吡咯喹啉醌三锂调控小胶质细胞极化治疗阿尔茨海默病的机制

项目名称： 吡咯喹啉醌三锂调控小胶质细胞极化治疗阿尔茨海默病的机制

项目编号： No.81500907

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： 赵蕾

作者单位： 上海交通大学

项目金额： 19万元

中文摘要： 寻找有多靶点作用的药物是当前治疗阿尔茨海默病（AD）的研究热点。吡咯喹啉醌三锂（Li3PQQ）是自主合成的新型化合物，可显著改善AD小鼠的认知及病理损害。我们发现，除改善线粒体功能和抑制糖合酶激酶外，Li3PQQ还可调控小胶质细胞极化减轻炎症反应，但机制不明。锂可激活PI3K/Akt下调NF-kB，抑制有促炎作用的M1型小胶质细胞极化。而PQQ可激活Jak/STAT表达Jmjd3，促进有神经保护功能的M2型小胶质细胞极化。据此我们推测：Li3PQQ通过作用于PI3K/Akt/NF-kB及Jak/STAT/Jmjd3通路，调控小胶质细胞极化改善AD。为此，本项目拟利用激活的小胶质细胞及AD小鼠模型，明确Li3PQQ调控小胶质细胞极化的作用，阐明Li3PQQ通过PI3K/Akt/NF-kB及Jak/STAT/Jmjd3通路调控小胶质细胞极化改善AD的机制，为Li3PQQ的临床应用提供理论基础。

中文关键词： 阿尔茨海默病；吡咯喹啉醌三锂；药物治疗；小胶质细胞极化；炎症反应

英文摘要： Multiple target therapy is currently a hotspot in research of Alzheimer's disease (AD). In our previous study, we synthesized a new organic lithium salt, tri-lithium pyrroloquinoline quinonein(Li3PQQ). We showed that Li3PQQ could improve the learning and memory ability of AD mice model via facilitating hippocampus long-term potentiation, reducing cerebral amyloid deposition and phosphorylated tau level. We also found that Li3PQQ could alleviate inflammation by modulating microglia phenotype polarization. Lithum could inhibit microglia M1 phenotype polarization via upregulating PI3K/Akt and down regulating NF-kB. PQQ could benefit to microglia M2 phenotype polarization via activating Jak/STAT pathway and expressing Jmjd3. Therefore, we make hypothesis that Li3PQQ could modulate microglia phenotype polarization via interfering PI3K/Akt/NF-kB and Jak/STAT/Jmjd3 pathways. Hence we plan to utilize activated microglia and AD mice model to clarify the effect of Li3PQQ on microglia phenotype polarization, illustrate the mechanism of Li3PQQ alleviating AD via modulating microglia polarization. The present study may provide theoretical basis for the clinical application for Li3PQQ in treatment of AD.

英文关键词： Alzheimer's disease;tri-lithium pyrroloquinoline quinone;chemical therapy;microglia phenotype polarization;inflammation