TY - JOUR. T1 - Control of Alzheimers amyloid beta toxicity by the high molecular weight immunophilin FKBP52 and copper homeostasis in Drosophila. AU - Sanokawa-Akakura, Reiko. AU - Cao, Weihuan. AU - Allan, Kirsten. AU - Patel, Khyati. AU - Ganesh, Anupama. AU - Heiman, Gary. AU - Burke, Richard. AU - Kemp, Francis W.. AU - Bogden, John D.. AU - Camakaris, James. AU - Birge, Raymond B.. AU - Konsolaki, Mary. PY - 2010/1/13. Y1 - 2010/1/13. N2 - FK506 binding proteins (FKBPs), also called immunophilins, are prolyl-isomerases (PPIases) that participate in a wide variety of cellular functions including hormone signaling and protein folding. Recent studies indicate that proteins that contain PPIase activity can also alter the processing of Alzheimers Amyloid Precursor Protein (APP). Originally identified in hematopoietic cells, FKBP52 is much more abundantly expressed in neurons, including the hippocampus, frontal cortex, and basal ganglia. Given the fact that the high molecular weight ...
Metal binding to the amyloid beta-peptide is suggested to be involved in the pathogenesis of Alzheimers disease. We used high-resolution NMR to study zinc binding to amyloid beta-peptide 1-40 at physiologic pH. Metal binding induces a structural change in the peptide, which is in chemical exchange on an intermediate rate, between the apo-form and the holo-form, with respect to the NMR timescale. This causes loss of NMR signals in the resonances affected by the binding. Heteronuclear correlation experiments, N-15-relaxation and amide proton exchange experiments on amyloid beta-peptide 1-40 revealed that zinc binding involves the three histidines (residues 6, 13 and 14) and the N-terminus, similar to a previously proposed copper-binding site [Syme CD, Nadal RC, Rigby SE, Viles JH (2004) J Biol Chem279, 18169-18177]. Fluorescence experiments show that zinc shares a common binding site with copper and that the metals have similar affinities for amyloid beta-peptide. The dissociation constant K-d of ...
Recent preliminary data suggest that vaccination with Alzheimers Abeta might reduce senile plaque load and stabilize cognitive decline in human Alzheimers disease. To examine the mechanisms and consequences of anti-Abeta-antibody formation in a species more closely related to humans, rhesus monkeys (Macaca mulatta) were vaccinated with aggregated Abeta(1-42). Immunized monkeys developed anti-Abeta titers exceeding 1:1000, and their plasma Abeta levels were 5-10-fold higher than the plasma Abeta levels observed in monkeys vaccinated with aggregated amylin. These data support the use of non-human primates to model certain phenomena associated with vaccination of humans with aggregated Alzheimers Abeta. ...
Soluble oligomeric aggregates of the amyloid-beta peptide (Abeta) have been implicated in the pathogenesis of Alzheimers disease (AD). Although the conformation adopted by Abeta within these aggregates is not known, a beta-hairpin conformation is known to be accessible to monomeric Abeta. Here we show that this beta-hairpin is a building block of toxic Abeta oligomers by engineering a double-cysteine mutant (called Abetacc) in which the beta-hairpin is stabilized by an intramolecular disulfide bond. Abeta(40)cc and Abeta(42)cc both spontaneously form stable oligomeric species with distinct molecular weights and secondary-structure content, but both are unable to convert into amyloid fibrils. Biochemical and biophysical experiments and assays with conformation-specific antibodies used to detect Abeta aggregates in vivo indicate that the wild-type oligomer structure is preserved and stabilized in Abetacc oligomers. Stable oligomers are expected to become highly toxic and, accordingly, we find ...
Amyloid-beta peptide (Abeta) binding alcohol dehydrogenase (ABAD), an enzyme present in neuronal mitochondria, is a cofactor facilitating Abeta-induced cell stress. We hypothesized that ABAD provides a direct link between Abeta and cytotoxicity via mitochondrial oxidant stress. Neurons cultured from …
Alzheimers disease (AD) is the most common cause of dementia and accounts for 50%-75% of all cases. It has been identified as a protein misfolding disease caused by plaque accumulation of abnormally folded beta amyloid and tau amyloid proteins in the brain.[2] Plaques are made up of small peptides, 39-43 amino acids in length, called beta-amyloid (Aβ) which is a fragment from a larger protein called amyloid precursor protein (APP), which is critical to neuron growth, survival and post-injury repair.[3][4] In AD, a proteolysis process causes APP to be divided into smaller fragments [5] which gives rise to fibrils of beta-amyloid that deposit outside neurons in dense formations known as senile plaques.[1][6]. Exactly how disturbances of production and aggregation of the beta-amyloid peptide gives rise to the pathology of AD is not known.[7][8 ...
The amyloid cascade hypothesis postulates that the initial event which triggers neuronal degradation in Alzheimers disease is enhanced amyloid-β generation and aggregation.
Amyloid beta-protein (Aβ) is the major component of senile plaques and cerebrovascular amyloid deposits in individuals with Alzheimers disease. Aβ is known to increase free radical production in neur
There is striking overlap between the spatial distribution of amyloid-β pathology in patients with Alzheimers disease and the spatial distribution of high intrinsic functional connectivity in healthy persons. This overlap suggests a mechanistic link between amyloid-β and intrinsic connectivity, and indeed there is evidence in patients for the detrimental effects of amyloid-β plaque accumulation on intrinsic connectivity in areas of high connectivity in heteromodal hubs, and particularly in the default mode network. However, the observed spatial extent of amyloid-β exceeds these tightly circumscribed areas, suggesting that previous studies may have underestimated the negative impact of amyloid-β on intrinsic connectivity. We hypothesized that the known positive baseline correlation between patterns of amyloid-β and intrinsic connectivity may mask the larger extent of the negative effects of amyloid-β on connectivity. Crucially, a test of this hypothesis requires the within-patient comparison of
Cows wring protein allergy is a woman of the most common food allergies in the first year of existencePlatelet microparticles as carriers of soluble Alzheimers amyloid beta (sAbeta), Ann N Y Acad Sci VolRoflumilast in moderate-to-severe long-lasting obstructive pulmonary infirmity treated with desire acting bronchodilators: two randomised clinical trialsHay fever (allergic rhinitis) can agent sneezing, congestion, and itchy abrade, eyes and nose, as stream as a cough ,a href=https://clubusa.net/collect/buy-cialis-extra-dosage/,purchase cialis extra dosage 100mg amex,/a,. This is solicitous with the need felt at near the being to handle a substance because it makes him or her feel propitious in some personality or helps him or her to handleTo whatever manner, the inordinate liability liabilities of copiously may call dehydration and this may be life-threatening in the precise boyish and older people, whose water control systems may be embryonic or weak spotIn the ?ve cases where both tunnels ...
ABSTRACT: Alzheimer's disease (AD) is the most common cause of senile dementia worldwide. AD is a neurodegenerative disorder characterized by the loss of memory and language skill, collapse of the cognitive function, and distortion of social behavior. As of today, the onset mechanisms of AD and cure are unknown; however, three hallmarks are commonly encountered: extra and intracellular accumulation of amyloid beta (Abeta) peptide plaques, formation of intracellular neurofibrillary tangles, and inevitable neuronal death. Hypothetically, a possible scenario provoking or involved in the onset of AD is a cascade effect that starts with an imbalance in the production and clearance of Abeta peptide that consequently leads to its accumulation, formation of tau protein tangles and neuronal death. This work studied and characterized the mechanisms governing Abeta peptide aggregation and the effects of using anti-Abeta monoclonal antibodies to modify this process. These mechanisms play an important ...
Today, Crossbeta Biosciences and AdAlta announced that they have established a collaborative relationship in which AdAlta will deploy its i-body technology to develop oligomer-specific i-bodies for therapeutic and diagnostic applications in Alzheimers disease using Crossbetas stabilized beta-amyloid oligomers.. Alzheimers disease is the most common form of dementia, primarily affecting people above the age of 60. Over 26 million people are suffering from Alzheimers disease today, a number that is projected to triple over the coming 40 years. Alzheimers disease remains to be an area of great unmet need with huge and growing social and economic impact. Beta-amyloid oligomers are implicated in Alzheimers disease pathology and there is no effective treatment yet.. AdAltas innovative i-body technology represents the next generation of biological therapeutics merging the highly selective specificity of antibodies with the advantages of drug-like molecules, such as small size and extreme ...
TY - JOUR. T1 - Degradation of fibrillar forms of Alzheimers amyloid β-peptide by macrophages. AU - Majumdar, Amitabha. AU - Chung, Haeyong. AU - Dolios, Georgia. AU - Wang, Rong. AU - Asamoah, Nikiya. AU - Lobel, Peter. AU - Maxfield, Frederick R.. PY - 2008/5. Y1 - 2008/5. N2 - Cultured microglia internalize fibrillar amyloid Aβ (fAβ) and deliver it to lysosomes. Degradation of fAβ by microglia is incomplete, but macrophages degrade fAβ efficiently. When mannose-6 phosphorylated lysosomal enzymes were added to the culture medium of microglia, degradation of fAβ was increased, and the increased degradation was inhibited by excess mannose-6-phosphate, which competes for binding and endocytic uptake. This suggests that low activity of one or more lysosomal enzymes in the microglia was responsible for the poor degradation of fAβ. To further characterize the degradation of fAβ in late endosomes and lysosomes, we analyzed fAβ-derived intracellular degradation products in macrophages and ...
beta-Amyloid (Abeta) pathology is an essential pathogenic component in Alzheimers disease (AD). However, the significance of Abeta pathology, including Abeta deposits/oligomers and glial reactions, to neurodegeneration is unclear. In particular, despite the Abeta neurotoxicity indicated by in vitro studies, mouse models with significant Abeta deposition lack robust and progressive loss of forebrain neurons. Such results have fueled the view that Abeta pathology is insufficient for neurodegeneration in vivo. In this study, because monoaminergic (MAergic) neurons show degenerative changes at early stages of AD, we examined whether the APPswe/PS1DeltaE9 mouse model recapitulates progressive MAergic neurodegeneration occurring in AD cases. We show that the progression forebrain Abeta deposition in the APPswe/PS1DeltaE9 model is associated with progressive losses of the forebrain MAergic afferents. Significantly, axonal degeneration is associated with significant atrophy of cell bodies and ...
Alzheimers disease is characterized by the presence of neurotoxic beta amyloid (Aß) deposits in the brain. This article briefly explains the production of Aß from amyloid precursor protein (APP).
In Alzheimers disease (AD), abnormal accumulations of beta-amyloid are present in the brain and degenerating neurons exhibit cytoskeletal aberrations (neurofibrillary tangles). Roles for beta-amyloid in the neuronal degeneration of AD have been suggested based on recent data obtained in rodent studies demonstrating neurotoxic actions of beta- amyloid. However, the cellular mechanism of action of beta-amyloid is unknown, and there is no direct information concerning the biological activity of beta-amyloid in human neurons. We now report on experiments in human cerebral cortical cell cultures that tested the hypothesis that beta-amyloid can destabilize neuronal calcium regulation and render neurons more vulnerable to environmental stimuli that elevate intracellular calcium levels. Synthetic beta-amyloid peptides (beta APs) corresponding to amino acids 1-38 or 25-35 of the beta-amyloid protein enhanced glutamate neurotoxicity in cortical cultures, while a peptide with a scrambled sequence was ...
The role of lipids in the aggregation of three Alzheimer model peptides was investigated with circular dichroism spectroscopy and high-sensitivity titration calorimetry under conditions of low ionic strength. In solution, the peptides beta AP(25-35)OH and beta AP(25-35Nle)NH2 exhibit a reversible random-coilbeta-sheet (or beta-structured aggregate) transition. Addition of lipid vesicles containing negatively charged lipids shifts the random-coilbeta-sheet equilibrium almost completely toward beta-sheet structure, which can be explained by the specific conditions created at the membrane surface: the cationic peptides are attracted to the negatively charged membrane, and the increase in peptide concentration together with the partial alignment of the peptide molecules then facilitates beta-sheet formation. The third peptide, beta AP-(25-35)NH2, also binds to the lipid membrane but was found to adopt an essentially random-coil structure, both with and without lipids. A quantitative characterization ...
Readers,. Amyloid plaques and neurofibrillary tangles (NFTs) are the two classic hallmarks of Alzheimers disease (AD), but the connection between their two respective proteins-beta-amyloid and tau-has remained mysterious. Now, a paper published on July 21 in the prestigious journal Cell details a molecular mechanism that links tau to beta-amyloid toxicity at the synapse. The groundbreaking new study was led by Professor Jürgen Götz and Dr Lars Ittner, based at the University of Sydney.. Back in 2004, scientists from the University of California at Irvine injected anti-beta-amyloid antibodies in the brains of transgenic mice that develop both beta-amyloid deposits and NFTs. This treatment led to a rapid reduction of beta-amyloid deposits and reversed the accumulation of abnormal tau (Oddo et al., 2004). When the anti-beta-amyloid antibodies were removed, the beta-amyloid pathology re-emerged. This was followed by the reappearance of tau pathology. These findings from animal models provided ...
A non‐invasive intrinsic fluorescence sensing of the early stages of Alzheimers beta amyloid peptide aggregation in the presence of copper ions is reported. By using time‐resolved fluorescence techniques the formation of beta amyloid‐copper complexes and the accelerated peptide aggregation are demonstrated. The shifts in the emission spectral peaks indicate that the peptides exhibit different aggregation pathways than in the absence of copper.. ...
Beta-amyloid production results from cleavage in the extracellular domain of APP by the beta-secretase (BACE1) , which results in the production of the APP C-terminal fragment C99. This fragment is further cleaved by the gamma-secretase at residues 40-42 to produce beta-amyloid 40 and 42 peptides. Beta-amyloid aggregation and neuritic plaque formation are pathologic hallmarks of Alzheimer disease. This peptide corresponds to the human beta-amyloid 1-40 peptide ...
Although the amyloid hypothesis offers a broad framework to explain AD pathogenesis, it is currently lacking in detail, and certain observations do not fit easily with the simplest version of the hypothesis. The most frequently voiced objection is that the number of amyloid deposits in the brain does not correlate well with the degree of cognitive impairment that the patient experienced in life. Indeed, some humans without symptoms of AD have many cortical Aβ deposits. However, the latter are almost exclusively diffuse forms of amyloid plaques that are not associated with surrounding neuritic and glial pathology. Such diffuse Aβ deposits may be analogous to early fatty streaks of cholesterol that are the harbingers of mature, symptom-producing atherosclerotic plaques. Moreover, the degree of dementia in AD correlates much better with Aβ assayed biochemically than with histologically determined plaque counts, and the concentration of soluble Aβ species (which are invisible to ...
Although the amyloid hypothesis offers a broad framework to explain AD pathogenesis, it is currently lacking in detail, and certain observations do not fit easily with the simplest version of the hypothesis. The most frequently voiced objection is that the number of amyloid deposits in the brain does not correlate well with the degree of cognitive impairment that the patient experienced in life. Indeed, some humans without symptoms of AD have many cortical Aβ deposits. However, the latter are almost exclusively diffuse forms of amyloid plaques that are not associated with surrounding neuritic and glial pathology. Such diffuse Aβ deposits may be analogous to early fatty streaks of cholesterol that are the harbingers of mature, symptom-producing atherosclerotic plaques. Moreover, the degree of dementia in AD correlates much better with Aβ assayed biochemically than with histologically determined plaque counts, and the concentration of soluble Aβ species (which are invisible to ...
TY - JOUR. T1 - RS-0406 arrests amyloid-b oligomer-induced behavioural deterioration in vivo. AU - OHare, Eugene. AU - Scopes, David I C. AU - Treherne, Mark J. AU - Norwood, Kelly. AU - Spanswick, David. AU - Kim, Eun-Mee. PY - 2010. Y1 - 2010. U2 - 10.1016/j.bbr.2010.01.044. DO - 10.1016/j.bbr.2010.01.044. M3 - Article. VL - 210. SP - 32. EP - 37. JO - Behavioural Brain Research. JF - Behavioural Brain Research. SN - 0166-4328. ER - ...
The purpose of this work is the reduction in the Abeta amyloid peptide burden in brain of Alzheimers disease (AD) transgenic mice without the concomitant elevation in plasma Abeta amyloid peptide. APPswe,PSEN1dE9 mice were studied at 12 months of age. The mice were shown to have considerable Abeta amyloid plaques in cerebral cortex based on immunocytochemistry. The mice were treated every 3C4 days by intravenous injections of either saline or the cTfRMAb-ScFv fusion protein at an injection dose of 1 1 mg/kg for 12 consecutive weeks. The brain A1C42 concentration was reduced 40% in the fusion protein treated mice, without any elevation in plasma A1C42 concentration. No cerebral micro-hemorrhage was observed in the treated mice. These results display that brain-penetrating antibody pharmaceutics can be developed for mind disorders such as AD TAE684 following a re-engineering of the antibody like a fusion protein that is transferred across the BBB via receptor-mediated transport. Keywords: ...
Transgenic mouse models that overexpress APP develop senile plaques over time that resemble those found in human Alzheimers disease. These animals are a valuable tool toward understanding the physiology and pathology of senile plaques in living tissue and are ideal for evaluating therapeutics aimed at clearance of amyloid-β deposits in the brain. With the recent success using immunotherapy for prevention of amyloid-β deposits in these animals (Schenk et al., 1999; Bard et al., 2000), as well as clearance of existing plaques (Bacskai et al., 2001), this treatment seems very promising. Recent reports have also indicated that immunotherapy may have positive effects on behavioral deficits exhibited in transgenic mouse models (Janus et al., 2000; Morgan et al., 2000). These findings are important for predicting whether anti-amyloid therapies will prove beneficial not just in arresting deposition of amyloid-β but also in prevention of the associated dementia. Microglial cells were implicated in ...
Antibodies , OptimAb Antibodies , OptimAbᵀᴹ Beta-Amyloid 17-24 , Monoclonal Antibody, purified; Beta-Amyloid forms are deposited in the CNS of patients with Alzheimer s disease and Down s syndrome. Biochemical analysis of the amyloid peptides isolated from Alzheimer s disease brain indicates that Beta-Amyloid (1-42) is the principal species associated with senile plaque amyloids, while Beta-Amyloid (1-40) is more abundant in cerebrovascular amyloid deposits. Both result from the cleavage of Amyloid Precursor Protein (APP) by secretases. The mAb 4G8 reacts to the abnormally processed isoforms, as well as precursor forms.; Host:MouseClone: 4G8Isotype: IgG2bReactivity: Human, MouseImmunogen: This antibody is reactive to residues 17-24 of Beta-Amyloid. The epitope lies within amino acids 18-22 of Beta-Amyloid (VFFAE)Concentration:1 mg/mLFormulation:PBS (no preservatives); The Ab was purified on Protein GApplications:The Ab is effective in immunoblotting (WB),
Amyloid-β PET and CSF Aβ42 yield discordant results in 10-20% of memory clinic patients, possibly providing unique information. Although the predictive power of demographic, clinical, genetic, and imaging features for amyloid positivity has previously been investigated, it is unknown whether these features differentially predict amyloid-β status based on PET or CSF or whether this differs by disease stage. We included 768 patients (subjective cognitive decline (SCD, n = 194), mild cognitive impairment (MCI, n = 127), dementia (AD and non-AD, n = 447) with amyloid-β PET and CSF Aβ42 measurement within 1 year. Ninety-seven (13%) patients had discordant PET/CSF amyloid-β status. We performed parallel random forest models predicting separately PET and CSF status using 17 patient features (demographics, APOE4 positivity, CSF (p)tau, cognitive performance, and MRI visual ratings) in the total patient group and stratified by syndrome diagnosis. Thereafter, we selected features with the highest variable
The search for effective therapies and early detection strategies for Alzheimers Disease (AD), the major cause of dementia in Europe, is imperative. It is known that beta-amyloid (Abeta) peptide plays a central role in neurodegeneration. In AD brain, Abeta is released in a soluble form that progressively becomes insoluble forming aggregates; extracellular plaques mainly composed of Abeta are a hallmark of post-mortem brains. These premises strongly suggest brain Abeta as a possible target for therapy and diagnosis of AD. In addition, it is known that brain and blood Abeta pools are in equilibrium via the blood-brain-barrier (BBB). Accordingly, it has been reported that removal of blood Abeta may withdraw the excess of brain Abeta by a sink effect. Thus, blood Abeta is another potential target. The aim of this project is to utilize nanoparticles (NPs) specifically engineered for targeting brain Abeta, for the combined diagnosis and therapy (theranostics) of AD. NPs (liposomes, solid lipid NPs, ...
Alzheimers disease (AD) involves increased accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles as well as neuronal loss in various regions of the neocortex. Neuroinflammation is also present, but its role in AD is not fully understood. We previously showed increased levels of pro-inflammatory cytokine interleukin-18 (IL-18) in different regions of AD brains, where it co-localized with Aβ-plaques, as well as the ability of IL-18 to increase expression of glycogen synthase kinase-3β (GSK-3β) and cyclin dependent kinase 5, involved in hyperphosphorylation of tau-protein. Elevated IL-18 has been detected in several risk conditions for AD, including obesity, type-II diabetes, and cardiovascular diseases as well as in stress. We differentiated SH-SY5Y neuroblastoma cells as neuron-like and exposed them to IL-18 for various times. We examined the protein levels of amyloid-β precursor protein (APP) and its processing products, its cleaving enzymes, involved in amyloidogenic processing of
in Journal of Neurochemistry (2010), 114(2), 576-586. Alzheimers disease (AD) is characterized by the presence of extracellular deposits referred to beta-amyloid (Abeta) complexes or senile plaques. Abeta peptide is firstly produced as monomers, readily ... [more ▼]. Alzheimers disease (AD) is characterized by the presence of extracellular deposits referred to beta-amyloid (Abeta) complexes or senile plaques. Abeta peptide is firstly produced as monomers, readily aggregating to form multimeric complexes, of which the smallest aggregates are known to be the most neurotoxic. In AD patients, abundant reactive microglia migrate to and surround the Abeta plaques. Though it is well known that microglia are activated by Abeta, little is known about the peptide conformation and the signaling cascades responsible for this activation. In this study, we have stimulated murine microglia with different Abeta(1-42) forms, inducing an inflammatory state, which was peptide conformation-dependent. The ...
Sigma-Aldrich offers abstracts and full-text articles by [Juliet A Moncaster, Roberto Pineda, Robert D Moir, Suqian Lu, Mark A Burton, Joy G Ghosh, Maria Ericsson, Stephanie J Soscia, Anca Mocofanescu, Rebecca D Folkerth, Richard M Robb, Jer R Kuszak, John I Clark, Rudolph E Tanzi, David G Hunter, Lee E Goldstein].
P05067: Amyloid beta A4 protein; ABPP; APPI; APP; Alzheimer disease amyloid protein; Cerebral vascular amyloid peptide; CVAP; PreA4; Protease nexin-II; PN-II; N-APP; Soluble APP-alpha; S-APP-alpha; Soluble APP-beta; S-APP-beta; C99; Beta-amyloid protein 42; Beta-APP42; Beta-amyloid protein 40; Beta-APP40; C83; P3(42); P3(40); C80; Gamma-secretase C-terminal fragment 59; Amyloid intracellular domain 59; AICD-59; AID(59); Gamma-CTF(59); Gamma-secretase C-terminal fragment 57; Amyloid intracellular domain 57; AICD-57; AID(57); Gamma-CTF(57); Gamma-secretase C-terminal fragment 50; Amyloid intracellular domain 50; AICD-50; AID(50); Gamma-CTF(50); C31; ...
Live discussion held 5 December 2001, noon-1 p.m. (EST).. Participants: Dick Lloyd, Sam Gandy, June Kinoshita, Richard Bowen, Nico Stanculescu, Seth Shaw, Mark Smith, Steve Fiander, Gunnar Gouras, Larry Tusick, Alan Lerner, Alexei R. Koudinov, Mike Shelanski, Rena Li, Gabrielle Strobel, Craig Atwood, and the mysterious Guest 2.. Note: The transcript has been edited for clarity and accuracy.. June: First, let me welcome you all to todays live discussion.. Sam Gandy: Thanks for organizing it, June.. June: I know that Richard Bowen has been eager to discuss some of the points in your discussion. Richard, would you like to ask the first question?. Richard L. Bowen: Yes, June: I wanted to know if Sam has looked at the ovariectomized mice and beta amyloid study, and have you had a chance to look at gonadotrophin levels?. Sam Gandy: We havent studied gonadotrophin levels under any circumstances. A paper on ovariectomy effects on Ab load in transgenic mice is in press at J. Neurochem. Co-authors are ...
Physical exercise has been suggested to reduce the risk of developing Alzheimers disease (AD) as well as ameliorate the progression of the disease. However, we recently published results from two large epidemiological studies showing no such beneficial effects on the development of AD. In addition, long-term, voluntary running in the 5xFAD mouse model of AD did not affect levels of soluble amyloid beta (Aβ), synaptic proteins or cognitive function. In this follow-up study, we investigate whether running could impact other pathological aspects of the disease, such as insoluble Aβ levels, the neuroinflammatory response and non-cognitive behavioral impairments. We investigated the effects of 24 weeks of voluntary wheel running in female 5xFAD mice (n = 30) starting at 2-3 months of age, before substantial extracellular plaque formation. Running mice developed hindlimb clasping earlier (p = 0.009) compared to sedentary controls. Further, running exacerbated the exploratory behavior in Elevated plus maze
Dear Amyloid/Ageing subscribers: I began to study Alzheimers amyloid beta (Ab) protein in 1992, at the time when it was becoming clear that this protein exists normally in a soluble form (soluble Ab) and that it is not just a pathological protein. My research activities yielded an on-going project, devoted to understanding in more detail the normal biology of amyloid beta. Understanding the normal biology of Ab would answer the questions of why soluble Ab does not undergo fibrillogenesis in biological fluids but does polymerize into amyloid fibrils in the disease, and what the biological consequences of Ab deposition within the brain tissue are. This, in turn, would be crucial for understanding the pathophysiology of Alzheimers disease and for delineating pathologically grounded new approaches to therapy. My current postdoctoral position at NYU Medical Center just expired. Thus, to continue my research I have to find another position. I would be happy to continue my research as a part of your ...
Beta-amyloid is a protein fragment at the focus of research into the causes of Alzheimers disease. It is normally found in the brain but during the disease process, it forms small clumps known as oligomers, which are thought to be toxic to nerve cells. Eventually, beta-amyloid oligomers combine to form even larger structures known as fibrils, which then form amyloid plaques in the brain, one of the characteristic features of Alzheimers disease. Stephen Meredith, M.D., Ph.D., and colleagues have been studying the detailed molecular structure of beta-amyloid fibrils and working to identify what may trigger their development in Alzheimers disease. They have found that fibrils can have different structures from one person to the next, but that the fibrils found in different parts of the brain of a single person are generally the same. The researchers hypothesize that formation of an initial oligomer or fibril in one area of the brain may trigger the accumulation of other oligomers and subsequent ...
Immunotherapy for Alzheimers disease (AD) relies on antibodies directed against toxic amyloid-beta peptide (Abeta), which circulate in the bloodstream and remove Abeta from the brain. In mouse models of AD, the administration of anti-Abeta antibodies directly into the brain, in comparison to the bl …
Product Name: Amyloid beta-Protein (Human, 34-40) Antiserum (50 ul vial) Product Number: NAB-14356-v Synonym(s): Amyloid beta-Protein (1-40) Specific Antiserum (Rabbit) Antiserum Application: Our undiluted antisera are suitable for immuno-histochemical use, for application to radioimmunoassay (RIA), or other non-isotop
In the field of neurobiology, there is great discussion about which particular species of amyloid-beta oligomers (AβOs) contributes to the pathogenesis of Alzheimers disease (AD), a progressive neurodegenerative disease. Previously, our group has found, using molecular weight cutoff filters (MWCO), that AβOs are primarily 100-300 kilodaltons (kDa). The goal of this project is to verify this finding using size exclusion chromatography (SEC). SEC can be used to determine AβO molecular weight according to the amount of time it takes the AβOs to pass through the SEC column. Overall, the project yielded results showing significant portion of AβOs are either |1300 kDa or around 13 kDa. We are currently investigating further reasons why the MWCO and SEC data yield very different results.
Proteolytic cleavage of amyloid-β-protein precursor (AβPP) by β- and γ-secretases results in production of the amyloid-β peptide (Aβ) that accumulates in the brains of sufferers of Alzheimers disease (AD). We have developed a monoclonal antibody, 2B
Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. GTP hydrolysis in protein synthesis: two for Tu?
Soluble β-amyloid peptide (βAP) is measured in biological fluids at very low concentrations, typically in the range from 0.1 ng/ml to 10 ng/ml. The measurement of βAP concentrations in animals or conditioned medium from cultured cells can be used for drug screening, where test compounds are administered to the animals or exposed to the cultured cells and the accumulation of βAP in the animal or culture medium observed. It has been found that elevated levels of βAP in body fluids, such as blood and cerebrospinal fluid, is associated with the presence of a βAP-related condition in a patient, such as Alzheimers Disease. Methods for diagnosing and monitoring βAP-related conditions comprise measuring the levels of βAP in such body fluids from a patient.
My research is focussed on Alzheimers Drug Discovery and compounds that modify amyloid fibril toxicity. I have discovered amyloid peptide interactions with the Kisspeptin, Kissorphin and Neuropeptide-FF peptides, which prevent the toxicity of the amyloid peptides in vitro. I discovered that endocannabinoids are neuroprotective against the Alzheimers Amyloid-beta peptide in vitro. I have characterized interactions between amyloid peptides and the enzymes Catalase and Cyclin-Dependent-Kinase-1.. ...
Alzheimers disease researchers have been intrigued by the selective regional vulnerability of the brain to amyloid-ß plaques and tau neurofibrillary tangles. Post-mortem studies indicate that in ageing and Alzheimers disease tau tangles deposit early in the transentorhinal cortex, a region located in the anterior-temporal lobe that is critical for object memory. In contrast, amyloid-ß pathology seems to target a posterior-medial network that subserves spatial memory. In the current study, we tested whether anterior-temporal and posterior-medial brain regions are selectively vulnerable to tau and amyloid-ß deposition in the progression from ageing to Alzheimers disease and whether this is reflected in domain-specific behavioural deficits and neural dysfunction. 11C-PiB PET and 18F-flortaucipir uptake was quantified in a sample of 131 cognitively normal adults (age: 20-93 years; 47 amyloid-ß-positive) and 20 amyloid-ß-positive patients with mild cognitive impairment or Alzheimers disease ...
TY - JOUR. T1 - Always around, never the same. T2 - Pathways of amyloid beta induced neurodegeneration throughout the pathogenic cascade of Alzheimers disease. AU - Hoozemans, Jeroen J M. AU - Chafekar, Sidhartha M.. AU - Baas, Frank. AU - Eikelenboom, Piet. AU - Scheper, Wiep. PY - 2010/1/1. Y1 - 2010/1/1. N2 - There is an increasing amount of evidence showing the importance of intermediate aggregation species of amyloid β (Aβ) in the pathogenic cascade of Alzheimers disease (AD). Different Aβ assembly forms may mediate diverse toxic effects at different stages of the disease. Mouse models for AD suggest that intraneuronal accumulation of Aβ oligomers might be involved in AD pathogenesis at a very early stage of the disease. The detrimental effect of oligomeric Aβ on synaptic efficacy is suggested to be an early event in the pathogenic cascade. Also early neuronal responses as activation of the unfolded protein response are processes likely to be associated with the increased occurrence ...
misc{6494bef1-596c-4a8f-a511-b3b2760e7a57, author = {Linse, Sara and Thulin, Eva and Hellstrand, Erik and Sparr, Emma and Walsh, D.}, issn = {1742-464X}, language = {eng}, note = {Conference Abstract}, pages = {11--11}, publisher = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd}, series = {The FEBS Journal}, title = {Towards physico-chemical understanding of fibril formation of the Alzheimer disease-associated amyloid beta-peptide}, volume = {276}, year = {2009 ...
21st Century Biochemicals - Catalog: Beta Amyloid Peptides (also known as: Abeta peptides | Amyloid beta A4 | A beta P | amyloid beta-peptide | aa 1-40/42)
Osborne, C and West, E and Nolan, W and McHale-Owen, H and Williams, A and Bate, C (2016) Glimepiride protects neurons against amyloid-beta-induced synapse damage. NEUROPHARMACOLOGY, 101. pp. 225-236. ...
The presence of Abeta(pE3) (N-terminal truncated Abeta starting with pyroglutamate) in Alzheimers disease (AD) has received considerable attention since the discovery that this peptide represents a dominant fraction of Abeta peptides in senile plaques of AD brains. This was later confirmed by other reports investigating AD and Downs syndrome postmortem brain tissue. Importantly, Abeta(pE3) has a higher aggregation propensity, and stability, and shows an increased toxicity compared to full-length Abeta. We have recently shown that intraneuronal accumulation of Abeta(pE3) peptides induces a severe neuron loss and an associated neurological phenotype in the TBA2 mouse model for AD. Given the increasing interest in Abeta(pE3), we have generated two novel monoclonal antibodies which were characterized as highly specific for Abeta(pE3) peptides and herein used to analyze plaque deposition in APP/PS1KI mice, an AD model with severe neuron loss and learning deficits. This was compared with the plaque ...
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Using luminescent conjugated polyelectrolyte probes (LCPs), we demonstrate the possibility to distinguish amyloid-β 1-42 peptide (Aβ1-42) fibril conformations, by analyzing in vitro generated amyloid fibrils of Aβ1-42 formed under quiescent and agitated conditions. LCPs were then shown to resolve such conformational heterogeneity of amyloid deposits in vivo. A diversity of amyloid deposits depending upon morphology and anatomic location was illustrated with LCPs in frozen ex vivo brain sections from a transgenic mouse model (tg-APPswe) of Alzheimers disease. Comparative LCP fluorescence showed that compact-core plaques of amyloid β precursor protein transgenic mice were composed of rigid dense amyloid. A more abundant form of amyloid plaque displayed morphology of a compact center with a protruding diffuse exterior. Surprisingly, the compact center of these plaques showed disordered conformations of the fibrils, and the exterior was composed of rigid amyloid protruding from the disordered ...
TY - JOUR. T1 - Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimers disease-like neuropathology. AU - Bard, Frédérique. AU - Barbour, Robin. AU - Cannon, Catherine. AU - Carretto, Robert. AU - Fox, Michael. AU - Games, Dora. AU - Guido, Teresa. AU - Hoenow, Kathleen. AU - Hu, Kang. AU - Johnson-Wood, Kelly. AU - Khan, Karen. AU - Kholodenko, Dora. AU - Lee, Celeste. AU - Lee, Mike. AU - Motter, Ruth. AU - Nguyen, Minh. AU - Reed, Amanda. AU - Schenk, Dale. AU - Tang, Pearl. AU - Vasquez, Nicki. AU - Seubert, Peter. AU - Yednock, Ted. N1 - Copyright: Copyright 2008 Elsevier B.V., All rights reserved.. PY - 2003/2/18. Y1 - 2003/2/18. N2 - Transgenic PDAPP mice, which express a disease-linked isoform of the human amyloid precursor protein, exhibit CNS pathology that is similar to Alzheimers disease. In an age-dependent fashion, the mice develop plaques containing β-amyloid peptide (Aβ) and exhibit neuronal dystrophy and synaptic loss. It has ...
Yazawa H., Yu Z.-X., Takeda K., Le Y., Gong W., Ferrans V.J., Oppenheim J.J., Li C.C.H., Wang J.M.. The 42 amino acid form of beta amyloid (Abeta42) plays a pivotal role in neurotoxicity and the activation of mononuclear phagocytes in Alzheimers disease (AD). Our recent study revealed that FPRL1, a G-protein-coupled receptor, mediates the chemotactic and activating effect of Abeta42 on mononuclear phagocytes (monocytes and microglia), suggesting that FPRL1 may be involved in the proinflammatory responses in AD. We investigated the role of FPRL1 in cellular uptake and the subsequent fibrillar formation of Abeta42 by using fluorescence confocal microscopy. We found that upon incubation with macrophages or HEK293 cells genetically engineered to express FPRL1, Abeta42 associated with FPRL1 and the Abeta42/FPRL1 complexes were rapidly internalized into the cytoplasmic compartment. The maximal internalization of Abeta42/FPRL1 complexes occurred by 30 min after incubation. Removal of free Abeta42 from ...
TY - JOUR. T1 - Abnormal interaction of oligomeric amyloid-β with phosphorylated tau. T2 - Implications to synaptic dysfunction and neuronal damage. AU - Manczak, Maria. AU - Reddy, P (Hemachandra). PY - 2013. Y1 - 2013. N2 - Alzheimers disease (AD) is a progressive neurodegenerative mental illness characterized by memory loss, multiple cognitive impairments, and changes in personality and behavior. The purpose of our study was to determine the interaction between monomeric and oligomeric amyloid-β (Aβ) and phosphorylated tau in AD neurons. Using postmortem brains from AD patients at different stages of disease progression and control subjects, and also from AβPP, AβPPxPS1, and 3xTg-AD mice, we studied the physical interaction between Aβ and phosphorylated tau. Using immunohistological and double-immunofluorescence analyses, we also studied the localization of monomeric and oligomeric Aβ with phosphorylated tau. We found monomeric and oligomeric Aβ interacted with phosphorylated tau in ...
As has been described in naturally occurring CAA (1, 5), vascular amyloid deposition in APP23 mice is most frequently found in arteries/arterioles and occurs most often in vessels outside the brain parenchyma proper (e.g., pia, fissures). The arterial predilection suggests that an anatomical difference between arteries and veins (e.g., presence of significant amounts of smooth muscle) could contribute to the development of CAA. Indeed, it has been hypothesized that Aβ is deposited by vascular smooth muscle cells and/or perivascular microglia, and APP expression and Aβ production by vascular cells have been well documented (22, 23). These reports and the observation that vessels apart from the neuropil are more often affected strongly implicate local production or circulating Aβ as an important source, although these hypotheses fail to explain the exclusive localization of CAA to cerebral vessels. In the present study, through examination of APP transgenic mice on an App-null background, we ...
The ε4 allele of apolipoprotein E (ApoE) accounts for an estimated 45-60% of the genetic risk for late onset sporadic Alzheimers disease, suggesting that it may be possible to identify other genetic loci that could account for the remaining risk associated with this disease. Recently, a biallelic polymorphism (G/A) in the 3′ untranslated region (UTR) of the transcription factor LBP-1c/CP2/LSF (for brevity, CP2) has been implicated in Alzheimers disease susceptibility, with the 3′-UTR A allele being associated with a reduction in the risk of sporadic Alzheimers disease.1-3 The CP2 gene is a plausible candidate for influencing Alzheimers disease risk: it is located near the LDL receptor related protein gene within the Alzheimers disease linkage region on chromosome 12; it controls the expression of several genes (α2 macroglobulin, glycogen synthase kinase-3β); and it interacts with different proteins (serum amyloid A3, interleukin 1α, tumour necrosis factor α, and Fe65 protein) and ...
PubMedID: 25947203 | Platelet dysfunction in hypercholesterolemia mice, two Alzheimers disease mouse models and in human patients with Alzheimers disease. | Biogerontology | 8/1/2015
The pathological mechanisms underlying Alzheimers disease (AD) are still not understood. The disease pathology is characterized by 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 Alzheimers 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
Alzheimers disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-beta (Abeta), a major component of senile plaques, has various pathological effects on cell and organelle function. The extracellular Abeta oligomers may activate caspases through activation of cell surface death receptors. Alternatively, intracellular Abeta may contribute to pathology by facilitating tau hyper-phosphorylation, disrupting mitochondria function, and triggering calcium dysfunction. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specfically the more amyloidogenic form, Abeta42. ...
Synonyms: Amyloid Beta A4 Protein, APPI, ABPP, Alzheimer Disease Amyloid Protein, Beta-amyloid Precursor Protein, Cerebral Vascular Amyloid Peptide, CVAP, PreA4, Protease Nexin-II, PN-II ...
in Journal of Biological Chemistry (1996), 271(46), 28757-65. A series of natural peptides and mutants, derived from the Alzheimer beta-amyloid peptide, was synthesized, and the potential of these peptides to induce fusion of unilamellar lipid vesicles was ... [more ▼]. A series of natural peptides and mutants, derived from the Alzheimer beta-amyloid peptide, was synthesized, and the potential of these peptides to induce fusion of unilamellar lipid vesicles was investigated. These peptide domains were identified by computer modeling and correspond to respectively the C-terminal (e.g. residues 29-40 and 29-42) and a central domain (13-28) of the beta-amyloid peptide. The C-terminal peptides are predicted to insert in an oblique way into a lipid membrane through their N-terminal end, while the mutants are either parallel or perpendicular to the lipid bilayer. Peptide-induced vesicle fusion was demonstrated by several techniques, including lipid-mixing and core-mixing assays using pyrene-labeled ...
in Journal of Biological Chemistry (1996), 271(46), 28757-65. A series of natural peptides and mutants, derived from the Alzheimer beta-amyloid peptide, was synthesized, and the potential of these peptides to induce fusion of unilamellar lipid vesicles was ... [more ▼]. A series of natural peptides and mutants, derived from the Alzheimer beta-amyloid peptide, was synthesized, and the potential of these peptides to induce fusion of unilamellar lipid vesicles was investigated. These peptide domains were identified by computer modeling and correspond to respectively the C-terminal (e.g. residues 29-40 and 29-42) and a central domain (13-28) of the beta-amyloid peptide. The C-terminal peptides are predicted to insert in an oblique way into a lipid membrane through their N-terminal end, while the mutants are either parallel or perpendicular to the lipid bilayer. Peptide-induced vesicle fusion was demonstrated by several techniques, including lipid-mixing and core-mixing assays using pyrene-labeled ...
TY - GEN. T1 - Release of β-amyloid from high-density platelets. T2 - Implications for Alzheimers disease pathology. AU - Casoli, Tiziana. AU - Di Stefano, Giuseppina. AU - Giorgetti, Belinda. AU - Grossi, Yessica. AU - Balietti, Marta. AU - Fattoretti, Patrizia. AU - Bertoni-Freddari, Carlo. PY - 2007/1. Y1 - 2007/1. N2 - The main component of Alzheimers disease (AD) senile plaques in the brain is amyloid-β peptide (Aβ), a proteolytic fragment of the amyloid precursor protein (APP). Platelets contain both APP and Aβ and much evidence suggests that these cells may represent a useful tool to study bothamyloidogenic and nonamyloidogenic pathways of APP processing. It has been demonstrated that platelets activated by physiological agonists, such as thrombin and collagen, specifically secrete Aβ ending at residue 40. To verify whether APP β-processing could be observed also in an in vitro system of highly concentrated platelets, we measured the Aβ released in the incubation media of 5 ± ...
Amyloid accumulation in the brain of Alzheimers patients results from altered processing of the 39- to 43-amino acid amyloid protein (A). [1], [2]. The excessive accumulation of A peptides in AD may be due to enhanced endoproteolytic cleavage of membrane bound amyloid precursor protein (APP), over-expression of APP and/or decreased clearance of A from the central nervous system (CNS) [3]C[5]. Postmortem analyses of AD subjects reveal that amyloid plaques in the brain suffuse vascular cells in addition to the parenchymal. The ramifications of this vascular infiltration for AD has been less well analyzed than the parenchymal A, but has generated 61939-05-7 manufacture considerable interest with studies that -amyloid fibrils accumulate in small blood vessels, capillary vessels and arterioles of Rabbit Polyclonal to PRKY the human brain [6]C[8]. Cerebrovascular amyloid toxicity generally manifests itself in the break of the blood-brain-barrier and improved irritation in the cerebrovasculature [9], ...
Purpose: : Our lab has been investigating the striking degree of shared cell biology, developmental mechanisms, and gene expression in lens and brain, to understand shared mechanisms of age-related degenerative disease fundamental to both tissues. Work from this, and now from other, laboratories highlight a fundamental role for Alzheimer proteins in lens age-related disease. Moreover, this fundamental link can be exploited for diagnosis of the onset and severity of AD in brain. Considerable evidence in AD research demonstrates that system-wide factors in the body, and most strikingly high cholesterol in the diet together with copper bioavailabilty, have a key role in determining onset and severity of AD brain pathology in humans and in animal models. Further these factors are also critical determinants of cataract formation in the lens. Here we examined the role of Alzheimer proteins in animals on high cholesterol diet with 0.12 ppm Cu in water (10-fold under EPA standards for humans). Methods: ...
Brendel M., Kleinberger G., Probst F., Jaworska A., Overhoff F., Blume T., Albert NL., Carlsen J., Lindner S.; Gildehaus FJ., Ozmen L., Suárez-Calvet M., Bartenstein P., Baumann K., Ewers M., Herms J., Haass C., Rominger A. (2017) Increase of TREM2 during Aging of an Alzheimers Disease Mouse Model Is Paralleled by Microglial Activation and Amyloidosis. Front Aging Neurosci. 9:8. Rammes G., Mattusch C.; Wulff M., Seeser F., Kreuzer M., Zhu K., Deussing JM., Herms J., Parsons, CG. (2017) Involvement of GluN2B subunit containing N-methyl-d-aspartate (NMDA) receptors in mediating the acute and chronic synaptotoxic effects of oligomeric amyloid-beta (Aβ) in murine models of Alzheimers disease (AD). Neuropharmacology. [Epub ahead of print]. Blazquez-Llorca L., Valero-Freitag S., Rodrigues EF., Merchán-Pérez Á., Rodríguez JR., Dorostkar MM., DeFelipe J., Herms J. (2017) High plasticity of axonal pathology in Alzheimers disease mouse models. Acta Neuropathol Commun. 5(1):14. Zhu K. Xiang X., ...
The β-amyloid peptide (Aβ) may be the major constituent from the amyloid core of senile plaques within the mind of patients with Alzheimers disease (AD). resulted in a drastic reduced amount of Aβ42 and Aβ40 secretion. β-Cleavage of mutant APP HOE 32021 had not been inhibited and reduced amount of Aβ secretion resulted from inhibition of γ-cleavage. It had been anticipated that reduced γ-cleavage of mutant APP would derive from inhibition of its dimerization. Amazingly mutations from the GxxxG theme actually improved dimerization from the APP C-terminal fragments perhaps with a different TM α-helical user interface. Increased dimerization from the TM APP C-terminal area did not have an effect on AICD creation. These results obviously demonstrate that both orientation and dimerization from the APP TM area differently have an effect on Aβ and AICD creation. The intensifying deposition of β-amyloid peptide (Aβ)1 resulting in the forming of senile plaques can be an invariant feature of ...
Background: The cerebrospinal fluid (CSF) amyloid-β (Aβ)1-42, total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimers disease (AD). Objective: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands. Methods: Aβ pathology was determined by PET imaging, utilizing 11C-Pittsburgh Compound B, 18F-flutemetamol, or 18F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ1-42 ,544 ng/L, T-tau ,407 ng/L, and P-tau181P ,78 ng/L) employing a rank based method to define a positive CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology. ...
Calcium: A proven target in the war on Alzheimers disease Alzheimers disease is practically a household word these days, as the number of individuals dia
Abnormal production and accumulation of amyloid-β peptide (Aβ) plays a major role in the pathogenesis of Alzheimers disease (AD). β-secretase (BACE1) is responsible for the cleavage at the β-site in amyloid β protein precursor (AβPP/APP) to generate
Alzheimers disease (AD) is the most common cause of dementia in adults and is characterised at the microscopic level by extracellular amyloid plaques and intraneuronal tau tangles. Amyloid plaques are composed of fibrillar aggregates of a spectrum of amyloid beta (Aβ) peptides derived from the proteolytic cleavage of amyloid precursor protein (APP) (LaFerla et al., 2007). The significance of Aβ is underpinned by the numerous disease-linked mutations that dysregulate APP processing: mutations that result in a spectrum of Aβ peptides with a higher aggregation propensity have been linked to familial AD (Philipson et al., 2010), whereas sequence variation in APP that reduces Aβ production is protective (Jonsson et al., 2012). There is much evidence from cell-culture and animal-model systems (Iijima-Ando and Iijima, 2010; Philipson et al., 2010) that the conformers of Aβ that possess neurotoxic activity are likely to be soluble oligomeric species rather than the more easily detected amyloid ...
Chalmers, K., Blomqvist, M.-L., Andreasen, N., Bogdanovic, N. and Wilcock, G. (2005) Sequence variants of IDE are associated with the extent of beta-amyloid deposition in the Alzheimers disease brain. Neurobilogy of Aging, 26 (6). pp. 795-802. ISSN 0197-4580 Available from: http://eprints.uwe.ac.uk/1512 Full text not available from this repository. Publishers URL: http://dx.doi.org/10.1016/j.neurobiolaging.2004.07... ...
Alzheimer disease 3 (AD3) [MIM:607822]: A familial early-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. {ECO:0000269,PubMed:10025789, ECO:0000269,PubMed:10090481, ECO:0000269,PubMed:10200054, ECO:0000269,PubMed:10208579, ECO:0000269,PubMed:10439444, ECO:0000269,PubMed:10441572, ECO:0000269,PubMed:10447269, ECO:0000269,PubMed:10533070, ECO:0000269,PubMed:10631141, ECO:0000269,PubMed:10644793, ECO:0000269,PubMed:11027672, ...
Alzheimer disease 3 (AD3) [MIM:607822]: A familial early-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. {ECO:0000269,PubMed:10025789, ECO:0000269,PubMed:10090481, ECO:0000269,PubMed:10200054, ECO:0000269,PubMed:10208579, ECO:0000269,PubMed:10439444, ECO:0000269,PubMed:10441572, ECO:0000269,PubMed:10447269, ECO:0000269,PubMed:10533070, ECO:0000269,PubMed:10631141, ECO:0000269,PubMed:10644793, ECO:0000269,PubMed:11027672, ...
Neurodegeneration is characterized by dysfunction and death of cells in the nervous system. This results in impaired motor function and progressive dementia. Neurodegenerative diseases include prion disease, Parkinsons disease, Huntingtons disease, Amyotrophic Lateral Sclerosis (Lou Gehrigs disease), and various types of dementia, of which Alzheimers disease is the most common. Intense research focus on Alzheimers disease has identified 2 main pathways leading to characteristic protein deposits in the brain. These are pathologic breakdown of amyloid precursor protein leading to the formation of extracellular amyloid plaques, and hyperphosphorylation of the microtubule associated protein Tau, causing intracellular neurofibrillary tangles. Several genes have confirmed links to Alzheimers disease, and many genotyping and gene expression studies currently in progress aim to elucidate the causes, develop biomarkers for diagnosis, and identify potential drug targets ...
Neurodegeneration is characterized by dysfunction and death of cells in the nervous system. This results in impaired motor function and progressive dementia. Neurodegenerative diseases include prion disease, Parkinsons disease, Huntingtons disease, Amyotrophic Lateral Sclerosis (Lou Gehrigs disease), and various types of dementia, of which Alzheimers disease is the most common. Intense research focus on Alzheimers disease has identified 2 main pathways leading to characteristic protein deposits in the brain. These are pathologic breakdown of amyloid precursor protein leading to the formation of extracellular amyloid plaques, and hyperphosphorylation of the microtubule associated protein Tau, causing intracellular neurofibrillary tangles. Several genes have confirmed links to Alzheimers disease, and many genotyping and gene expression studies currently in progress aim to elucidate the causes, develop biomarkers for diagnosis, and identify potential drug targets ...
Recombinant Human Amyloid Precursor Protein Protein fragment datasheet (ab124588). Abcam offers quality products including antibodies, assays and other…
During the past decade my interest have focused on the pathogenesis of Alzheimers disease, one of the most destructive neurological diseases that affects millions worldwide. This insidious disease becomes clinically symptomatic during the sixth decade of life, but there are reasons for believing that the disease process may begin one or two decades earlier, and abnormal metabolism of amyloid abeta peptides may be an important contributing factor.. I have been analyzing naturally occurring auto-antibodies to the amyloid abeta protein as a measure of the bodys response to either elevated levels or abnormal forms of these peptides. It is my feeling that the development of a reliable way to identify individuals who are risk for AD before the disease is evident is a critical unmet need. This lack of early detection hampers our ability to develop new therapies.. Specialized Terms: Pathogenesis of Alzheimers disease; Neurodegeneration; Amyloid abeta metabolism; Auto-antibodies; ...
Researchers have found that a protein variation linked by some genetic studies to Alzheimers disease is consistently present in the brains of people with Alzheimers. In further biochemical and cell culture investigations, they have shown that this protein, known as ubiquilin-1, performs a critical Alzheimers-related function: it chaperones the formation of amyloid precursor protein, a molecule whose malformation has been directly tied to Alzheimers pathology.. What we saw here is that in all 20 of the Alzheimers brains we examined the ubiquilin-1 protein level was lower, and thats completely new, said University of Texas Medical Branch at Galveston assistant professor José Barral, co-author of a paper on the study now online in the Journal of Biological Chemistry. Our experiments looked at the consequences of decreased ubiquilin-1, and showed that its necessary for the proper handling of amyloid precursor protein.. APP has been a major focus of Alzheimers investigators for ...
Brussels, Belgium, 19 July 2017 - Today, the Innovative Medicines Initiative (IMI) is launching two new Calls for proposals with topics on Alzheimers disease, big data, vaccines, autoimmune disease, the blood-brain barrier, drug development, and the exploitation of IMI project results. The total budget for the two Calls stands at just over EUR 130 million. Around half of this comes from the European Commissions Horizon 2020 programme. The other half comes from EFPIA companies as well as IMI Associated Partners.
TY - JOUR. T1 - A novel γ-secretase assay based on detection of the putative C-terminal fragment-γ of amyloid β protein precursor. AU - Pinnix, Inga. AU - Musunuru, Usha. AU - Tun, Han W. AU - Sridharan, Arati. AU - Golde, Todd. AU - Eckman, Christopher. AU - Ziani-Cherif, Chewki. AU - Onstead, Luisa. AU - Sambamurti, Kumar. PY - 2001/1/5. Y1 - 2001/1/5. N2 - Alzheimers disease is characterized by the deposits of the 4-kDa amyloid β peptide (Aβ). The Aβ protein precursor (APP) is cleaved by β-secretase to generate a C-terminal fragment, CTFβ, which in turn is cleaved by γ-secretase to generate Aβ. Alternative cleavage of the APP by α-secretase at Aβ16/17 generates the C-terminal fragment, CTFα. In addition to Aβ, endoproteolytic cleavage of CTFα and CTFβ by γ-secretase should yield a C-terminal fragment of 57-59 residues (CTFγ). However, CTFγ has not yet been reported in either brain or cell lysates, presumably due to its instability in vivo. We detected the in vitro ...
Much of the genetic research on Alzheimers centers on amyloid-beta, a key component of brain plaques that build up in the brains of people with the disease. In the new study, the scientists identified several genes linked to the tau protein, which is found in the tangles that develop in the brain as Alzheimers progresses and patients develop dementia. The findings may help provide targets for a different class of drugs that could be used for treatment.. The researchers reported their findings online April 4 in the journal Neuron.. We measured the tau protein in the cerebrospinal fluid and identified several genes that are related to high levels of tau and also affect risk for Alzheimers disease, said senior investigator Alison M. Goate, DPhil, the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry. As far as were aware, three of these genes have no effect on amyloid-beta, suggesting that they are operating through a completely different pathway.. A fourth gene in the mix, APOE, ...
TY - JOUR. T1 - Binding of apolipoprotein E inhibits the oligomer growth of amyloid-β peptide in solution as determined by fluorescence cross-correlation spectroscopy. AU - Ly, Sonny. AU - Altman, Robin. AU - Petrlova, Jitka. AU - Lin, Yu. AU - Hilt, Silvia. AU - Huser, Thomas R. AU - Laurence, Ted A.. AU - Voss, John C. PY - 2013/4/26. Y1 - 2013/4/26. N2 - One of the primary neuropathological hallmarks of Alzheimer disease is the presence of extracellular amyloid plaques resulting from the aggregation of amyloid-β (Aβ) peptides. The intrinsic disorder of the Aβ peptide drives self-association and progressive reordering of the conformation in solution, and this dynamic distribution of Aβ complicates biophysical studies. This property poses a challenge for understanding the interaction of Aβ with apolipoprotein E (apoE). ApoE plays a pivotal role in the aggregation and clearance of Aβ peptides in the brain, and the ε4 allele of APOE is the most significant known genetic modulator of ...
Alzheimers disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease--ie, plaques, composed of amyloid beta (Abeta), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimers disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Abeta metabolism. By contrast with familial disease, sporadic Alzheimers disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, ...
TY - JOUR. T1 - Effects of 4-hydroxy-nonenal and amyloid-β on expression and activity of endothelin converting enzyme and insulin degrading enzyme in SH-SY5Y cells. AU - Wang, Rui. AU - Wang, Suqing. AU - Malter, James S.. AU - Wang, Deng Shun. PY - 2009. Y1 - 2009. N2 - The cerebral accumulation of amyloid-β (Aβ) is a consistent feature of and likely contributor to the development of Alzheimers disease (AD). In addition to dysregulated production, increasing experimental evidence suggests reduced catabolism plays an important role in Aβ accumulation. Although endothelin converting enzyme (ECE) and insulin degrading enzyme (IDE) degrade and thus contribute to regulating the steady-state levels of Aβ, how these enzymes are regulated remain poorly understood. In this study, we investigated the effects of 4-hydroxy-nonenal (HNE) and Aβ on the expression and activity of ECE-1 and IDE in human neuroblastoma SH-SY5Y cells. Treatment with HNE or Aβ upregulated ECE-1 mRNA and protein, while IDE ...
The structures of amyloid fibrils and oligomers represent a vast frontier, of yet unknown scope. The fibrils and aggregates that amyloidogenic peptides and proteins form are rich in β-sheets, and their structures are tremendously important in amyloid diseases. Many structures of amyloid fibrils have been discovered by solid-state NMR spectroscopy of amyloidogenic peptides and proteins and by X-ray crystallography of smaller fragments.1-4 Studying amyloid oligomer structures at high resolution is challenging, because amyloid oligomers are heterogeneous and dynamic, forming various species of different sizes and morphologies. Although a few structures of amyloid oligomers have been discovered in the last decade, there are not enough to provide a full understanding of amyloid assemblies.5-7 Our laboratory has pioneered the use of macrocyclic β-sheets as a tool for exploring the structures of amyloid oligomers. In collaboration with the Eisenberg group, we began using X-ray crystallography to ...
The purpose of this work is the reduction in the Abeta amyloid peptide burden in brain of Alzheimers disease (AD) transgenic mice without the concomitant elevation in plasma Abeta amyloid peptide. APPswe,PSEN1dE9 mice were studied at 12 months of age. The mice were shown to have considerable Abeta amyloid plaques in cerebral cortex based on immunocytochemistry. The mice were treated every 3C4 days by intravenous injections of either saline or the cTfRMAb-ScFv fusion protein at an injection dose of 1 1 mg/kg for 12 consecutive weeks. The brain A1C42 concentration was reduced 40% in the fusion protein treated mice, without any elevation in plasma A1C42 concentration. No cerebral micro-hemorrhage was observed in the treated mice. These results display that brain-penetrating antibody pharmaceutics can be developed for mind disorders such as AD TAE684 following a re-engineering of the antibody like a fusion protein that is transferred across the BBB via receptor-mediated transport. Keywords: ...
Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimers disease (AD), the focus is the amyloid beta peptide (Aß) that mediates familial Alzheimers disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.
Abeta peptide accumulation is thought to be the primary event in the pathogenesis of Alzheimers disease (AD), with downstream neurotoxic effects including the hyperphosphorylation of tau protein. Glycogen synthase kinase-3 (GSK-3) is increasingly implicated as playing a pivotal role in this amyloid cascade. We have developed an adult-onset Drosophila model of AD, using an inducible gene expression system to express Arctic mutant Abeta42 specifically in adult neurons, to avoid developmental effects. Abeta42 accumulated with age in these flies and they displayed increased mortality together with progressive neuronal dysfunction, but in the apparent absence of neuronal loss. This fly model can thus be used to examine the role of events during adulthood and early AD aetiology. Expression of Abeta42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued Abeta42 toxicity. Abeta42 pathogenesis was also reduced by removal of
Its often stated as fact that Alzheimers disease is the result of a buildup of beta-amyloid plaques in your brain. Such plaques may increase in your brain as you age, but tend to be far more abundant in people with Alzheimers disease.. Some people have a genetic mutation known to increase the production of beta-amyloid, but in most people the cause behind such buildup is unknown.. Provocative new research suggests that beta-amyloid buildup may not be intrinsically abnormal, and instead, may act as a natural antibiotic that protects your brain from infection. Alzheimers disease, then, might be a byproduct of your brains attempts to fight off infections.. Alzheimers Disease as a Byproduct of Infectious Disease. Harvard researchers have suggested that beta-amyloid proteins are antimicrobial peptides (part of your innate immune response) and have a beneficial role to play in your brain.. If viruses or bacteria cross your blood-brain barrier, the beta-amyloid traps the foreign invader and ...
Title: Non-Steroidal Anti-Inflammatory Drugs as Anti-Amyloidogenic Compounds. VOLUME: 14 ISSUE: 30. Author(s):Mie Hirohata, Kenjiro Ono and Masahito Yamada. Affiliation:Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan.. Keywords:Alzheimers disease, amyloid β-peptide (Aβ), amyloidosis, α-synuclein fibrils, central nervous system, neuroinflammation, non-steroidal anti-inflammatory drugs (NSAIDs), protein-misfolding disorders. Abstract: Amyloidosis is a clinical disorder caused by deposition of proteins that abnormally self-assemble into insoluble fibrils and impair organ function. More than 20 unrelated precursor proteins lose their native structure and misfold, leading to the formation of amyloid fibrils. The latter share cross-β core structure in vivo and in vitro and gain abnormal functions. Local amyloid deposition occurs in the central nervous system in Alzheimers disease (AD) and cerebral amyloid ...
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