五味子醇甲靶向作用Caspase-1双向调控AS-M1/M2表型转化介导AD神经元保护作用的机制研究

Neural immune microenvironment mediated by astroglial M1/M2 polarization plays a crucial role in the pathogenesis and development in Alzheimer’s disease. We separated and purified schizandrin from Schisandra chinensis. It was found that schizandrin improved the cognitive deficits of APP/PS1 transgenic mice, and was distributed into the brain. SIN repolarized astrocyte from M1 to M2 phenotype regulated by JAK/STATs signaling and accompanied with the decreased Caspase-1 expression. Bioinformatics predicted that SIN bound with the active binding sites Arg341, Arg179, suggesting that SIN possibly regulated astroglial M1/M2 polarization by targeting Caspase-1 so as to play the beneficial role in protecting the AD neurons. However, it still needs to be further studied. In this study, based on the results of repolarizing astroglial M1 to M2 phenotype by SIN treatment, we illuminate that SIN inhibits the activity of Caspase-1 to mediate the AS-M1/M2 polarization via JAK/STATs pathway. Furthermore, it was revealed the key binding sites and the action pattern of Caspase-1 interacting with SIN. The present study will provide new ideas on the neuro-immune microenvironment mediated by astroglial M1/M2 polarization and the neuroprotective efficacy on AD neurons, and find out novel targets for AD therapy.

星形胶质细胞（AS）M1/M2表型转化介导神经免疫微环境，与AD发生发展密切相关。申请者分离纯化得到五味子有效提取物五味子醇甲（SIN），发现其改善APP/PS1小鼠认知障碍，并可透过血脑屏障；SIN诱导AS-M2极化伴Caspase-1下调且与JAK/STATs通路相关；信息学预测SIN与Caspase-1活性口袋Arg341、Arg179结合，提示SIN可能通过与Caspase-1关键位点结合双向调控AS-M1/M2表型转化发挥AD神经元保护作用，但尚需证实。本项目拟在明确SIN调控AS-M1/M2表型转化的基础上，阐明SIN通过抑制Caspase-1活性介导JAK/STATs通路双向调控AS-M1/M2表型转化发挥神经元保护的分子机制，并进一步明确SIN与Caspase-1结合的关键位点与作用方式。本研究为深入研究AS表型转化介导神经免疫微环境对AD神经元保护作用提供新思路和新靶点。

星形胶质细胞（AS）M1/M2表型转化介导神经免疫微环境，与AD发生发展密切相关。本课题首先分离纯化得到五味子有效提取物五味子醇甲（SIN），实验证实其具有改善APP/PS1小鼠认知障碍功能，并可透过血脑屏障；同时实验证实SIN可以通过诱导AS-M2极化伴Caspase-1下调且与JAK/STATs通路相关；信息学预测SIN与Caspase-1活性口袋Arg341、Arg179结合，经具体实验证实 SIN发挥AD神经元保护作用通过与Caspase-1活性口袋关键位点结合，靶向抑制Caspase-1蛋白活性，从而抑制JAK2/STAT1介导的M1通路、激活JAK/STAT6介导的M2通路，双向调控AS-M1/M2表型转化改善神经免疫微环境，发挥AD神经元保护作用。在此基础上，我们通过建立基于代谢组学/肠道菌群关联分析的AD疾病标志物发现与诊断精准用药关键技术体系，绘制AD疾病的肠道菌群特征和代谢谱，鉴定AD疾病的潜在生物标志物，确定肠道菌群影响AD发生发展的潜在途径，最后结合Spearman相关性分析方法，探讨菌群的增减与宿主代谢产物的水平变化的相关性。为深入研究SIN抗AD作用提供新思路，为AD治疗新策略提供实验基础。