Ang-(1-7)/Mas旁路调控小胶质细胞功能状态参与AD病理进程的机制研究

Ang-(1-7)/Mas是新发现的肾素-血管紧张素系统旁路，其与AD的关联尚不明确。我们的前期研究提示：Ang-(1-7)/Mas旁路的失活与AD病程密切相关。我们的预实验结果表明：Mas受体在小胶质细胞高表达，且其可能参与调控小胶质细胞活化状态及功能。据此，我们提出“Ang-(1-7)/Mas旁路的失活使小胶质细胞活化状态及吞噬、促炎功能发生改变，从而参与AD病理进程”这一假说。在本项目中，我们拟使用Transwell细胞共培养系统及具有完整AD病理特征的3xTg小鼠，结合慢病毒介导的基因沉默技术，在细胞及活体层面验证上述假说。在此基础上，我们拟选用iPRECIO可编程微泵，观察靶向激活Ang-(1-7)/Mas旁路对3xTg小鼠AD病理特征及认知障碍的治疗作用。本项目的完成能揭示Ang-(1-7)/Mas旁路在AD病理进程中的角色，还能加深对AD发病机制的认识，并为其治疗提供新靶点。

Ang-(1-7)/Mas axis is a newly identified alternative axis of renin-angiotensin system, but its association with Alzheimer’s disease (AD) remains still unclear. Our previous studies demonstrated that inactivation of brain Ang-(1-7)/Mas axis might contribute to the pathogenesis of AD. Meanwhile, we showed that Mas, the receptor for Ang-(1-7), was highly expressed on microglia and might exert a modulatory effect on microglial activation state and pro-inflammatory and phagocytic functions. Based on these findings, we hypothesized that inactivation of brain Ang-(1-7)/Mas contributed to the pathogenesis of AD via affecting microglial activation state and pro-inflammatory and phagocytic functions. In this project, we will employ a Transwell microglial-neuronal co-culture system as well as 3xTg mice to test this hypothesis. In addition, by using a intracerebroventricular infusion strategy mediated by iPRECIO programmable electronic minipump, we intend to observe the therapeutic effects of Ang-(1-7) on AD-related pathology as well as cognitive deficits in 3xTg mice. The completion of this project will uncover the role of Ang-(1-7)/Mas axis in the pathogenesis of AD, and will offer novel target for therapies and drug development of this devastating disease.