极性蛋白Partitioning defective3 homolog (Par3) 参与阿尔兹海默症发病以及β-淀粉样蛋白蓄积的机制研究

阿尔茨海默病(AD)是老年期最常见的神经退行性疾病，患者认知障碍进行性加重。在AD的发病机理研究中，目前研究争论的焦点在于Aβ产生机制。目前研究多认为APP和BACE1的亚细胞定位改变可能直接涉及到了Aβ产生的细胞机制。申请人前期工作发现，神经元内极性蛋白Par3的缺失，可以使得神经元内APP和BACE1的定位改变，而这种改变可能直接造成细胞内Aβ蓄积。以此为重要研究基础，本课题将紧密围绕“极性蛋白Par3如何调节细胞内Aβ蓄积并因此参与AD发病”为中心，借助成熟的体外海马神经元培养基础，高分辨率激光共聚焦显微镜成像以及蛋白/转录组学研究，从以下3个方面展开研究：1 明确Par3缺失导致的细胞内Aβ蓄积发生在功能失活的溶酶体中；2 研究Par3调节溶酶体功能的相关分子机制；3在动物水平上验证Par3缺失对AD发病的促进作用。本课题将有助于明确细胞内Aβ的蓄积机制。

Alzheimer's disease is the most common neurodegenerative disease happened in elder population. Multiple genetic and environments factors are involved in AD occurence. Until now, there are many hypothesis regarding to AD occurence, and the most heavily debated topic is how and where Aβ is generated. In our previously work, we have found polarity protein Par3 could regulate APP and BACE1 intracellular distribution and thus regulate Aβ intracellular accumulation. Based on those important discovery, this proposal would be closely foused on "how polarity protein Par3 could regulate intracellular Aβ accumulation and thus involved in AD progress" through matural primary hippocampal neuronal culture, high resolution confocol living imaging and virals/plasmids transfection techanques. The current project included 3 purposes: 1 To determine whether dysfunctional lysosome/autophagosome is the original place to accumulate intracellular Aβ; 2 To examine mechanisms regulating the autophagy-lysosome degradation system by Par3; 3 To determin the role how Par3 dysfunction involved in Alzheimer’s disease progress. This proposed project would help to discover more accurate molecular mechanisms on how Par3 is involved in Alzheimer’s disease and intracellular Aβ accumulation.