Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
Nat Chem Biol. 2011 Nov 20;8(1):93-101. doi: 10.1038/nchembio.719.
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.
有几条证据表明，淀粉样蛋白-β（Aβ）多肽的原纤维前体组装体，如可溶性寡聚体或原纤维，而不是成熟的终末淀粉样纤维，会导致阿尔茨海默病中的神经元功能障碍和记忆损伤。这些发现表明，通过小分子介导的淀粉样蛋白聚合的刺激来减少瞬态中间体的流行可能会降低毒性。在这里，我们通过与紫红素相关的小分子 O4 的作用证明了 Aβ纤维形成的加速，O4 直接结合到 Aβ肽中的疏水性氨基酸残基上，并稳定了具有种子能力的富含β-片层的原纤维和纤维的自组装。值得注意的是，O4 介导的加速淀粉样蛋白纤维形成有效地降低了复杂、异质聚集反应中小的、有毒的 Aβ寡聚物的浓度。此外，O4 处理可抑制 Aβ寡聚物对海马脑片长时程增强的抑制作用。这些结果支持了这样一种假设，即小的、可扩散的原纤维前体淀粉样蛋白物种而不是成熟的纤维状聚集物对哺乳动物细胞有毒。
