Journal
NATURE CHEMICAL BIOLOGY
Volume 8, Issue 1, Pages 93-101Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.719
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Funding
- European Commission [241498, 242167]
- European Integrated Project APOPIS [503330]
- European Integrated Project EUROSCA [503304]
- Helmholtz Association
- Helmholtz Alliance for Mental Health in an Ageing Society
- Deutsche Forschungsgemeinschaft (DFG) [WA 1151/5]
- Bundesministerium fur Bildung und Forschung (BMBF) [NGFN1, 01KW0015, NGFN2, 01GR0471, 0311853, 0313881, 01GS08132]
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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.
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