Small-molecule conversion of toxic oligomers to nontoxic β-sheetg-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

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

394 Zitate (Scopus)

Abstract

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 moleculeg-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-sheetg-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.

OriginalspracheEnglisch
Seiten (von - bis)93-101
Seitenumfang9
FachzeitschriftNature Chemical Biology
Jahrgang8
Ausgabenummer1
DOIs
PublikationsstatusVeröffentlicht - Jan. 2012

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