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| Item Type: | Article |
|---|---|
| Title: | Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils |
| Creators Name: | Bieschke, J., Herbst, M., Wiglenda, T., Friedrich, R.P., Boeddrich, A., Schiele, F., Kleckers, D., Lopez Del Amo, J.M., Gruening, B.A., Wang, Q., Schmidt, M.R., Lurz, R., Anwyl, R., Schnoegl, S., Faendrich, M., Frank, R.F., Reif, B., Guenther, S., Walsh, D.M. and Wanker, E.E. |
| Abstract: | 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. |
| Keywords: | Amino Acid Sequence, Amyloid, Electron Microscopy, Hippocampus, Hydrophobic and Hydrophilic Interactions, Molecular Models, Oxazines, Peptide Fragments, Secondary Protein Structure, Synaptic Transmission, Tumor Cell Line |
| Source: | Nature Chemical Biology |
| ISSN: | 1552-4450 |
| Publisher: | Nature Publishing Group |
| Volume: | 8 |
| Number: | 1 |
| Page Range: | 93-101 |
| Date: | January 2012 |
| Official Publication: | https://doi.org/10.1038/nchembio.719 |
| PubMed: | View item in PubMed |
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