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JOURNAL ARTICLE

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

Jan Bieschke, Martin Herbst, Thomas Wiglenda, Ralf P Friedrich, Annett Boeddrich, Franziska Schiele, Daniela Kleckers, Juan Miguel Lopez del Amo, Björn A Grüning, Qinwen Wang, Michael R Schmidt, Rudi Lurz, Roger Anwyl, Sigrid Schnoegl, Marcus Fändrich, Ronald F Frank, Bernd Reif, Stefan Günther, Dominic M Walsh, Erich E Wanker
Nature Chemical Biology 2012, 8 (1): 93-101
22101602
Several lines of evidence indicate that prefibrillar assemblies of amyloid-β (Aβ) 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 Aβ fibrillogenesis through the action of the orcein-related small molecule O4, which directly binds to hydrophobic amino acid residues in Aβ peptides and stabilizes the self-assembly of seeding-competent, β-sheet-rich protofibrils and fibrils. Notably, the O4-mediated acceleration of amyloid fibril formation efficiently decreases the concentration of small, toxic Aβ oligomers in complex, heterogeneous aggregation reactions. In addition, O4 treatment suppresses inhibition of long-term potentiation by Aβ 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.

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