Nonfibrillar β-amyloid (Aβ) oligomers are considered as major neurotoxic species in the pathology of Alzheimer’s disease. The presence of Aβ oligomers was shown to cause membrane disruptions in a broad range of model systems. However, the molecular basis of such a disruption process remains unknown. We previously demonstrated that membrane-incorporated 40-residue Aβ (Aβ₄₀) oligomers could form coaggregates with phospholipids. This process occurred more rapidly than the fibrillization of Aβ₄₀ and led to more severe membrane disruption. The present study probes the time-dependent changes in lipid dynamics, bilayer structures, and peptide-lipid interactions along the time course of the oligomer-induced membrane disruption, using solid-state NMR spectroscopy. Our results suggest the presence of certain intermediate states with phospholipid molecules entering the C-terminal hydrogen-bonding networks of the Aβ₄₀ oligomeric cores. This work provides insights on the molecular mechanisms of Aβ₄₀-oligomer-induced membrane disruption.

中文翻译：

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与掺入β-淀粉样蛋白寡聚体的磷脂双层膜中随时间变化的脂质动力学，组织和肽-脂质相互作用。

非原纤维β-淀粉样蛋白（Aβ）低聚物被认为是阿尔茨海默氏病病理学中的主要神经毒性物质。在广泛的模型系统中，显示Aβ低聚物的存在会引起膜破裂。然而，这种破坏过程的分子基础仍然未知。我们先前证明，膜结合的40残基Aβ（_Aβ40）低聚物可与磷脂形成共聚集体。这个过程比_Aβ40的原纤维化更快并导致更严重的膜破裂。本研究使用固态NMR光谱探测了寡聚物诱导的膜破裂的时间过程中脂质动力学，双层结构和肽-脂相互作用的时间依赖性变化。我们的结果表明存在某些中间状态，其中磷脂分子进入_Aβ40低聚核心的C端氢键网络。这项工作提供了对Aβ的分子机制的见解₄₀ -oligomer诱导膜破坏。