APOE-TREM2/DAP12信号轴介导小胶质细胞表型转换在AD中的作用及补肾药对“仙茅-仙灵脾”的干预研究

The incidence of Alzheimer’s disease (AD) has been increasing year by year and has become a major problem affecting the elder’s health. The role of microglia in AD has been clearly defined, but its regulatory mechanism remains to be further determined. Recent studies have shown that APOE-TREM2/DAP12 signaling pathway may play an important role in maintaining the microglia phenotype (M1-M2) transition, thereby altering the immune and inflammatory environment in the AD focus area and ultimately influencing the survival and functions of microglia. Our preliminary study found that “Curculiginis Rhizoma and Epimedii Folium” (EX) effectively improved the symptoms of AD rats, and EX and its some compounds could induce the activation of TREM2. Therefore, the scientific hypothesis that “EX may have effect on APOE-TREM2/DAP12 signaling axis” was proposed. The in vivo and in vitro models of wild type mice (WT), APP/PS1 mice, TREM2-/- mice, APOE-/- mice and DAP12-/- mice are established to further investigate the action of APOE-TREM2 signaling, and the mechanism of EX on AD is also examined. This program is aim to provide the new targets and new drugs for the treatment of AD.

阿尔茨海默病（AD）的发病率逐年上升，已成为影响老年人健康的重大疾病。小胶质细胞在AD中的作用已经明确，但其调控机制仍有待明晰。最新研究表明，APOE-TREM2/DAP12信号可能在维持小胶质细胞表型（M1-M2）转换中起重要作用，从而改变AD病灶区的免疫炎症环境，最终影响小胶质细胞的存活与功能。项目组前期研究发现，补肾药对“仙茅-仙灵脾”（EX）能够有效改善AD大鼠的系列症状，且EX及其主要成分能激动TREM2。故提出“EX可作用于APOE-TREM2/DAP12信号轴，调控AD中小胶质细胞的表型转换，维持脑内微环境稳态”这一科学假说。拟分别制备Wild type鼠、APP/PS1鼠、TREM2-/-鼠、APOE-/-鼠和DAP12-/-鼠，建立AD的体内外模型，在深入挖掘APOE-TREM2信号传导机制的同时，开展EX防治AD的作用机制研究，以期为AD的防治提供新靶标和新药物。

小胶质细胞在AD中的作用已经明确，但其调控机制仍有待明晰。最新研究表明，APOE-TREM2/DAP12信号可能在维持小胶质细胞表型（M1-M2）转变中起重要作用，从而改变AD病灶区的免疫炎症环境，最终影响小胶质细胞的存活与功能。AD的中医病机与小胶质细胞免疫功能紊乱贯穿AD全过程是相似的，温补肾阳的药物在临床和实验研究中，体现了调节机体免疫功能改善AD的作用。通过4年的研究，我们基本弄清楚了Aβ刺激小胶质细胞后所导致的小胶质细胞形态改变，炎症因子释放增加等变化与TREM2蛋白密切相关；且补肾药对“仙茅-仙灵脾”（EX）可调控APOE-TREM2轴，介导不同表型的小胶质细胞的基因型改变，降低小鼠海马区小胶质细胞的活化程度；增加TREM2及其下游蛋白的表达，降低炎性反应。这些研究为AD的发病机制研究与防治提供了新思路。本课题共计发表论文3篇，其中SCI论文2篇（IF>5），发表专利1项，培养研究生6名（其中2名已毕业），在国际学术会议上做学术报告2次。