated the structural requirements of GAGs for facilitating the amyloid fibril formation of SAA. Spectroscopic analyses using structurally diverse GAG analogs suggested that the fibril formation of SAA was facilitated irrespective of the backbone structure of GAGs; however, the facilitating effect was strongly correlated with the degree of sulfation. Microscopic analyses revealed that the morphologies of SAA aggregates were modulated by the GAGs. The HS molecule, which is less sulfated than heparin but contains highly sulfated domains, exhibited a relatively high potential to facilitate fibril formation compared to other GAGs. The length dependence of fragmented heparins on the facilitating effect suggested that a high density of sulfate groups is also required. These results indicate that not only the degree of sulfation but also the lengths of sulfated domains in GAG play important roles in fibril formation of SAA. PMID:27097047

  14. Clinical and pathological correlations in endometrial pathology

    PubMed Central

    Bohîlțea, RE; Sajin, M; Furtunescu, F; Bohîlțea, LC; Mihart, A; Baros, A; Anca, AF

    2015-01-01

    The incidence and mortality rate of endometrial cancer has been registering an increasing trend both in Romania and in the whole world. The paper’s aim is to analyze the diagnostic approach of endometrial pathology in the University Emergency Hospital Bucharest, on a four years period. The medium age of the patients was of 50.51 ± 10.924 years, and the median age was of 48 years. The youngest patient suffering from endometrial cancer was of 30 years. Dilation and uterine curettage represent the main method used in the performance of endometrial biopsy, based on which the certitude etiologic histopathologic diagnosis was established in 68.4% of the patients with endometrial pathology. Hyperplasias represented half of the pathology (54.9%), most of them being without atypias. Endometrial carcinoma was identified in 19% of the patients. The diagnosis of the disease in IA stage represents 5.5% of the total endometrial cases and the diagnosis of the disease in the stage of its limitation to the uterus (stage IA, IB and IC) was of 64.2%. The endometrioid adenocarcinoma represents the most encountered histopathological form and the degree of tumor differentiation established for 68,15% of the cases was predominantly 1 and 2 (88%). The main symptom, which determines the patients’ decision to go to the physician, is the abnormal uterine bleeding. 66% of the cases of endometrial cancer in the stage of the disease limited to the uterus are diagnosed in Romania based on the abnormal uterine bleeding. However, 34% of the cases are diagnosed in advanced stages, presenting a significantly low life expectancy. PMID:26664489

  15. Amyloid-beta: a crucial factor in Alzheimer's disease.

    PubMed

    Sadigh-Eteghad, Saeed; Sabermarouf, Babak; Majdi, Alireza; Talebi, Mahnaz; Farhoudi, Mehdi; Mahmoudi, Javad

    2015-01-01

    Alzheimer's disease (AD) is the most prevalent form of dementia which affects people older than 60 years of age. In AD, the dysregulation of the amyloid-beta (Aβ) level leads to the appearance of senile plaques which contain Aβ depositions. Aβ is a complex biological molecule which interacts with many types of receptors and/or forms insoluble assemblies and, eventually, its nonphysiological depositions alternate with the normal neuronal conditions. In this situation, AD signs appear and the patients experience marked cognitional disabilities. In general, intellect, social skills, personality, and memory are influenced by this disease and, in the long run, it leads to a reduction in quality of life and life expectancy. Due to the pivotal role of Aβ in the pathobiology of AD, a great deal of effort has been made to reveal its exact role in neuronal dysfunctions and to finding efficacious therapeutic strategies against its adverse neuronal outcomes. Hence, the determination of its different molecular assemblies and the mechanisms underlying its pathological effects are of interest. In the present paper, some of the well-established structural forms of Aβ, its interactions with various receptors and possible molecular and cellular mechanisms underlying its neurotoxicity are discussed. In addition, several Aβ-based rodent models of AD are reviewed. PMID:25471398

  16. Amyloid-beta neuroprotection mediated by a targeted antioxidant

    PubMed Central

    Giordano, Courtney R.; Terlecky, Laura J.; Bollig-Fischer, Aliccia; Walton, Paul A.; Terlecky, Stanley R.

    2014-01-01

    Amyloid-beta (Aβ)-induced neurotoxicity is a major contributor to the pathologies associated with Alzheimer's disease (AD). The formation of reactive oxygen species (ROS), an early response induced by the peptide and oligomeric derivatives of Aβ, plays a significant role in effecting cellular pathogenesis. Here we employ particularly toxic forms of Aβ with cultured primary cortical/hippocampal neurons to elicit ROS and drive cellular dysfunction. To prevent and even reverse such effects, we utilized a cell-penetrating, peroxisome-targeted, protein biologic – called CAT-SKL. We show the recombinant enzyme enters neurons, reverses Aβ-induced oxidative stress, and increases cell viability. Dramatic restorative effects on damaged neuronal processes were also observed. In addition, we used DNA microarrays to determine Aβ's effects on gene expression in neurons, as well as the ability of CAT-SKL to modify such Aβ-induced expression profiles. Our results suggest that CAT-SKL, a targeted antioxidant, may represent a new therapeutic approach for treatment of disorders, like Alzheimer's disease, that are driven through oxidative stress. Preclinical testing is ongoing. PMID:24828380

  17. Imipramine and citalopram facilitate amyloid precursor protein secretion in vitro.

    PubMed

    Pákáski, Magdolna; Bjelik, Annamária; Hugyecz, Marietta; Kása, Péter; Janka, Zoltán; Kálmán, János

    2005-08-01

    Comorbid depression of Alzheimer's disease (AD) is a common mood disorder in the elderly and a broad spectrum of antidepressants have been used for its treatment. Abeta peptides and other derivatives of the amyloid precursor protein (APP) have been implicated as central to the pathogenesis of AD. However, the functional relationship of APP and its proteolytic derivatives to antidepressant therapy is not known. In this study, Western blotting was used to test the ability of the tricyclic antidepressant (TCA) imipramine or the selective serotonin reuptake inhibitor (SSRI) citalopram to change the release of APP and the protein kinase C (PKC) content. Both antidepressants increased APP secretion in primary rat neuronal cultures. Imipramine or citalopram enhanced the level of secreted APP by 3.2- or 3.4-fold, respectively. Increases in PKC level were observed only after imipramine treatment. These in vitro data suggest that both TCA and SSRI are able to interfere with the APP metabolism. Imipramine promotes the non-amyloidogenic route of APP processing via stimulatory effects on PKC. We propose that PKC is not involved in the mechanism underlying the effects of citalopram on the APP metabolism. Since the secreted APP is not further available for the pathological cleavage of beta- and gamma-secretases, antidepressant medication might be beneficial in AD therapy. PMID:15955598

  18. Amyloid-β immunisation for Alzheimer’s disease

    PubMed Central

    Wisniewski, Thomas; Konietzko, Uwe

    2009-01-01

    Alzheimer’s disease is the main cause of dementia in elderly people and is becoming an ever greater problem as societies worldwide age. Treatments that stop or at least effectively modify disease course do not yet exist. In Alzheimer’s disease, the conversion of the amyloid-β peptide (Aβ) from a physiological water-soluble monomeric form into neurotoxic oligomeric and fibrillar forms rich in stable β-sheet conformations is an important event. The most toxic forms of Aβ are thought to be oligomers, and dimers might be the smallest neurotoxic species. Numerous immunological approaches that prevent the conversion of the normal precursor protein into pathological forms or that accelerate clearance are in development. More than ten new approaches to active and passive immunotherapy are under investigation in clinical trials with the aim of producing safe methods for immunological therapy and prevention. A delicate balance between immunological clearance of an endogenous protein with acquired toxic properties and the induction of an autoimmune reaction must be found. PMID:18667360

  19. A review of β-amyloid neuroimaging in Alzheimer's disease

    PubMed Central

    Adlard, Paul A.; Tran, Bob A.; Finkelstein, David I.; Desmond, Patricia M.; Johnston, Leigh A.; Bush, Ashley I.; Egan, Gary F.

    2014-01-01

    Alzheimer's disease (AD) is the most common cause of dementia worldwide. As advancing age is the greatest risk factor for developing AD, the number of those afflicted is expected to increase markedly with the aging of the world's population. The inability to definitively diagnose AD until autopsy remains an impediment to establishing effective targeted treatments. Neuroimaging has enabled in vivo visualization of pathological changes in the brain associated with the disease, providing a greater understanding of its pathophysiological development and progression. However, neuroimaging biomarkers do not yet offer clear advantages over current clinical diagnostic criteria for them to be accepted into routine clinical use. Nonetheless, current insights from neuroimaging combined with the elucidation of biochemical and molecular processes in AD are informing the ongoing development of new imaging techniques and their application. Much of this research has been greatly assisted by the availability of transgenic mouse models of AD. In this review we summarize the main efforts of neuroimaging in AD in humans and in mouse models, with a specific focus on β-amyloid, and discuss the potential of new applications and novel approaches. PMID:25400539

  20. Can Alzheimer disease be prevented by amyloid-β immunotherapy?

    PubMed Central

    Lemere, Cynthia A.; Masliah, Eliezer

    2010-01-01

    Alzheimer disease (AD) is the most common form of dementia. The amyloid-β (Aβ) peptide has become a major therapeutic target in AD on the basis of pathological, biochemical and genetic evidence that supports a role for this molecule in the disease process. Active and passive Aβ immunotherapies have been shown to lower cerebral Aβ levels and improve cognition in animal models of AD. In humans, dosing in the phase II clinical trial of the AN1792 Aβ vaccine was stopped when ~6% of the immunized patients developed meningoencephalitis. However, some plaque clearance and modest clinical improvements were observed in patients following immunization. As a result of this study, at least seven passive Aβ immunotherapies are now in clinical trials in patients with mild to moderate AD. Several second-generation active Aβ vaccines are also in early clinical trials. On the basis of preclinical studies and the limited data from clinical trials, Aβ immunotherapy might be most effective in preventing or slowing the progression of AD when patients are immunized before or in the very earliest stages of disease onset. Biomarkers for AD and imaging technology have improved greatly over the past 10 years and, in the future, might be used to identify presymptomatic, at-risk individuals who might benefit from Aβ immunization. PMID:20140000

  1. Imaging Brain Metabolism and Pathology in Alzheimer’s Disease with Positron Emission Tomography

    PubMed Central

    Shokouhi, S; Claassen, D; Riddle, WR

    2014-01-01

    Current Positron Emission Tomography (PET) biomarkers for Alzheimer’s disease (AD) assess either neuronal function, or associated pathological features of this common neurodegenerative disease. The most widely accepted clinical PET tool for AD is 18-fluorodeoxyglucose PET (FDG-PET), which measures cerebral metabolic glucose utilization rate (CMRglc). FDG-PET is a marker of synaptic activity, neuronal function, and neuronal metabolic activity. AD is characterized by a distinct pattern of hypometabolism, as seen with the FDG images. This pattern can show variability across different subjects and is present before a patient is demented, specifically in amnestic mild cognitive impairment a clinical diagnosis defined as an intermediate state from normal aging to dementia. In addition to FDG PET, novel PET approaches assess known pathological hallmarks of AD including extracellular amyloid-beta plaques (Aβ) and intracellular neurofibrillary tangles composed of tau fibrils. Already, amyloid PET imaging is a tool that allows in vivo imaging of extracellular beta-amyloid levels. Efforts to bring tau imaging into clinical use continue, but this approach is hampered by the intracellular nature of tau protein deposition, subsequent weak radiotracer binding, and low image contrast. Several new candidate probes for tau-specific PET imaging are currently available but have not found their way into broad clinical applications. This study gives an overview of the most recent PET-based neuroimaging techniques for AD. We place special emphasis on PET data analysis and interpretation techniques, as well as radiochemistry for imaging metabolism and assessing Aβ and tau pathology. PMID:25343059

  2. Amyloids, Melanins and Oxidative Stress in Melanomagenesis

    PubMed Central

    Liu-Smith, Feng; Poe, Carrie; Farmer, Patrick J.; Meyskens, Frank L.

    2015-01-01

    Melanoma has traditionally been viewed as an ultra-violet (UV) radiation induced malignancy. While UV is a common inducing factor, other endogenous stresses such as metal ion accumulation or the melanin pigment itself, may provide alternative pathways to melanoma progression. Eumelanosomes within melanoma often exhibit disrupted membranes and fragmented pigment which may be due to alterations in their amyloid-based striatial matrix. The melanosomal amyloid can itself be toxic, especially in combination with reactive oxygen species (ROS) and reactive nitrogen species (RNS) generated by endogenous NADPH oxidase (NOX) and nitric oxide synthase (NOS) enzymes; a toxic mix that may initiate melanomagenesis. Further understanding of the loss of the melanosomal organization, the behavior of the exposed melanin, and the induction of ROS/RNS in melanomas may provide critical insights into this deadly disease. PMID:25271672

  3. Stability and cytotoxicity of crystallin amyloid nanofibrils.

    PubMed

    Kaur, Manmeet; Healy, Jackie; Vasudevamurthy, Madhusudan; Lassé, Moritz; Puskar, Ljiljana; Tobin, Mark J; Valery, Celine; Gerrard, Juliet A; Sasso, Luigi

    2014-11-01

    Previous work has identified crystallin proteins extracted from fish eye lenses as a cheap and readily available source for the self-assembly of amyloid nanofibrils. However, before exploring potential applications, the biophysical aspects and safety of this bionanomaterial need to be assessed so as to ensure that it can be effectively and safely used. In this study, crude crystallin amyloid fibrils are shown to be stable across a wide pH range, in a number of industrially relevant solvents, at both low and high temperatures, and in the presence of proteases. Crystallin nanofibrils were compared to well characterised insulin and whey protein fibrils using Thioflavin T assays and TEM imaging. Cell cytotoxicity assays suggest no adverse impact of both mature and fragmented crystallin fibrils on cell viability of Hec-1a endometrial cells. An IR microspectroscopy study supports long-term structural integrity of crystallin nanofibrils. PMID:25255060

  4. General anesthetics and β-amyloid protein.

    PubMed

    Xie, Zhongcong; Xu, Zhipeng

    2013-12-01

    With roughly 234 million people undergoing surgery with anesthesia each year worldwide, it is important to determine whether commonly used anesthetics can induce any neurotoxicity. Alzheimer