The Experts below are selected from a list of 23499 Experts worldwide ranked by ideXlab platform
Dennis J Selkoe - One of the best experts on this subject based on the ideXlab platform.
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soluble Protein oligomers in neurodegeneration lessons from the alzheimer s Amyloid Beta peptide
Nature Reviews Molecular Cell Biology, 2007Co-Authors: Christian Haass, Dennis J SelkoeAbstract:The distinct Protein aggregates that are found in Alzheimer's, Parkinson's, Huntington's and prion diseases seem to cause these disorders. Small intermediates - soluble oligomers - in the aggregation process can confer synaptic dysfunction, whereas large, insoluble deposits might function as reservoirs of the bioactive oligomers. These emerging concepts are exemplified by Alzheimer's disease, in which Amyloid Beta-Protein oligomers adversely affect synaptic structure and plasticity. Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded Proteins.
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toward a comprehensive theory for alzheimer s disease hypothesis alzheimer s disease is caused by the cerebral accumulation and cytotoxicity of Amyloid β Protein
Annals of the New York Academy of Sciences, 2006Co-Authors: Dennis J SelkoeAbstract:: A central challenge of research on Alzheimer's disease (AD) is to assemble the enormous body of scientific observations about the disorder, some of them seemingly in conflict with others, into a coherent and credible mechanism of pathogenesis. In this article, I attempt to synthesize the disparate findings on AD into a unified sequence that essentially begins with alterations in the production or clearance of the Amyloid Beta-Protein (A Beta). Mounting evidence from many laboratories supports an A Beta accumulation in limbic and association cortices as the fundamental initiator of the disease, with attendant therapeutic implications.
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natural oligomers of the Amyloid Beta Protein specifically disrupt cognitive function
Nature Neuroscience, 2005Co-Authors: James P Cleary, Dominic M Walsh, Dennis J Selkoe, Ganesh M Shankar, J Hofmeister, Michael A Kuskowski, Karen H. AsheAbstract:A central unresolved problem in research on Alzheimer disease is the nature of the molecular entity causing dementia. Here we provide the first direct experimental evidence that a defined molecular species of the Amyloid-β Protein interferes with cognitive function. Soluble oligomeric forms of Amyloid-β, including trimers and dimers, were both necessary and sufficient to disrupt learned behavior in a manner that was rapid, potent and transient; they produced impaired cognitive function without inducing permanent neurological deficits. Although β-Amyloidosis has long been hypothesized to affect cognition, the abnormally folded Protein species associated with this or any other neurodegenerative disease has not previously been isolated, defined biochemically and then specifically characterized with regard to its effects on cognitive function. The biochemical isolation of discrete Amyloid-β moieties with pathophysiological properties sets the stage for a new approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders.
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naturally secreted oligomers of Amyloid Beta Protein potently inhibit hippocampal long term potentiation in vivo
Nature, 2002Co-Authors: Dominic M Walsh, Igor Klyubin, Julia V Fadeeva, William K Cullen, Roger Anwyl, Michael S Wolfe, Michael J Rowan, Dennis J SelkoeAbstract:Although extensive data support a central pathogenic role for Amyloid Beta Protein (ABeta) in Alzheimer's disease, the Amyloid hypothesis remains controversial, in part because a specific neurotoxic species of ABeta and the nature of its effects on synaptic function have not been defined in vivo. Here we report that natural oligomers of human ABeta are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell. Cerebral microinjection of cell medium containing these oligomers and abundant ABeta monomers but no Amyloid fibrils markedly inhibited hippocampal long-term potentiation (LTP) in rats in vivo. Immunodepletion from the medium of all ABeta species completely abrogated this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades ABeta monomers but not oligomers, did not prevent the inhibition of LTP. Therefore, ABeta oligomers, in the absence of monomers and Amyloid fibrils, disrupted synaptic plasticity in vivo at concentrations found in human brain and cerebrospinal fluid. Finally, treatment of cells with gamma-secretase inhibitors prevented oligomer formation at doses that allowed appreciable monomer production, and such medium no longer disrupted LTP, indicating that synaptotoxic ABeta oligomers can be targeted therapeutically.
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in vitro studies of Amyloid Beta Protein fibril assembly and toxicity provide clues to the aetiology of flemish variant ala692 gly alzheimer s disease
Biochemical Journal, 2001Co-Authors: Dominic M Walsh, Dean M Hartley, Margaret M Condron, Dennis J Selkoe, David B TeplowAbstract:In a Flemish kindred, an Ala(692)-->Gly amino acid substitution in the Amyloid Beta-Protein precursor (ABetaPP) causes a form of early-onset Alzheimer's disease (AD) which displays prominent Amyloid angiopathy and unusually large senile plaque cores. The mechanistic basis of this Flemish form of AD is unknown. Previous in vitro studies of Amyloid Beta-Protein (ABeta) production in HEK-293 cells transfected with cDNA encoding Flemish ABetaPP have shown that full-length [ABeta(1-40)] and truncated [ABeta(5-40) and ABeta(11-40)] forms of ABeta are produced. In an effort to determine how these peptides might contribute to the pathogenesis of the Flemish disease, comparative biophysical and neurotoxicity studies were performed on wild-type and Flemish ABeta(1-40), ABeta(5-40) and ABeta(11-40). The results revealed that the Flemish amino acid substitution increased the solubility of each form of peptide, decreased the rate of formation of thioflavin-T-positive assemblies, and increased the SDS-stability of peptide oligomers. Although the kinetics of peptide assembly were altered by the Ala(21)-->Gly substitution, all three Flemish variants formed fibrils, as did the wild-type peptides. Importantly, toxicity studies using cultured primary rat cortical cells showed that the Flemish assemblies were as potent a neurotoxin as were the wild-type assemblies. Our results are consistent with a pathogenetic process in which conformational changes in ABeta induced by the Ala(21)-->Gly substitution would facilitate peptide adherence to the vascular endothelium, creating nidi for Amyloid growth. Increased peptide solubility and assembly stability would favour formation of larger deposits and inhibit their elimination. In addition, increased concentrations of neurotoxic assemblies would accelerate neuronal injury and death.
David B Teplow - One of the best experts on this subject based on the ideXlab platform.
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elucidation of Amyloid Beta Protein oligomerization mechanisms discrete molecular dynamics study
Journal of the American Chemical Society, 2010Co-Authors: Brigita Urbanc, M Betnel, L Cruz, Gal Bitan, David B TeplowAbstract:Oligomers of Amyloid Beta-Protein (ABeta) play a central role in the pathology of Alzheimer's disease. Of the two predominant ABeta alloforms, ABeta(1-40) and ABeta(1-42), ABeta(1-42) is more strongly implicated in the disease. We elucidated the structural characteristics of oligomers of ABeta(1-40) and ABeta(1-42) and their Arctic mutants, [E22G]ABeta(1-40) and [E22G]ABeta(1-42). We simulated oligomer formation using discrete molecular dynamics (DMD) with a four-bead Protein model, backbone hydrogen bonding, and residue-specific interactions due to effective hydropathy and charge. For all four peptides under study, we derived the characteristic oligomer size distributions that were in agreement with prior experimental findings. Unlike ABeta(1-40), ABeta(1-42) had a high propensity to form paranuclei (pentameric or hexameric) structures that could self-associate into higher-order oligomers. Neither of the Arctic mutants formed higher-order oligomers, but [E22G]ABeta(1-40) formed paranuclei with a similar propensity to that of ABeta(1-42). Whereas the best agreement with the experimental data was obtained when the charged residues were modeled as solely hydrophilic, further assembly from spherical oligomers into elongated protofibrils was induced by nonzero electrostatic interactions among the charged residues. Structural analysis revealed that the C-terminal region played a dominant role in ABeta(1-42) oligomer formation whereas ABeta(1-40) oligomerization was primarily driven by intermolecular interactions among the central hydrophobic regions. The N-terminal region A2-F4 played a prominent role in ABeta(1-40) oligomerization but did not contribute to the oligomerization of ABeta(1-42) or the Arctic mutants. The oligomer structure of both Arctic peptides resembled ABeta(1-42) more than ABeta(1-40), consistent with their potentially more toxic nature.
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effects of the arctic e22 g mutation on Amyloid Beta Protein folding discrete molecular dynamics study
Journal of the American Chemical Society, 2008Co-Authors: Alfonso Lam, David B Teplow, H E Stanley, Brigita UrbancAbstract:The 40-42 residue Amyloid Beta-Protein (ABeta) plays a central role in the pathogenesis of Alzheimer's disease (AD). Of the two main alloforms, ABeta40 and ABeta42, the longer ABeta42 is linked particularly strongly to AD. Despite the relatively small two amino acid length difference in primary structure, in vitro studies demonstrate that ABeta40 and ABeta42 oligomerize through distinct pathways. Recently, a discrete molecular dynamics (DMD) approach combined with a four-bead Protein model recapitulated the differences in ABeta40 and ABeta42 oligomerization and led to structural predictions amenable to in vitro testing. Here, the same DMD approach is applied to elucidate folding of ABeta40, ABeta42, and two mutants, [G22]ABeta40 and [G22]ABeta42, which cause a familial ("Arctic") form of AD. The implicit solvent in the DMD approach is modeled by amino acid-specific hydropathic and electrostatic interactions. The strengths of these effective interactions are chosen to best fit the temperature dependence of the average Beta-strand content in ABeta42 monomer, as determined using circular dichroism (CD) spectroscopy. In agreement with these CD data, we show that at physiological temperatures, the average Beta-strand content in both alloforms increases with temperature. Our results predict that the average Beta-strand propensity should decrease in both alloforms at temperatures higher than approximately 370 K. At physiological temperatures, both ABeta40 and ABeta42 adopt a collapsed-coil conformation with several short Beta-strands and a small (<1%) amount of alpha-helical structure. At slightly above physiological temperature, folded ABeta42 monomers display larger amounts of Beta-strand than do ABeta40 monomers. At increased temperatures, more extended conformations with a higher amount of Beta-strand (approximately < 30%) structure are observed. In both alloforms, a Beta-hairpin at A21-A30 is a central folding region. We observe three additional folded regions: structure 1, a Beta-hairpin at V36-A42 that exists in ABeta42 but not in ABeta40; structure 2, a Beta-hairpin at R5-H13 in ABeta42 but not in ABeta40; and structure 3, a Beta-strand A2-F4 in ABeta40 but not ABeta42. At physiological temperatures, the Arctic mutation, E22G, disrupts contacts in the A21-A30 region of both [G22]ABeta peptides, resulting in a less stable main folding region relative to the wild type peptides. The Arctic mutation induces a significant structural change at the N-terminus of [G22]ABeta40 by preventing the formation of structure 3 observed in ABeta40 but not ABeta42, thereby reducing the structural differences between [G22]ABeta40 and [G22]ABeta42 at the N-terminus. [G22]ABeta40 is characterized by a significantly increased amount of average Beta-strand relative to the other three peptides due to an induced Beta-hairpin structure at R5-H13, similar to structure 2. Consequently, the N-terminal folded structure of the Arctic mutants closely resembles the N-terminal structure of ABeta42, suggesting that both Arctic ABeta peptides might assemble into structures similar to toxic ABeta42 oligomers.
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Amyloid Beta Protein assembly as a therapeutic target of alzheimer s disease
Current Pharmaceutical Design, 2008Co-Authors: Ghiam Yamin, Kenjiro Ono, Mohammed Inayathullah, David B TeplowAbstract:Alzheimer's disease (AD), the most common neurodegenerative disorder in the aged, is characterized by the cerebral deposition of fibrils formed by the Amyloid Beta-Protein (ABeta), a 40-42 amino acid peptide. The folding of ABeta into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is hypothesized to be the key pathologic event in AD. ABeta is formed through cleavage of the ABeta precursor Protein by two endoProteinases, Beta-secretase and gamma-secretase, that cleave the ABeta N-terminus and C-terminus, respectively. These facts support the relevance of therapeutic strategies targeting ABeta production, assembly, clearance, and neurotoxicity. Currently, no disease-modifying therapeutic agents are available for AD patients. Instead, existing therapeutics provide only modest symptomatic benefits for a limited time. We summarize here recent efforts to produce therapeutic drugs targeting ABeta assembly. A number of approaches are being used in these efforts, including immunological, nutraceutical, and more classical medicinal chemical (peptidic inhibitors, carbohydrate-containing compounds, polyamines, "drug-like" compounds, chaperones, metal chelators, and osmolytes), and many of these have progressed to phase III clinical trails. We also discuss briefly a number of less mature, but intriguing, strategies that have therapeutic potential. Although initial trials of some disease-modifying agents have failed, we argue that substantial cause for optimism exists.
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the tottori d7n and english h6r familial alzheimer disease mutations accelerate aβ fibril formation without increasing protofibril formation
Journal of Biological Chemistry, 2007Co-Authors: Yukiko Hori, Margaret M Condron, David B Teplow, Takaomi C Saido, Tadafumi Hashimoto, Yosuke Wakutani, Katsuya Urakami, Kenji Nakashima, Satoshi Tsubuki, Takeshi IwatsuboAbstract:A subset of Alzheimer disease cases is caused by autosomal dominant mutations in genes encoding the Amyloid Beta-Protein precursor or presenilins. Whereas some Amyloid Beta-Protein precursor mutations alter its metabolism through effects on ABeta production, the pathogenic effects of those that alter amino acid residues within the ABeta sequence are not fully understood. Here we examined the biophysical effects of two recently described intra-ABeta mutations linked to early-onset familial Alzheimer disease, the D7N Tottori-Japanese and H6R English mutations. Although these mutations do not affect ABeta production, synthetic ABeta(1-42) peptides carrying D7N or H6R substitutions show enhanced fibril formation. In vitro analysis using ABeta(1-40)-based mutant peptides reveal that D7N or H6R mutations do not accelerate the nucleation phase but selectively promote the elongation phase of Amyloid fibril formation. Notably, the levels of protofibrils generated from D7N or H6R ABeta were markedly inhibited despite enhanced fibril formation. These N-terminal ABeta mutations may accelerate Amyloid fibril formation by a unique mechanism causing structural changes of ABeta peptides, specifically promoting the elongation process of Amyloid fibrils without increasing metastable intermediates.
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Amyloid Beta Protein monomer structure a computational and experimental study
Protein Science, 2006Co-Authors: Andrij Baumketner, David B Teplow, Gal Bitan, Summer L Bernstein, Thomas Wyttenbach, Michael T Bowers, Joanemma SheaAbstract:The structural properties of the ABeta42 peptide, a main constituent of the Amyloid plaques formed in Alzheimer's disease, were investigated through a combination of ion-mobility mass spectrometry and theoretical modeling. Replica exchange molecular dynamics simulations using a fully atomic description of the peptide and implicit water solvent were performed on the -3 charge state of the peptide, its preferred state under experimental conditions. Equilibrated structures at 300 K were clustered into three distinct families with similar structural features within a family and with significant root mean square deviations between families. An analysis of secondary structure indicates the ABeta42 peptide conformations are dominated by loops and turns but show some helical structure in the C-terminal hydrophobic tail. A second calculation on ABeta42 in a solvent-free environment yields compact structures turned "inside out" from the solution structures (hydrophobic parts on the outside, polar parts on the inside). Ion mobility experiments on the ABeta42 -3 charge state electrosprayed from solution yield a bimodal arrival time distribution. This distribution can be quantitatively fit using cross-sections from dehydrated forms of the three families of calculated solution structures and the calculated solvent-free family of structures. Implications of the calculations on the early stages of aggregation of ABeta42 are discussed.
Dominic M Walsh - One of the best experts on this subject based on the ideXlab platform.
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Amyloid Beta Protein dimers rapidly form stable synaptotoxic protofibrils
The Journal of Neuroscience, 2010Co-Authors: Brian Onuallain, Darragh B Freir, Andrew J Nicoll, Emmanuel Risse, Neil Ferguson, Caroline E Herron, John Collinge, Dominic M WalshAbstract:Nonfibrillar, water-soluble low-molecular weight assemblies of the Amyloid β-Protein (Aβ) are believed to play an important role in Alzheimer's disease (AD). Aqueous extracts of human brain contain Aβ assemblies that migrate on SDS-polyacrylamide gels and elute from size exclusion as dimers (∼8 kDa) and can block long-term potentiation and impair memory consolidation in the rat. Such species are detected specifically and sensitively in extracts of Alzheimer brain suggesting that SDS-stable dimers may be the basic building blocks of AD-associated synaptotoxic assemblies. Consequently, understanding the structure and properties of Aβ dimers is of great interest. In the absence of sufficient brain-derived dimer to facilitate biophysical analysis, we generated synthetic dimers designed to mimic the natural species. For this, Aβ(1-40) containing cysteine in place of serine 26 was used to produce disulphide cross-linked dimer, (AβS26C)2. Such dimers had no detectable secondary structure, produced an analytical ultracentrifugation profile consistent for an ∼8.6 kDa Protein, and had no effect on hippocampal long-term potentiation (LTP). However, (AβS26C)2 aggregated more rapidly than either AβS26C or wild-type monomers and formed parastable β-sheet rich, thioflavin T-positive, protofibril-like assemblies. Whereas wild-type Aβ aggregated to form typical Amyloid fibrils, the protofibril-like structures formed by (AβS26C)2 persisted for prolonged periods and potently inhibited LTP in mouse hippocampus. These data support the idea that Aβ dimers may stabilize the formation of fibril intermediates by a process distinct from that available to Aβ monomer and that higher molecular weight prefibrillar assemblies are the proximate mediators of Aβ toxicity.
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inhibition of Amyloid Beta Protein fibrillation by polymeric nanoparticles
Journal of the American Chemical Society, 2008Co-Authors: Celia Cabaleirolago, Dominic M Walsh, Fiona Quinlanpluck, Iseult Lynch, Stina Lindman, Aedin M Minogue, Eva Thulin, Kenneth A Dawson, Sara LinseAbstract:Copolymeric NiPAM:BAM nanoparticles of varying hydrophobicity were found to retard fibrillation of the Alzheimer’s disease-associated Amyloid β Protein (Aβ). We found that these nanoparticles affect mainly the nucleation step of Aβ fibrillation. The elongation step is largely unaffected by the particles, and once the Aβ is nucleated, the fibrillation process occurs with the same rate as in the absence of nanoparticles. The extension of the lag phase for fibrillation of Aβ is strongly dependent on both the amount and surface character of the nanoparticles. Surface plasmon resonance studies show that Aβ binds to the nanoparticles and provide rate and equilibrium constants for the interaction. Numerical analysis of the kinetic data for fibrillation suggests that binding of monomeric Aβ and prefibrillar oligomers to the nanoparticles prevents fibrillation. Moreover, we find that fibrillation of Aβ initiated in the absence of nanoparticles can be reversed by addition of nanoparticles up to a particular time po...
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natural oligomers of the Amyloid Beta Protein specifically disrupt cognitive function
Nature Neuroscience, 2005Co-Authors: James P Cleary, Dominic M Walsh, Dennis J Selkoe, Ganesh M Shankar, J Hofmeister, Michael A Kuskowski, Karen H. AsheAbstract:A central unresolved problem in research on Alzheimer disease is the nature of the molecular entity causing dementia. Here we provide the first direct experimental evidence that a defined molecular species of the Amyloid-β Protein interferes with cognitive function. Soluble oligomeric forms of Amyloid-β, including trimers and dimers, were both necessary and sufficient to disrupt learned behavior in a manner that was rapid, potent and transient; they produced impaired cognitive function without inducing permanent neurological deficits. Although β-Amyloidosis has long been hypothesized to affect cognition, the abnormally folded Protein species associated with this or any other neurodegenerative disease has not previously been isolated, defined biochemically and then specifically characterized with regard to its effects on cognitive function. The biochemical isolation of discrete Amyloid-β moieties with pathophysiological properties sets the stage for a new approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders.
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naturally secreted oligomers of Amyloid Beta Protein potently inhibit hippocampal long term potentiation in vivo
Nature, 2002Co-Authors: Dominic M Walsh, Igor Klyubin, Julia V Fadeeva, William K Cullen, Roger Anwyl, Michael S Wolfe, Michael J Rowan, Dennis J SelkoeAbstract:Although extensive data support a central pathogenic role for Amyloid Beta Protein (ABeta) in Alzheimer's disease, the Amyloid hypothesis remains controversial, in part because a specific neurotoxic species of ABeta and the nature of its effects on synaptic function have not been defined in vivo. Here we report that natural oligomers of human ABeta are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell. Cerebral microinjection of cell medium containing these oligomers and abundant ABeta monomers but no Amyloid fibrils markedly inhibited hippocampal long-term potentiation (LTP) in rats in vivo. Immunodepletion from the medium of all ABeta species completely abrogated this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades ABeta monomers but not oligomers, did not prevent the inhibition of LTP. Therefore, ABeta oligomers, in the absence of monomers and Amyloid fibrils, disrupted synaptic plasticity in vivo at concentrations found in human brain and cerebrospinal fluid. Finally, treatment of cells with gamma-secretase inhibitors prevented oligomer formation at doses that allowed appreciable monomer production, and such medium no longer disrupted LTP, indicating that synaptotoxic ABeta oligomers can be targeted therapeutically.
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in vitro studies of Amyloid Beta Protein fibril assembly and toxicity provide clues to the aetiology of flemish variant ala692 gly alzheimer s disease
Biochemical Journal, 2001Co-Authors: Dominic M Walsh, Dean M Hartley, Margaret M Condron, Dennis J Selkoe, David B TeplowAbstract:In a Flemish kindred, an Ala(692)-->Gly amino acid substitution in the Amyloid Beta-Protein precursor (ABetaPP) causes a form of early-onset Alzheimer's disease (AD) which displays prominent Amyloid angiopathy and unusually large senile plaque cores. The mechanistic basis of this Flemish form of AD is unknown. Previous in vitro studies of Amyloid Beta-Protein (ABeta) production in HEK-293 cells transfected with cDNA encoding Flemish ABetaPP have shown that full-length [ABeta(1-40)] and truncated [ABeta(5-40) and ABeta(11-40)] forms of ABeta are produced. In an effort to determine how these peptides might contribute to the pathogenesis of the Flemish disease, comparative biophysical and neurotoxicity studies were performed on wild-type and Flemish ABeta(1-40), ABeta(5-40) and ABeta(11-40). The results revealed that the Flemish amino acid substitution increased the solubility of each form of peptide, decreased the rate of formation of thioflavin-T-positive assemblies, and increased the SDS-stability of peptide oligomers. Although the kinetics of peptide assembly were altered by the Ala(21)-->Gly substitution, all three Flemish variants formed fibrils, as did the wild-type peptides. Importantly, toxicity studies using cultured primary rat cortical cells showed that the Flemish assemblies were as potent a neurotoxin as were the wild-type assemblies. Our results are consistent with a pathogenetic process in which conformational changes in ABeta induced by the Ala(21)-->Gly substitution would facilitate peptide adherence to the vascular endothelium, creating nidi for Amyloid growth. Increased peptide solubility and assembly stability would favour formation of larger deposits and inhibit their elimination. In addition, increased concentrations of neurotoxic assemblies would accelerate neuronal injury and death.
Nobuhiro Suzuki - One of the best experts on this subject based on the ideXlab platform.
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secreted Amyloid β Protein similar to that in the senile plaques of alzheimer s disease is increased in vivo by the presenilin 1 and 2 and app mutations linked to familial alzheimer s disease
Nature Medicine, 1996Co-Authors: Donalyn Scheuner, Christopher B. Eckman, John Hardy, Nobuhiro Suzuki, Martin Citron, Malene Jensen, X Song, T D Bird, Mike HuttonAbstract:To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and Amyloid Beta-Protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of Amyloid Beta-Protein (A Beta) ending at A Beta 42(43) in vivo, we performed a blinded comparison of plasma A Beta levels in carriers of these mutations and controls. A Beta 1-42(43) was elevated in plasma from subjects with FAD-linked PS1 (P < 0.0001), PS2N1411 (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV7171 (one subject) mutations. A Beta ending at A Beta 42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Alzhelmer's disease by increasing the extracellular concentration of A Beta 42(43), thereby fostering cerebral deposition of this highly Amyloidogenic peptide.
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secreted Amyloid Beta Protein similar to that in the senile plaques of alzheimer s disease is increased in vivo by the presenilin 1 and 2 and app mutations linked to familial alzheimer s disease
Nature Medicine, 1996Co-Authors: Donalyn Scheuner, Christopher B. Eckman, John Hardy, Nobuhiro Suzuki, Martin Citron, Malene Jensen, X Song, T D Bird, Mike HuttonAbstract:To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and Amyloid Beta-Protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of Amyloid Beta-Protein (A Beta) ending at A Beta 42(43) in vivo, we performed a blinded comparison of plasma A Beta levels in carriers of these mutations and controls. A Beta 1-42(43) was elevated in plasma from subjects with FAD-linked PS1 (P < 0.0001), PS2N1411 (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV7171 (one subject) mutations. A Beta ending at A Beta 42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Alzhelmer's disease by increasing the extracellular concentration of A Beta 42(43), thereby fostering cerebral deposition of this highly Amyloidogenic peptide.
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gm1 ganglioside bound Amyloid Beta Protein a Beta a possible form of preAmyloid in alzheimer s disease
Nature Medicine, 1995Co-Authors: Katsuhiko Yanagisawa, Nobuhiro Suzuki, Asano Odaka, Yasuo IharaAbstract:The earliest event so far known that occurs in the brain affected with Alzheimer's disease (AD) is the deposition and fibril formation of Amyloid Beta-Protein (A Beta). A Beta is cleaved from a glycosylated membrane Protein, called Beta-Amyloid Protein precursor, and normally secreted into the extracellular space. Here we report on the presence of membrane-bound A Beta that tightly binds GM1 ganglioside. This suggests that this novel A Beta species, rather than secreted A Beta, may act as a 'seed' for Amyloid and further that intracellular abnormalities in the membrane recycling already exist at the stage of Amyloidogenesis.
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long Amyloid Beta Protein secreted from wild type human neuroblastoma imr 32 cells
Biochemistry, 1995Co-Authors: Asano Asamiodaka, Yoshihiro Ishibashi, Takashi Kikuchi, Chieko Kitada, Nobuhiro SuzukiAbstract:The 39- to 43-amino acid Amyloid Beta-Protein (A Beta) is deposited as Amyloid in Alzheimer's disease. Recent studies have suggested that short A Beta (A Beta 39 or A Beta 40) and long A Beta (A Beta 42 or A Beta 43) play different roles in Alzheimer-type pathology. However, little attempt has been made to investigate the cellular mechanisms underlying the generation of short and long A Beta individually. In the present report, we first measured the amount of short and long A Beta that are secreted from wild-type human and rodent cells with neuron- or glia-like properties using highly sensitive sandwich-ELISAs that discriminate long A Beta from short A Beta. The results showed that long A Beta secreted by all cells constitutes approximately 10% of the total A Beta. To identify the molecular species of long A Beta, we next isolated the A Beta species secreted from human neuroblastoma IMR-32 cells by affinity chromatography, gel-filtration HPLC, and reverse-phase HPLC. Mass spectrometric analysis demonstrated unequivocally that IMR-32 cells produce A Beta 1-42 together with A Beta 1-37, A Beta 1-38, A Beta 1-39, and most predominantly, A Beta 1-40. Finally, to investigate the cellular mechanisms that generate A Beta 1-42, we studied the effects of brefeldin A and monensin on the production of A Beta 1-40 and A Beta 1-42 in IMR-32 cells. These reagents reduced the production of both A Beta 1-40 and A Beta 1-42 simultaneously in a concentration-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)
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Amyloid Beta Protein a Beta in alzheimer s disease brain biochemical and immunocytochemical analysis with antibodies specific for forms ending at a Beta 40 or a Beta 42 43
Journal of Biological Chemistry, 1995Co-Authors: Stephen A Gravina, Christopher B. Eckman, Nobuhiro Suzuki, Laszlo Otvos, Kristin E Long, Linda H Younkin, Steven G. YounkinAbstract:Biochemical and immunocytochemical analyses were performed to evaluate the composition of the Amyloid Beta Protein (A Beta) deposited in the brains of patients with Alzheimer's disease (AD). To quantitate all A Beta s present, cerebral cortex was homogenized in 70% formic acid, and the supernatant was analyzed by sandwich enzyme-linked immunoabsorbent assays specific for various forms of A Beta. In 9 of 27 AD brains examined, there was minimal congophilic angiopathy and virtually all A Beta (96%) ended at A Beta 42(43). The other 18 AD brains contained increasing amounts of A Beta ending at A Beta 40. From this set, 6 brains with substantial congophilic angiopathy were separately analyzed. In these brains, the amount of A Beta ending at A Beta 42(43) was much the same as in brains with minimal congophilic angiopathy, but a large amount of A Beta ending at A Beta 40 (76% of total A Beta) was also present. Immunocytochemical analysis with monoclonal antibodies selective for A Beta s ending at A Beta 42(43) or A Beta 40 confirmed that, in brains with minimal congophilic angiopathy, virtually all A Beta is A Beta ending at A Beta 42(43) and showed that this A Beta is deposited in senile plaques of all types. In the remaining AD brains, A Beta 42(43) was deposited in a similar fashion in plaques, but, in addition, widely varying amounts of A Beta ending at A Beta 40 were deposited, primarily in blood vessel walls, where some A Beta ending at A Beta 42(43) was also present. These observations indicate that A Beta s ending at A Beta 42(43), which are a minor component of the A Beta in human cerebrospinal fluid and plasma, are critically important in AD where they deposit selectively in plaques of all kinds.
Yasuo Ihara - One of the best experts on this subject based on the ideXlab platform.
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accumulation and aggregation of Amyloid Beta Protein in late endosomes of niemann pick type c cells
Journal of Biological Chemistry, 2001Co-Authors: Tsuneo Yamazaki, Christian Haass, Tayuan Chang, Yasuo IharaAbstract:There is growing evidence suggesting that cholesterol metabolism is linked to susceptibility to Alzheimer's disease by influencing Amyloid Beta-Protein (ABeta) metabolism. However, the precise cellular linkage sites between cholesterol and ABeta have not yet been clarified. To address this issue, we investigated Niemann-Pick type C (NPC) model cells and NPC mutant cells, which showed aberrant cholesterol trafficking. We observed a remarkable ABeta accumulation in late endosomes of both NPC model cells and mutant cells where cholesterol accumulates and a significant accumulation in the NPC mouse brain. This ABeta accumulation was independent of its constitutive secretion and production through an endocytic pathway. In addition, it is characterized by a marked predominance of ABeta42 and insolubility in SDS, suggesting the presence of aggregated ABeta in late endosomes. Most importantly, ABeta accumulation is coupled with the cholesterol levels in late endosomes. Thus, late endosomes of NPC cells are a novel pool of aggregated ABeta42 as well as cholesterol, suggesting a direct interaction between aggregated ABeta and cholesterol.
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oxidative stress induces intracellular accumulation of Amyloid Beta Protein aBeta in human neuroblastoma cells
Biochemistry, 2000Co-Authors: Hiroaki Misonou, Maho Morishimakawashima, Yasuo IharaAbstract:Several lines of evidence suggest that enhanced oxidative stress is involved in the pathogenesis and/or progression of Alzheimer's disease (AD). Amyloid Beta-Protein (ABeta) that composes senile plaques, a major neuropathological hallmark of AD, is considered to have a causal role in AD. Thus, we have studied the effect of oxidative stress on ABeta metabolism within the cell. Here, we report that oxidative stress induced by H(2)O(2) (100-250 microM) caused an increase in the levels of intracellular ABeta in human neuroblastoma SH-SY5Y cells. Treatment with 200 microM H(2)O(2) caused significant decreases in the Protein levels of full-length Beta-Amyloid precursor Protein (APP) and its COOH-terminal fragment that is generated by Beta-cleavage, while the gene expression of APP was not altered under these conditions. A pulse-chase experiment further showed a decrease in the half-life of this Amyloidogenic COOH-terminal fragment but not in that of nonAmyloidogenic counterpart in the H(2)O(2)-treated cells. These results suggest that oxidative stress promotes intracellular accumulation of ABeta through enhancing the Amyloidogenic pathway.
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gm1 ganglioside bound Amyloid Beta Protein a Beta a possible form of preAmyloid in alzheimer s disease
Nature Medicine, 1995Co-Authors: Katsuhiko Yanagisawa, Nobuhiro Suzuki, Asano Odaka, Yasuo IharaAbstract:The earliest event so far known that occurs in the brain affected with Alzheimer's disease (AD) is the deposition and fibril formation of Amyloid Beta-Protein (A Beta). A Beta is cleaved from a glycosylated membrane Protein, called Beta-Amyloid Protein precursor, and normally secreted into the extracellular space. Here we report on the presence of membrane-bound A Beta that tightly binds GM1 ganglioside. This suggests that this novel A Beta species, rather than secreted A Beta, may act as a 'seed' for Amyloid and further that intracellular abnormalities in the membrane recycling already exist at the stage of Amyloidogenesis.
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Amyloid Beta Protein a Beta deposition a Beta 42 43 precedes a Beta 40 in down syndrome
Annals of Neurology, 1995Co-Authors: Takeshi Iwatsubo, Nobuhiro Suzuki, Asano Odaka, David M A Mann, Yasuo IharaAbstract:The chronological relationship regarding deposition of Amyloid Beta Protein (A Beta) species, A Beta 40 and A Beta 42(43), was investigated in 16 brains from Down syndrome patients aged 31 to 64 years. The frontal cortex was probed with two end-specific monoclonals that recognize A Beta 40 or A Beta 42(43). All senile plaques detected with an authentic Beta monoclonal were also A Beta 42(43) positive, but only a varying proportion was A Beta 40 positive. In young ( 50 years old) brains contained many mature senile plaques with Amyloid cores in addition to diffuse and immature plaques and the proportion of A Beta 40-positive senile plaques was increased (mean, 42% of total). Cerebral Amyloid angiopathy was more abundant in old Down syndrome brains and was positive for both A Beta 40 and A Beta 42(43). In cerebral Amyloid angiopathy, A Beta 40 predominated over A Beta 42(43) in both staining intensity and number of positive vessels. These results indicate that (1) the A Beta species initially deposited in the brain as senile plaques is A Beta 42(43) and A Beta 40 only appears a decade later, and (2) in cerebral Amyloid angiopathy A Beta 40 appears as early as A Beta 42(43).