Chandra Bappaditya, Mithu Venus Singh, Bhowmik Debanjan, Das Anand Kant, Sahoo Bankanidhi, Maiti Sudipta, Madhu Perunthiruthy K
Department of Chemical Sciences, Tata Institute of Fundamental Research, Colaba, Mumbai, India.
Department of Chemistry, Guru Nanak Dev University, Amritsar, India.
Biophys J. 2017 Apr 25;112(8):1597-1608. doi: 10.1016/j.bpj.2017.02.043.
There are three specific regions in the Amyloid beta (Aβ) peptide sequence where variations cause enhanced toxicity in Alzheimer's disease: the N-terminus, the central salt bridge, and the C-terminus. Here, we investigate if there is a close conformational connection between these three regions, which may suggest a concerted mechanism of toxicity. We measure the effects of Zn and curcumin on Aβ, and compare these with their previously reported effects on Aβ. Aβ and Aβ differ only near the C-terminus, where curcumin interacts, while Zn interacts near the N-terminus. Therefore, this comparison should help us differentiate the effect of modulating the C- and the N-termini. We find that curcumin allows fibril-like structures containing the salt bridge to emerge in the mature Aβ aggregates, but not in Aβ. In contrast, we find no difference in the effects of Zn on Aβ and Aβ. In the presence of Zn, both of these fail to form proper fibrils, and the salt bridge remains disrupted. These results indicate that modulations of the Aβ termini can determine the fate of a salt bridge far away in the sequence, and this has significant consequences for Aβ toxicity. We also infer that small molecules can alter oligomer-induced toxicity by modulating the aggregation pathway, without substantially changing the final product of aggregation.
淀粉样β（Aβ）肽序列中有三个特定区域，其变异会在阿尔茨海默病中导致毒性增强：N端、中央盐桥和C端。在此，我们研究这三个区域之间是否存在紧密的构象联系，这可能暗示一种协同的毒性机制。我们测量了锌和姜黄素对Aβ的影响，并将其与之前报道的它们对Aβ的影响进行比较。Aβ和Aβ仅在姜黄素相互作用的C端附近有所不同，而锌在N端附近相互作用。因此，这种比较应有助于我们区分调节C端和N端的效果。我们发现，姜黄素能使含有盐桥的纤维状结构在成熟的Aβ聚集体中出现，但在Aβ中则不会。相反，我们发现锌对Aβ和Aβ的影响没有差异。在有锌存在的情况下，这两种情况都无法形成合适的纤维，盐桥仍然被破坏。这些结果表明，Aβ末端的调节可以决定序列中远处盐桥的命运，这对Aβ毒性具有重大影响。我们还推断，小分子可以通过调节聚集途径来改变寡聚物诱导的毒性，而不会实质性地改变聚集的最终产物。
