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

β-淀粉样肽早期聚集诱导膜破坏的分子机制

基本信息

批准号：
10319959
负责人：
Wei Qiang
金额：
$ 27.65万
依托单位：
STATE UNIVERSITY OF NY,BINGHAMTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319959
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Amyloid Amyloid Fibrils Amyloid beta-Protein Architecture Binding Biological Models Biophysics Cell membrane Cellular Membrane Development Environment Evaluation Extravasation Failure Goals Heterogeneity Individual Lead Lipids Liposomes Membrane Modeling Molecular Morphology NMR Spectroscopy Nature Neurons Nuclear Outcome Pathologic Pathway interactions Peptides Phospholipids Physiological Play Problem Solving Process Protocols documentation Regulation Resolution Role Side Societies Structure Synapses Synaptic Membranes System Techniques Therapeutic Time Vesicle Work abeta accumulation abeta toxicity amyloid peptide beta pleated sheet biophysical properties design experimental study in vitro Model insight neurotoxic neurotoxicity oAβ prevent solid state nuclear magnetic resonance

项目摘要

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.

项目摘要由于最近的抗淀粉样疗法治疗策略的发展失败阿尔茨海默氏病（AD），促使人们从所有可能的情况下重新评估现有的淀粉样蛋白级联假设方面。在所有这些努力中，β-淀粉样蛋白聚集体的生物物理和结构特征体外模型系统，尤其是涉及高分辨率固态核磁的作品共振（SSNMR）光谱法提供了来自基本方面的宝贵信息。但是到目前为止这些高分辨率作品中的大多数都集中在淀粉样蛋白原纤维或非 - 的原子结构上纤维骨料。几乎没有进行高分辨率研究以直接探测细胞由β-淀粉样肽的聚集过程引起的膜破坏作用，这可能是与β-淀粉样蛋白聚集体的神经毒性机制相关。一项主要挑战，阻止了对β-淀粉样蛋白诱导的膜的高分辨率研究模型系统中的破坏效应是异质性，通常涉及多重的共存具有混合中间结构的膜破坏途径。该建议试图解决这个问题通过生成具有不同主要膜破坏效应的模型系统来解决问题。这些模型包含不同β淀粉样蛋白聚集体和磷脂脂质体的系统的特征是独特的时间依赖性膜破坏特征和结构均匀的终点。所以，它们可以使用高分辨率SSNMR来单独研究其膜破坏效果方法。如果成功的话，该提案的结果将提供有关高分辨率的关键见解负责膜的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元细胞毒性，该毒性是进一步有助于重新评估淀粉样蛋白级联假设。