虫草素诱导MG-M2表型转化上调NGF表达介导AD神经元保护作用的分子机制

项目名称： 虫草素诱导MG-M2表型转化上调NGF表达介导AD神经元保护作用的分子机制

项目编号： No.81501098

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： 刘明妍

作者单位： 中国医科大学

项目金额： 19万元

中文摘要： MG-M1/M2表型转化介导神经免疫微环境影响AD发生发展。申请者发现：抗AD药物调节NGF-TrkA/p75NTR通路平衡发挥神经保护作用；虫草素改善APP/PS1小鼠认知障碍与脑内M1/M2表型标志物及NGF表达相关，并伴有CREB激活；信息学预测CREB可与NGF启动子结合调控NGF表达，提示JAK/CREB通路参与虫草素诱导MG-M2表型转化上调NGF分泌与表达，并通过神经元NGF-TrkA/p75NTR通路平衡发挥AD神经元保护作用，但尚需研究证实。本项目在确认CREB调控NGF表达关键位点基础上，阐明虫草素诱导MG-M2表型转化通过JAK/CREB通路介导NGF表达的分子机制，明确虫草素诱导MG-M2表型转化上调NGF表达调控AD神经元NGF-TrkA/p75NTR通路平衡介导AD神经元保护作用。本研究为深入探讨MG表型转化介导免疫微环境与AD发生发展相关性提供新思路和新靶点。

中文关键词： 虫草素；小胶质细胞M1/M2表型转化；神经生长因子；JAK/CREB通路；阿尔茨海默病

英文摘要： Neuro-immune microenvironment mediated by microglial M1/M2 polarization is the crucial factor for the pathogenesis and development in Alzheimer’s disease. In previous studies, we found that anti-AD drugs exerted the neuroprotective effects by adjusting the balance of NGF-TrkA/p75NTR signaling. Cordycepin improved the cognitive deficits of APP/PS1 transgenic AD mice, promoted microglial M2 polarization and increased NGF expression, accompanied by the enhanced CREB phosphorylation. Bioinformatics predicted that CREB bound with NGF promoter to regulate the NGF transcription. The results above mentioned suggested that cordycepin increased NGF expression by promoting microglial M2 polarization to elicit the anti-AD effects via balancing the NGF-TrkA/p75NTR signaling in AD neurons . However, it still needs to be further studied. In this study, based on the key CRE site confirmation of CREB bound with NGF promoter to reveal that cordycepin promoted microglial M2 polarization to secrete NGF via JAK/CREB signaling. Furthermore, it was testified that the neuronal beneficial effects of the secreted NGF upregulated by cordycepin-induced microglial M2 polarization was mediated by the balance of NGF-TrkA/p75NTR signaling in AD neurons by MG/neuron co-culture. The study will provide new ideas on the interaction between neuro-immune microenvironment modulated by microglial polarization and the progression and development of AD, and find novel targets for AD therapy.

英文关键词： Cordycepin;Microglia M1/M2 polarization;Nerve growth factor;JAK/CREB sigaling;Alzheimer's disease