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

• DOI: 10.1038/nchembio.719
• Publication Date: 2011-11-20T19:59:30Z
• Authors: Jan Bieschke; Martin Herbst; Thomas Wiglenda; Ralf P Friedrich; Annett Boeddrich; Franziska Schiele; Daniela Kleckers; Juan Miguel Lopez...; 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
• Keywords: Fibrillogenesis; Amyloid (mycology); Oligomer; Amyloid disease

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.