Department of Chemistry, Binghamton University, The State University of New York, Vestal, New York, USA.
Department of Chemistry, Binghamton University, The State University of New York, Vestal, New York, USA.
J Biol Chem. 2022 Oct;298(10):102491. doi: 10.1016/j.jbc.2022.102491. Epub 2022 Sep 14.
Molecular interactions between β-amyloid (Aβ) peptide and membranes contribute to the neuronal toxicity of Aβ and the pathology of Alzheimer's disease. Neuronal plasma membranes serve as biologically relevant environments for the Aβ aggregation process as well as affect the structural polymorphisms of Aβ aggregates. However, the nature of these interactions is unknown. Here, we utilized solid-state NMR spectroscopy to explore the site-specific interactions between Aβ peptides and lipids in synaptic plasma membranes at the membrane-associated nucleation stage. The key results show that different segments in the hydrophobic sequence of Aβ initiate membrane binding and interstrand assembling. We demonstrate early stage Aβ-lipid interactions modulate lipid dynamics, leading to more rapid lipid headgroup motion and reduced lateral diffusive motion. These early events influence the structural polymorphisms of yielded membrane-associated Aβ fibrils with distinct C-terminal quaternary interface structure compared to fibrils grown in aqueous solutions. Based on our results, we propose a schematic mechanism by which Aβ-lipid interactions drive membrane-associated nucleation processes, providing molecular insights into the early events of fibrillation in biological environments.
β-淀粉样蛋白（Aβ）肽与膜之间的分子相互作用导致 Aβ 的神经元毒性和阿尔茨海默病的病理学。神经元质膜作为 Aβ聚集过程的生物学相关环境，并影响 Aβ聚集物的结构多态性。然而，这些相互作用的性质尚不清楚。在这里，我们利用固态 NMR 光谱法在膜相关成核阶段研究突触质膜中 Aβ 肽与脂质之间的特定部位相互作用。主要结果表明，Aβ 疏水序列中的不同片段起始与膜的结合和链间组装。我们证明早期 Aβ-脂质相互作用调节脂质动力学，导致更快的脂质头部基团运动和减少横向扩散运动。这些早期事件影响了产生的与膜相关的 Aβ 原纤维的结构多态性，与在水溶液中生长的原纤维相比，其具有不同的 C 末端四级界面结构。基于我们的结果，我们提出了一个示意图机制，即 Aβ-脂质相互作用驱动与膜相关的成核过程，为生物环境中纤化的早期事件提供了分子见解。
