Probing the roles of membrane and cholesterol on Aβ biogenesis and prion protein interactions

探讨膜和胆固醇对 Aβ 生物合成和朊病毒蛋白相互作用的作用

• 批准号: 9926884
• 负责人: JOHN E. STRAUB
• 金额: $ 37.94万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926884
• 关键词: Address; Affect; Alzheimer' s Disease; Amyloid Proteins; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Area; Binding; Biogenesis; Biophysics; Brain; Cause of Death; Cell Surface Receptors; Characteristics; Cholesterol; Collaborations; Complex; Computer Models; Computer Simulation; Computing Methodologies; Development; Disease; Elderly; Environment; Enzymes; Future; Goals; Growth; Heterogeneity; In Vitro; Knowledge; Link; Lipids; Mediating; Membrane; Membrane Lipids; Membrane Microdomains; Membrane Proteins; Methods; Molecular; Mutation; Neurodegenerative Disorders; Outcome; Pathogenicity; Pathway interactions; Play; Population; PrP; Presenile Alzheimer Dementia; Preventive; Probability; Process; Production; Proteins; Proteolytic Processing; Research; Research Proposals; Role; Route; Senile dementia; Structural Protein; Structure; Symptoms; System; Therapeutic; Toxic effect; Transmembrane Domain; United States; abeta accumulation; abeta oligomer; amyloid precursor protein processing; cofactor; computer studies; conformational conversion; cytotoxicity; experimental study; familial Alzheimer disease; fundamental research; insight; monomer; neuron loss; novel; protein aggregation; protein function; receptor; receptor binding; secretase; simulation; theories

Project Summary Aggregation of proteins of known sequence is linked to a variety of neurodegenerative disorders. Familial mutations in the Amyloid Precursor Protein (APP), from which the amyloid β (Aβ) protein is derived, have been linked with the early onset of Alzheimer's disease (AD). After fifteen years of fundamental research using computer simulations guided by experiments to identify the factors that determine in vitro aggregation of Aβ, the stage is now set to address questions of utmost relevance to AD. They arise in the context of how heterogeneous membrane environments, cholesterol, and downstream interactions with cofactors affect the cleavage of APP, the production of Aβ, and subsequent interactions of Aβ oligomers and receptors mediating their toxic effects. We are uniquely poised to use computational models to answer these questions and drive advances in critical areas of AD research. In this computational and theoretical research proposal, augmented by synergistic experimental research collaborations, we address fundamental biophysical questions with substantial practical implications articulated in three specific aims. (1) Developing a quantitative understanding of how membrane lipid composition and structural heterogeneity impacts the partitioning of APP and secretases critical to the processing of APP in the genesis Aβ. (2) Elucidating the crucial role cholesterol plays in determining the extent of amyloidogenic cleavage in the differential processing of APP. (3) Characterizing at the molecular-level the conformational transitions and interactions involved in the binding of Aβ monomer and oligomers to cellular prion protein (PrPC), implicated in a plausible mechanism of Aβ cytotoxicity. The proposed coordinated studies will lead to a fundamental molecular-level understanding of the network of interactions that are essential to the biogenesis of Aβ protein and its role as a pathogenic agent in AD. Through the development of novel computational models and identification of new concepts, the expected outcomes could change the landscape for the use of simulations and theory not only in the AD field but also in the general study of membrane- protein interactions.!

项目摘要 已知序列的蛋白质的聚集与多种神经退行性 疾病。淀粉样前体蛋白（APP）中的家族突变，淀粉样蛋白β （Aβ）蛋白质被得出，已与阿尔茨海默氏病（AD）的早期发作有关。后 使用实验指导的计算机模拟进行了十五年的基础研究 确定确定Aβ体外聚集的因素，现在将阶段设置为解决 与AD最相关的问题。它们是在异质性的背景下出现的 膜环境，胆固醇和与辅因子的下游相互作用会影响 APP的切割，Aβ的产生以及Aβ低聚物和随后的相互作用 受体介导其毒性作用。我们很毒，可以使用计算模型 回答这些问题并推动广告研究关键领域的进步。 在这项计算和理论研究建议中，由协同实验增强 研究合作，我们以实质性的方式解决了基本的生物物理问题 在三个特定目标中阐明的实际含义。 （1）开发定量 了解膜脂质组成和结构异质性如何影响 APP的分区和对GenesisAβ中APP处理至关重要的分泌。 （2） 阐明胆固醇在确定淀粉样蛋白原的程度方面的关键作用 在应用程序的差分处理中进行分解。 （3）以分子级为特征 与Aβ单体结合涉及的构象转变和相互作用 在Aβ细胞毒性的合理机制中暗示的寡聚物与细胞prion蛋白（PRPC）。 提出的协调研究将导致对分子级的基本理解 相互作用网络对Aβ蛋白的生物发生至关重要及其作用 AD中的致病剂。通过开发新颖的计算模型和 识别新概念，预期的结果可能会改变使用的景观 模拟和理论不仅在AD领域，而且在膜的一般研究中 蛋白质相互作用。！