The early oligomerization of amyloid β-protein (Aβ) is a crucial step in the etiology of Alzheimer's disease (AD), in which soluble and highly neurotoxic oligomers are produced and accumulated inside neurons. In search of therapeutic solutions for AD treatment and prevention, potent inhibitors that remodel Aβ assembly and prevent neurotoxic oligomer formation offer a promising approach. In particular, several polyphenolic compounds have shown anti-aggregation properties and good efficacy on inhibiting oligomeric amyloid formation. 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose is a large polyphenol that has been shown to be effective at inhibiting aggregation of full-length Aβ1-40 and Aβ1-42, but has the opposite effect on the C-terminal fragment Aβ25-35. Here, we use a combination of ion mobility coupled to mass spectrometry (IMS-MS), transmission electron microscopy (TEM) and molecular dynamics (MD) simulations to elucidate the inhibitory effect of PGG on aggregation of full-length Aβ1-40 and Aβ1-42. We show that PGG interacts strongly with these two peptides, especially in their N-terminal metal binding regions, and suppresses the formation of Aβ1-40 tetramer and Aβ1-42 dodecamer. By exploring multiple facets of polyphenol-amyloid interactions, we provide a molecular basis for the opposing effects of PGG on full-length Aβ and its C-terminal fragments.

中文翻译：

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1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose 与 N 端金属结合区结合，抑制淀粉样蛋白 β-蛋白寡聚体和原纤维的形成

淀粉样蛋白 β 蛋白 (Aβ) 的早期寡聚化是阿尔茨海默病 (AD) 病因学中的关键步骤，其中可溶性和高度神经毒性的寡聚体在神经元内产生并积累。在寻找用于 AD 治疗和预防的治疗解决方案时，重塑 Aβ 组装和防止神经毒性寡聚体形成的强效抑制剂提供了一种有前景的方法。特别是，几种多酚化合物已显示出抗聚集特性和抑制低聚淀粉样蛋白形成的良好功效。1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose 是一种大的多酚，已被证明可有效抑制全长 Aβ1-40 和 Aβ1-42 的聚集，但具有对 C 端片段 Aβ25-35 产生相反的影响。在这里，我们使用了离子淌度与质谱联用 (IMS-MS) 的组合，透射电子显微镜 (TEM) 和分子动力学 (MD) 模拟阐明 PGG 对全长 Aβ1-40 和 Aβ1-42 聚集的抑制作用。我们表明 PGG 与这两种肽强烈相互作用，尤其是在它们的 N 端金属结合区域，并抑制 Aβ1-40 四聚体和 Aβ1-42 十二聚体的形成。通过探索多酚-淀粉样蛋白相互作用的多个方面，我们为 PGG 对全长 Aβ 及其 C 端片段的相反作用提供了分子基础。并抑制 Aβ1-40 四聚体和 Aβ1-42 十二聚体的形成。通过探索多酚-淀粉样蛋白相互作用的多个方面，我们为 PGG 对全长 Aβ 及其 C 端片段的相反作用提供了分子基础。并抑制 Aβ1-40 四聚体和 Aβ1-42 十二聚体的形成。通过探索多酚-淀粉样蛋白相互作用的多个方面，我们为 PGG 对全长 Aβ 及其 C 端片段的相反作用提供了分子基础。