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Characterization of Aβ aggregation mechanism probed by congo red

机译：刚果红探测Aβ聚集机制的表征

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摘要

β-Amyloid peptide (Aβ) aggregates are toxic to neuron and the main cause of Alzheimer's disease (AD). The role of congo red (CR) on Aβ aggregation is controversial in aqueous solution. Both prevention and promotion of Aβ aggregation have been proposed, suggesting that CR may interact with Aβ of different structural conformations resulting in different effects on Aβ aggregation behavior. CR with these characteristics can be applied to probe the molecular mechanism of Aβ aggregation. Therefore, in the present study, we used CR as a probe to study the Aβ aggregation behavior in sodium dodecyl sulfate (SDS) condition. Our results show that Aβ 40 adopts two short helices at Q15-S26 and K28-L34 in the SDS environment. CR can interact with the helical form of Aβ 40, and the main interaction site is located at the first helical and hydrophobic core region, residues 17-25, which is assigned as a discordant helix region. Furthermore, CR may prevent Aβ 40 undergoing α-helix to β-strand conversion, and therefore aggregation through stabilizing the helical conformation of discordant helix in SDS environment, suggesting that the discordant helix plays a key role on the conformational stabilization of Aβ. Our present study implies that any factors or molecules that can stabilize the discordant helical conformation may also prevent the Aβ aggregation in membrane associated state. This leads to a new therapeutic strategy for the development of lead compounds to AD.
机译：β-淀粉样肽（Aβ）聚集体对神经元有毒，是阿尔茨海默氏病（AD）的主要原因。在水溶液中，刚果红（CR）对Aβ聚集的作用是有争议的。已经提出了预防和促进Aβ聚集的建议，这表明CR可能与具有不同结构构象的Aβ相互作用，从而导致对Aβ聚集行为的不同影响。具有这些特征的CR可用于探索Aβ聚集的分子机制。因此，在本研究中，我们使用CR作为探针来研究十二烷基硫酸钠（SDS）条件下Aβ的聚集行为。我们的结果表明，在SDS环境中，Aβ40在Q15-S26和K28-L34处采用两个短螺旋。 CR可以与Aβ40的螺旋形式相互作用，并且主要的相互作用位点位于第一螺旋和疏水核心区域，残基17-25，其被指定为不一致的螺旋区域。此外，CR可以防止Aβ40经历α-螺旋向β-链的转化，并因此通过稳定SDS环境中不和谐螺旋的螺旋构象而聚集，这表明不和谐螺旋在Aβ的构象稳定中起关键作用。我们目前的研究表明，任何可以稳定螺旋构象不一致的因素或分子也可以阻止Aβ聚集在膜相关状态。这导致了将铅化合物发展为AD的新治疗策略。

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