Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils

Bieschke, J.; Herbst, M.; Wiglenda, T.; Friedrich, R.P.; Boeddrich, A.; Schiele, F.; Kleckers, D.; Lopez Del Amo, J.M.; Gruening, B.A.; Wang, Q.; Schmidt, M.R.; Lurz, R.; Anwyl, R.; Schnoegl, S.; Faendrich, M.; Frank, R.F.; Reif, B.; Guenther, S.; Walsh, D.M.; Wanker, E.E.

Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils

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Item Type:	Article
Title:	Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils
Creators Name:	Bieschke, J., Herbst, M., Wiglenda, T., Friedrich, R.P., Boeddrich, A., Schiele, F., Kleckers, D., Lopez Del Amo, J.M., Gruening, B.A., Wang, Q., Schmidt, M.R., Lurz, R., Anwyl, R., Schnoegl, S., Faendrich, M., Frank, R.F., Reif, B., Guenther, S., 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
ISSN:	1552-4450
Publisher:	Nature Publishing Group
Volume:	8
Number:	1
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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