Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils
Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils
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DOI：
10.1038/nchembio.719
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发表时间：
2012-01-01
影响因子：
14.8
通讯作者：
Wanker, Erich E.
中科院分区：
文献类型：
--
作者：
Bieschke, Jan;Herbst, Martin;Wanker, Erich E.
几条证据表明，淀粉样蛋白-β（A β）多肽的前原纤维组装体，如可溶性低聚物或原纤维，而不是成熟的终末期淀粉样蛋白原纤维，导致阿尔茨海默病中的神经元功能障碍和记忆障碍。这些发现表明，通过小分子介导的刺激淀粉样蛋白聚合来减少瞬时中间体的流行可能会降低毒性。在这里，我们证明了加速A β原纤维形成的作用，通过orcein相关的小分子O 4，它直接结合到疏水氨基酸残基的A β肽和稳定的自组装的播种能力，β片层丰富的原纤维和原纤维。值得注意的是，O 4介导的淀粉样蛋白原纤维形成的加速有效地降低了复杂的非均相聚集反应中小的有毒A β寡聚体的浓度。此外，O 4处理抑制海马脑片中A β寡聚体对长时程增强的抑制。这些结果支持了这样的假设，即小的，可扩散的前纤维淀粉样物质，而不是成熟的纤维聚集体是有毒的哺乳动物细胞。
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.