补肾化痰中药复方对3×Tg-AD转基因小鼠脑内未折叠蛋白反应的调节机制研究

项目名称： 补肾化痰中药复方对3×Tg-AD转基因小鼠脑内未折叠蛋白反应的调节机制研究

项目编号： No.81503625

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： 张学凯

作者单位： 北京中医药大学

项目金额： 18万元

中文摘要： 背景：β-淀粉样蛋白(Aβ)和过度磷酸化Tau蛋白(P-Tau)堆积是阿尔茨海默病（AD）的主要病理改变，目前认为这些病理蛋白的出现与脑内未折叠蛋白反应(UPR)失调密切相关。AD属于中医痴呆范畴，肾虚痰浊是其主要病机。前期研究发现补肾化痰方-金思维能显著改善患者认知、减少模型Aβ沉积，其是否通过调节UPR起效？具体作用机制如何？目的：在观察金思维对AD转基因小鼠药效学指标的基础上，进一步研究金思维对小鼠脑内UPR及三条通路的影响。方法：应用跳台实验和Morris水迷宫检测小鼠空间记忆学习能力，应用免疫组化和Western blot对AD病理标志Aβ、Tau，UPR标记物GRP78/Bip，以及UPR的PERK/eIF2α途径、IRE-1/XBP1途径、ATF6途径的关键蛋白进行检测。意义：揭示AD转基因小鼠脑内UPR的改变，明确金思维对UPR的调节作用及具体作用靶点。

中文关键词： 补肾化痰；3×Tg-AD转基因小鼠；未折叠蛋白反应；阿尔茨海默病；中药复方

英文摘要： Background: β-amyloid deposition and hyperphosphorylated tau are two core pathological changes in Alzheimer's disease (AD), which have been found closely related with the dysregulation of unfolded protein response (UPR). AD can be classified as Chidai in Chinese medicine, and its main mechanism is the kidney deficiency and phlegm-turbidity. Jinsiwei, a effective herbal formula developed by our team according to reinforcing kidney and clearing phlegm method, which has been found effectively in improving patient cognition and reducing Aβ deposition in mouse model. Whether Jinsiwei exert such effects via adjusting UPR? And its specific targets are not investigated yet. Aim: Present research aims at observing the influence of Jinsiwei on behavioral, hippocampal and cortical pathological (β-amyloid and hyperphosphorylated tau depositions) changes in AD transgenic mouse and then observing influence of Jinsiwei on changes of UPR and its three classical signaling pathways in AD mouse. Method: Diving platform experiment and Morris water maze experiment will be used to check memory and behavior of AD transgenic mouse; immunohistochemisty and Western blot will be used to test expressions of AD pathological markders β-amyloid and tau, UPR markder GRP78/Bip and key proteins in UPR pathways of PERK/eIF2α pathway, IRE-1/XBP1 pathway, and ATF6 pathway. Application: The whole picture of UPR in AD transgenic mouse will be depicted and pharmaceutical targets in UPR pathways of herbal formula with reinforcing kidney clearing phlegm will be revealed.

英文关键词： Boosting kidney and clearing phlegm;3×Tg-AD transgenic mouse ;unfolded protein response ;Alzheimer's disease;Herbal formula