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Small-molecule conversion of toxic oligomers to nontoxic {beta}-sheet-rich amyloid fibrils

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Item Type:Article
Title:Small-molecule conversion of toxic oligomers to nontoxic {beta}-sheet-rich amyloid fibrils
Creators Name:Bieschke, J. and Herbst, M. and Wiglenda, T. and Friedrich, R.P. and Boeddrich, A. and Schiele, F. and Kleckers, D. and Lopez Del Amo, J.M. and Gruening, B.A. and Wang, Q. and Schmidt, M.R. and Lurz, R. and Anwyl, R. and Schnoegl, S. and Faendrich, M. and Frank, R.F. and Reif, B. and Guenther, S. and Walsh, D.M. and Wanker, E.E.
Abstract:Several lines of evidence indicate that prefibrillar assemblies of amyloid-{beta} (A{beta}) polypeptides, such as soluble oligomers or protofibrils, rather than mature, end-stage amyloid fibrils cause neuronal dysfunction and memory impairment in Alzheimer's disease. These findings suggest that reducing the prevalence of transient intermediates by small molecule-mediated stimulation of amyloid polymerization might decrease toxicity. Here we demonstrate the acceleration of A{beta} fibrillogenesis through the action of the orcein-related small molecule O4, which directly binds to hydrophobic amino acid residues in A{beta} peptides and stabilizes the self-assembly of seeding-competent, {beta}-sheet-rich protofibrils and fibrils. Notably, the O4-mediated acceleration of amyloid fibril formation efficiently decreases the concentration of small, toxic A{beta} oligomers in complex, heterogeneous aggregation reactions. In addition, O4 treatment suppresses inhibition of long-term potentiation by A{beta} oligomers in hippocampal brain slices. These results support the hypothesis that small, diffusible prefibrillar amyloid species rather than mature fibrillar aggregates are toxic for mammalian cells.
Keywords:Amino Acid Sequence, Amyloid, Electron Microscopy, Hippocampus, Hydrophobic and Hydrophilic Interactions, Molecular Models, Oxazines, Peptide Fragments, Secondary Protein Structure, Synaptic Transmission, Tumor Cell Line
Source:Nature Chemical Biology
Publisher:Nature Publishing Group (U.S.A.)
Page Range:93-101
Date:January 2012
Official Publication:https://doi.org/10.1038/nchembio.719
PubMed:View item in PubMed

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