大气细颗粒物PM2.5通过NLRP3炎症小体途径促进阿尔茨海默病的机制研究

项目名称： 大气细颗粒物PM2.5通过NLRP3炎症小体途径促进阿尔茨海默病的机制研究

项目编号： No.81500916

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 时建铨

作者单位： 南京医科大学

项目金额： 17.5万元

中文摘要： 近期，一项大样本临床研究提示大气细颗粒物（PM2.5）暴露显著增加阿尔茨海默病（AD）发病风险，然具体机制不明。NLRP3炎症小体途径能调节小胶质细胞（MG）功能影响AD发病。预实验证实PM2.5暴露显著增加APPswe/PS1dE9转基因鼠脑内β淀粉样蛋白（Aβ）的沉积；同时，PM2.5显著上调Aβ预处理BV-2细胞NLRP3炎症小体的活性及分泌IL-1β的水平。本课题拟深入探索PM2.5暴露对APPswe/PS1dE9转基因鼠行为学特征、病理学特征、脑内炎症反应及NLRP3炎症小体激活的影响；同时，运用慢病毒为载体的基因过表达及干扰技术，在活体层面和细胞层面对NLRP3炎症小体途径进行靶向干预，研究其对APPswe/PS1dE9转基因鼠病理特征/行为特征的影响及对小胶质细胞功能的调控，以全面阐明PM2.5增加AD发病风险的机制，为开发特异性干预策略及制定国家公共卫生政策提供理论依据。

中文关键词： 阿尔茨海默病；细颗粒物PM2.5；NLRP3炎症小体；小胶质细胞；炎性反应

英文摘要： Recently, a large-scale cohort study suggested that long-term exposure to PM2.5 were associated with increased risk of newly diagnosed Alzheimer's disease (AD). But the detailed mechanisms need to be clarified. NLRP3 inflammasome plays a key role in regulating microglial function in AD. In our preliminary studies, we provided the evidence that PM2.5 exposure was associated with elevated Amyloid Beta (Aβ) deposition in APPswe/PS1dE9 transgenic mice. Meanwhile, PM2.5 increased the activity of NLRP3 inflammasome and the secretion of IL-1β in BV-2 cell. Based on these findings, we intend to investgate the effects of PM2.5 exposure on neuropathology, cognition, neuroinflammation and the activity of NLRP3 inflammasome in APPswe/PS1dE9 transgenic mice. Afterwards, we intend to manipulate NLRP3 inflammasome using lentivirus vectors to reveal its modulation on neuropathology, cognition in APPswe/PS1dE9 transgenic mice as well as function of microglia. The completion of this project will clarify the mechanisms that PM2.5 exposure increased the risk of AD. It will provide a basis to develop specific intervention strategies and make national public health policy.

英文关键词： Alzheimer's disease ;fine particulate matter ;NLRP3 inflammasome ;microglia;inflammation