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 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.

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是新发现的肾素-血管紧张素系统旁路，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，而其参与AD病理的具体机制不明。本项目主要研究内容：1、研究Ang-(1-7)/Mas旁路调控小胶质细胞促炎状态参与衰老相关神经炎症的机制；2、研究Ang-(1-7)/Mas旁路影响阿尔茨海默病样神经病理及认知功能障碍的作用；3、探明Ang-(1-7)/Mas旁路通过调控星形胶质细胞介导的神经炎症缓解AD病理进程的机制。. 结果表明：Ang-(1-7)/Mas旁路抑制SAMP8小鼠脑内Aβ1-42的沉积，tau蛋白过度磷酸化，促进小胶质细胞M2极化，抑制慢性神经炎症，改善记忆认知障碍。另外，血管紧张素-(1-7)拟似物AVE0991通过lncRNA SNHG14/ miR-230-3p/NLRP3通路调节星形细胞介导的神经炎症，并在APP/PS1双转基因小鼠模型中提供神经保护作用。