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

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.

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。

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。本项目在细胞层面对NLRP3炎症小体途径进行靶向干预，研究PM2.5暴露对AD细胞模型中神经元损伤及炎症反应的影响；然后在活体层面探索PM2.5暴露对APPswe/PS1dE9转基因鼠病理学特征、脑内炎症反应及NLRP3炎症小体激活的影响。结果发现，PM2.5暴露加重AD细胞模型中神经元损伤及NLRP3炎症小体激活；PM2.5暴露加重APPswe/PS1dE9转基因鼠病理学特征、脑内炎症反应及NLRP3炎症小体激活。. 另一方面，本项目验证中文版Addenbrooke认知评估量表III（ACE-III）用于痴呆诊断的可靠性，进而比较ACE-III和MMSE的诊断精确性；结果发现：中文版ACE-III是诊断痴呆的可靠评估工具。. 本项目阐明了PM2.5增加AD发病风险的机制，将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。