Amyloid-β (Aβ) aggregation and neuroinflammation are consistent features in Alzheimer's disease (AD) and strong candidates for the initiation of neurodegeneration. S100B is one of the most abundant proinflammatory proteins that is chronically up-regulated in AD and is found associated with senile plaques. This recognized biomarker for brain distress may, thus, play roles in amyloid aggregation which remain to be determined. We report a novel role for the neuronal S100B protein as suppressor of Aβ42 aggregation and toxicity. We determined the structural details of the interaction between monomeric Aβ42 and S100B, which is favored by calcium binding to S100B, possibly involving conformational switching of disordered Aβ42 into an α-helical conformer, which locks aggregation. From nuclear magnetic resonance experiments, we show that this dynamic interaction occurs at a promiscuous peptide-binding region within the interfacial cleft of the S100B homodimer. This physical interaction is coupled to a functional role in the inhibition of Aβ42 aggregation and toxicity and is tuned by calcium binding to S100B. S100B delays the onset of Aβ42 aggregation by interacting with Aβ42 monomers inhibiting primary nucleation, and the calcium-bound state substantially affects secondary nucleation by inhibiting fibril surface-catalyzed reactions through S100B binding to growing Aβ42 oligomers and fibrils. S100B protects cells from Aβ42-mediated toxicity, rescuing cell viability and decreasing apoptosis induced by Aβ42 in cell cultures. Together, our findings suggest that molecular targeting of S100B could be translated into development of novel approaches to ameliorate AD neurodegeneration.

中文翻译：

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神经元 S100B 蛋白是β-淀粉样蛋白聚集的钙调节抑制剂。

淀粉样蛋白-β (Aβ) 聚集和神经炎症是阿尔茨海默病 (AD) 的一致特征，并且是神经退行性变开始的有力候选者。S100B 是最丰富的促炎蛋白之一，在 AD 中长期上调，并且发现与老年斑有关。因此，这种公认的大脑窘迫生物标志物可能在淀粉样蛋白聚集中发挥作用，但仍有待确定。我们报告了神经元 S100B 蛋白作为 Aβ42 聚集和毒性抑制剂的新作用。我们确定了单体 Aβ42 和 S100B 之间相互作用的结构细节，这有利于钙与 S100B 结合，可能涉及将无序 Aβ42 构象转换为锁定聚集的 α-螺旋构象异构体。从核磁共振实验中，我们表明，这种动态相互作用发生在 S100B 同源二聚体界面裂缝内的混杂肽结合区域。这种物理相互作用与抑制 Aβ42 聚集和毒性的功能作用相结合，并通过钙与 S100B 的结合来调节。S100B 通过与抑制初级成核的 Aβ42 单体相互作用来延迟 Aβ42 聚集的开始，并且钙结合状态通过 S100B 与生长中的 Aβ42 低聚物和原纤维结合抑制原纤维表面催化反应来显着影响次级成核。S100B 保护细胞免受 Aβ42 介导的毒性，挽救细胞活力并减少细胞培养物中 Aβ42 诱导的细胞凋亡。一起，