Molecular mechanisms of membrane disruption induced by early-stage aggregation of beta-amyloid peptides

项目摘要 由于最近在开发抗淀粉样蛋白治疗策略方面的失败 阿尔茨海默病(AD)，迫切需要重新评估现有的淀粉样级联假说 方面。在所有这些努力中，β-淀粉样聚集体的生物物理和结构特征在... 体外模型系统，特别是涉及高分辨率固态核磁的工作 核磁共振波谱提供了来自基波方面的宝贵信息。然而到目前为止， 这些高分辨率的工作大多集中在淀粉样纤维或非淀粉样蛋白的原子结构上。 纤维状聚集体。很少进行高分辨率的研究来直接探测细胞 潜在的β-淀粉样多肽聚集过程诱导的膜破坏效应 与β-淀粉样蛋白聚集体的神经毒性机制有关。 阻碍β-淀粉样多肽诱导膜高分辨率研究的主要挑战 模型系统中的扰动效应是异构性的，通常涉及多个 具有混合中间结构的膜破裂途径。这项提案试图解决这个问题 通过生成具有明显的主要膜破坏效应的模型系统来解决这个问题。这些模型 含有不同β淀粉样聚集体和磷脂脂质体的体系的特征是 明显的随时间变化的膜破裂特征和结构上的同质终点。因此， 它们可以用高分辨率的单层核磁共振分别研究它们的膜破坏效应。 接近了。 这项提议的结果，如果成功，将提供关于高分辨率 β淀粉样蛋白聚集体与膜之间的分子相互作用 颠覆。这些信息有助于解释β-淀粉样聚集体的神经细胞毒性， 进一步有助于对淀粉样蛋白级联假说的重新评价。

Project Summary Because of the recent failures in the development of anti-amyloid therapeutic strategies for curing Alzheimer's disease (AD), it is prompt to re-evaluate the existing amyloid cascade hypothesis from all possible aspects. Among all these efforts, biophysical and structural characterizations of β-amyloid aggregates in in- vitro model systems, especially the works that involve the high-resolution solid-state nuclear magnetic resonance (ssNMR) spectroscopy, provide invaluable information from the fundamental sides. However so far, most of these high-resolution works have been focused on the atomic structures of either amyloid fibrils or non- fibrillar aggregates. Very little high-resolution studies have been performed to directly probe the cellular membrane disruption effects induced by the aggregation process of β-amyloid peptides, which are potentially associated with the neurotoxicity mechanisms of the β-amyloid aggregates. A major challenge that prevented the high-resolution studies of β-amyloid-peptide-induced membrane disruption effects in model systems was the heterogeneity, which usually involved co-existence of multiple membrane disruption pathways with mixed intermediate structures. This proposal attempts to solve this problem by generating model systems with distinct predominant membrane disruption effects. These model systems, which contain different β amyloid aggregates and phospholipid liposomes, are characterized by distinct time-dependent membrane disruption features and structurally homogeneous endpoints. Therefore, they can be studied individually in terms of their membrane disruption effects using high-resolution ssNMR approaches. The outcomes of this proposal, if successful, will provide crucial insights on the high-resolution molecular interactions between β amyloid aggregates and membranes that are responsible to the membrane disruption. These information help to explain the neuronal cellular toxicity of β-amyloid aggregates, which further contribute to the re-evaluation of amyloid cascade hypothesis.