mTOR-STAT3-Notch信号通路介导的自噬在ALDH2改善阿尔茨海默病认知障碍中的作用

项目名称： mTOR-STAT3-Notch信号通路介导的自噬在ALDH2改善阿尔茨海默病认知障碍中的作用

项目编号： No.81471409

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 葛伟

作者单位： 中国人民解放军第四军医大学

项目金额： 70万元

中文摘要： ALDH2是介导细胞内源性保护的关键物质。据报道，ALDH2基因缺失增加患AD风险；ALDH2敲除小鼠更易遭受氧化应激损伤、导致AD。新近Nature报道自噬在AD发生发展中起着至关重要的作用。我们前期研究结果显示ALDH2过表达确能改善AD鼠认知障碍，并伴有AD鼠自噬蛋白LC3BII显著上调、自噬上游信号分子mTOR-STAT3-Notch下调，提示ALDH2改善AD认知障碍可能通过激活mTOR-STAT3-Notch介导的自噬起作用。然而ALDH2发挥AD神经保护的自噬机制及其关键信号分子是什么？AD中自噬是敌是友？国内外未见明确报道。本研究拟应用国际首创的ALDH2过表达AD小鼠模型，从行为学、组织学、细胞生物学、生理学等多方位、全面深入探讨ALDH2改善AD认知障碍中mTOR-STAT3-Notch介导自噬及其作用地位。为ALDH2应用于AD治疗提供证据，为AD药物研发开辟思路

中文关键词： 阿尔茨海默病；自噬；乙醛脱氢酶2；神经系统老化

英文摘要： More and more evidence shows that aldehyde dehydrogenase-2 (ALDH2) is the key mediator of endogenous cytoprotection. It's reported that ALDH2 gene deficiency results in an elevated incidence of Alzheimer's Disease (AD), and ALDH2-knockout mice are more susceptible to oxidative stress injury, age-related neurodegenerative diseases and amnesia. Recently Nature reported that the autophagy plays a crucial role in the occurrence and development of AD. Our previous study showed overexpression of ALDH2 can improve the cognitive impairment in AD mice, accompanied by AD mice significantly upregulated autophagy related protein, and down-regulation of upstream signal molecule mTOR-STAT3-Notch of autophagy, suggesting that ALDH2 may play a role in improving cognitive impairment of AD by activating mTOR-STAT3-Notch mediated autophagy. However, what is the key signalling contribute to ALDH2-induced neuroprotection against recognitive dysfunction and autophagy under AD? Autophagy under AD is a friend or enemy? They are not clear. In this project, the ALDH2 overexpressed AD mouse will be used which is our lab's initiative. To give a deep insight into the autophagy mechanism of neuroprotective effect of ALDH2 on improving cognitive dysfunction in AD, the methods such as behavior study, histology, cell biology and physiology will be used. The study will provide direct evidence for ALDH2 used in the AD treatment, and broaden the new concepts in discovering drugs in AD treatment.

英文关键词： Alzheimer's Disease;Autophagy;Aldehyde Dehydrogenase-2 (ALDH2);Aging of the Nervous System