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

项目摘要 由于最近在抗淀粉样蛋白治疗策略的发展中失败， 阿尔茨海默病（AD），这是提示重新评估现有的淀粉样蛋白级联假说，从所有可能的 方面在所有这些努力中，β-淀粉样蛋白聚集体的生物物理学和结构特征， 体外模型系统，特别是涉及高分辨率固态核磁共振的工作， 核磁共振（ssNMR）光谱，提供了宝贵的信息，从基本方面。然而到目前为止， 这些高分辨率的工作大多集中在淀粉样蛋白原纤维或非淀粉样蛋白原纤维的原子结构上， 纤维状聚集体。很少有高分辨率的研究已经进行了直接探测细胞 β-淀粉样肽的聚集过程诱导的膜破裂效应，这可能是 与β-淀粉样蛋白聚集体的神经毒性机制相关。 阻碍β-淀粉样肽诱导的膜的高分辨率研究的主要挑战 模式系统的干扰效应是异质性，通常涉及多种干扰的共存 具有混合中间结构的膜破坏途径。该提案试图解决这一问题 通过生成具有不同的主导膜破坏效应的模型系统来解决问题。这些模型 含有不同β淀粉样蛋白聚集体和磷脂脂质体的系统的特征在于： 不同的时间依赖性膜破裂特征和结构均匀的终点。因此，我们建议， 可以使用高分辨率ssNMR单独研究它们的膜破坏效应 接近。 这项提案的结果如果成功，将为高分辨率 β淀粉样蛋白聚集体和膜之间的分子相互作用， 破坏这些信息有助于解释β-淀粉样蛋白聚集体的神经细胞毒性， 进一步有助于重新评估淀粉样蛋白级联假说。

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.