Beclin 1-VPS34复合体对神经细胞内β淀粉样蛋白稳态的调控作用及机制研究

项目名称： Beclin 1-VPS34复合体对神经细胞内β淀粉样蛋白稳态的调控作用及机制研究

项目编号： No.31500831

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 神经、认识与心理学

项目作者： 路嘉宏

作者单位： 珠海澳大科技研究院

项目金额： 19万元

中文摘要： 阿尔兹海默病是最常见的神经退行性疾病。研究显示神经细胞内β淀粉样蛋白(Aβ)毒性是引起突触损伤以及记忆和认知功能障碍的重要病理机制。Beclin 1-VPS34复合体参与细胞内囊泡运输，通过各亚基调控转运，自噬，内吞和分泌等细胞过程。近年来研究发现Beclin 1-VPS34复合体功能在AD发病过程以及细胞内Aβ稳态调控过程中发挥重要作用，但具体调控机制缺乏系统研究。我们前期发现天然的Beclin 1-VPS34激活剂Corynoxine B可以降低细胞内Aβ含量，但其激活Beclin 1-VPS34通路的机制不明。本项目将系统研究Beclin 1-VPS34复合体各个亚基在细胞内Aβ稳态中的调控作用，并将深入阐明Corynoxine B激活Beclin 1-VPS34通路的分子机制。本项目将为Bcelin 1-VPS34复合体作为细胞内Aβ调控和AD治疗新靶点提供重要实验数据。

中文关键词： 阿尔茨海默病；β淀粉样蛋白；β淀粉样蛋白前体蛋白；Beclin；1-VPS34；复合体；自噬

英文摘要： Alzheimer’s disease (AD) is the most common neurodegenerative disease which is characterized by amyloid plaques and neurofibrillary tangle formation in the brain. Amyloid beta peptide (Aβ) is the major component of amyloid plaques and intra-neuronal Aβ has been regarded as the critical event leading to synaptic toxicity as well as the memory and cognitive impairment in AD. Beclin 1-VPS34 complex plays an important role in regulating cellular vesicles trafficking. Through its multiple subunits, Beclin 1-VPS34 complex modulates the trafficking, autophagy, endocytosis and secretion process. Recent discoveries indicate Beclin 1-VPS34 complex plays important roles in the pathogenesis of AD and in the regulation of intra-neuronal Aβ homeostasis. Beclin 1-VPS34 complex is involved in a wide spectrum of biological process. The function of its subunits are quite different thus likely play different roles in regulating intra-neuronal Aβ homeostasis, which needed systematic study to illustrate. In our previous study, a natural Beclin 1-VPS34 complex activator Corynoxine B (Cory B) has been identified, without knowing its molecular target. To study the molecular mechanism by which Cory B activates Beclin 1-VPS34 will provide insightful understanding towards the working model to regulate Beclin 1-VPS34 complex activity. Collectively, the purpose of this project is to systematically investigate the roles and mechanisms of Beclin 1-VPS34 complex subunits in regulating intra-neuronal Aβ homeostasis, and to illustrate the molecular mechanism by which Cory B activates Beclin 1-VPS34 complex. The findings from this project will provide important information for evaluating the potential of Beclin 1-VPS34 complex as novel therapeutic target in regulating intra-neuronal Aβ homeostasis and treating AD.

英文关键词： Alzheimer's disease;Beta amyloid peptide;Amyloid precursor protein;Beclin 1-VPS34 complex;autophagy