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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We thank S. Kostka, G. Grelle and S. Rautenberg for technical assistance; A. Otto for analysis of compound mixtures by MS; and M. Peters for expert discussions. The research leading to these results has received funding from the European Commission FP7 grants EUROSPIN (241498) and SYNSYS (242167) and from the European Integrated Projects APOPIS (503330) and EUROSCA (503304) as well as from the Initiative and Networking Fund of the Helmholtz Association (MSBN, TP3, TP5) and the Helmholtz Alliance for Mental Health in an Ageing Society to E.E.W. Furthermore, this work was supported by grants from Deutsche Forschungsgemeinschaft (DFG) (WA 1151/5), Bundesministerium für Bildung und Forschung (BMBF) (NGFN1, 01KW0015; NGFN2, 01GR0471; BioFuture, 0311853; GO-Bio, 0313881) to E.E.W., BMBF (NGFN-Plus, 01GS08132) to J.B. and E.E.W. and DFG (BI 1409/2-1) to J.B.
The authors declare no competing financial interests.
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Bieschke, J., Herbst, M., Wiglenda, T. et al. Small-molecule conversion of toxic oligomers to nontoxic β-sheet–rich amyloid fibrils. Nat Chem Biol 8, 93–101 (2012). https://doi.org/10.1038/nchembio.719
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