基于TBP2/NLRP3炎症调节通路探讨六味地黄丸改善阿尔茨海默病的作用研究

项目名称： 基于TBP2/NLRP3炎症调节通路探讨六味地黄丸改善阿尔茨海默病的作用研究

项目编号： No.U1504829

项目类型： 联合基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 宋军营

作者单位： 河南中医药大学

项目金额： 27万元

中文摘要： Aβ沉积引发的神经炎症反应是阿尔茨海默病（AD）最重要的发病机制之一，NLRP3炎症小体的活化在其中扮演重要角色。TBP2是NLRP3的上游调节因子，在AD中的作用尚不清楚。我们的前期研究发现，Aβ诱导小胶质细胞TBP2的表达及NLRP3炎症小体的活化；六味地黄丸能降低TBP2的表达，抑制胶质细胞的活化，以及改善AD小鼠的学习记忆功能。据此我们推测，Aβ诱发TBP2的增加可能对NLRP3炎症小体的活化起关键作用；六味地黄丸防治AD的作用可能是通过下调TBP2的表达而抑制神经炎症反应来实现的。因此本项目将以离体培养小胶质细胞和APP/PS1小鼠为研究对象，探讨TBP2对NLRP3炎症小体的调控作用，并观察六味地黄丸能否通过调节TBP2表达，降低NLRP3介导的炎症反应，抑制Aβ斑块的形成，改善AD小鼠的学习记忆能力。本项目可为AD的治疗提供新的靶点，以及为六味地黄丸防治AD提供理论依据。

中文关键词： 阿尔茨海默病；六味地黄丸；炎症反应；TBP2；NLRP3

英文摘要： Amyloid-β (Aβ) deposition-induced neuroinflammation is one of the most important mechanisms for the pathogenesis of Alzheimer’s disease (AD). NLRP3-mediated inflammation plays an important role in these processes. TBP2 is a critical regulator for NLRP3 activation. However, it is still unknown whether TBP2 plays roles in the pathogenesis of AD. Recently, we found that Aβ could induce TBP2 expression and activate NLRP3 inflammasome in microglia. In addition, Liuwei dihuang pill could significantly decrease NLRP3 expression, inhibit glia activation and improve the functions of learning and memory in APP/PS1 mice. These results suggest that Aβ-induced TBP2 expression is important for the activation of NLRP3 inflammasome in microglia, and the protective effects of Six-Ingredient Rehmannia pill in AD may be due to the decreased expression of TBP2 and subsequently attenuation of neuro-inflammation. Using in vitro microglia and APP/PS1 transgenic mice, the aim of the project is to examine the effects of TBP2 on NLRP3 inflammasome activation. We will also examine whether Liuwei dihuang pill could improve the functions of learning and memory through targeting TBP2, subsequently inhibiting NLRP3-mediated inflammation and reducing Aβ deposition. Our project will provide a novel therapeutic target for AD and theoretical basis for the prevention of Liuwei dihuang pill in AD.

英文关键词： Alzhemer's disease;Liuwei dihuang pill;inflammation;TBP2;NLRP3