PLA2G6基因突变在AD中介导线粒体自噬异常与慢性神经炎症发生的机制研究

神经慢性炎症是AD发生的重要事件，研究表明线粒体自噬异常可诱发炎症反应并介导细胞死亡或凋亡；单核-巨噬细胞系统凋亡、死亡使得中枢系统对细胞碎片、Aβ等吞噬及代谢能力下降，从而进一步促进中枢慢性神经炎症发生。前期我们的研究结果表明促进单核-巨噬细胞系统对Aβ吞噬可通过TLRs通路有效减少炎症反应并显著改善痴呆模型动物认知功能。研究已表明PLA2G6基因与AD发病相关，其在介导神经细胞凋亡、线粒体自噬、中枢慢性神经炎症中发挥极其重要的作用，然而尚不明确其在AD的致病具体机制。本研究将通过建立PLA2G6基因干扰敲除与过表达及基因位点突变的细胞及动物模型，采用流式细胞、细胞与组织电镜、免疫组化、行为学测试等手段从分子、细胞、组织以及整体水平研究其与线粒体自噬、中枢慢性炎症发生的关系；进一步探讨该基因突变与线粒体自噬及炎症发生的作用机制，基于“土壤-种子”理论学说初步探讨其在AD发病的过程。

Chronic neuroinflammation is a significant event that underpins Alzheimer disease (AD). Studies have shown that abnormal mitochondrial autophagy induces inflammation and mediates cell death or apoptosis; The apoptosis of mononuclear phagocyte system diminishes the engulfment of cell debris or Aβ by the central nervous system, which further promotes the pathogenesis of chronic neuroinflammation. Our previous researches showed that enhancement of Aβ plaques phagocytosis by the monocyte-macrophage system effectively diminished neuroinflammation through the TLRs pathway and significantly ameliorated cognitive decline in mouse models. Studies have implicated that PLA2G6 is associated with AD, it plays a crucial role in mediating neuronal apoptosis, mitophagy, and chronic neuroinflammation. However, the specific pathogenesis of PLA2G6 in AD is uncertain. Here we generate models of mouse and cell by knocking out (KO) locus mutation to assess the interaction of PLA2G6 with mitophagy and chronic neuroinflammation at the molecular and cellular level using FACS analysis, Electron Microscopy Study, Immunohistochemical Staining, Behavioral Assessments. Therefore, we preliminarily explore the effects of PLA2G6 in the pathogenesis of AD on the basis of "Soil-Seed" Theory.