p38 MAPK/ATF2信号通路对BACE1表达和Aβ生成的调控作用及其分子机制

项目名称： p38 MAPK/ATF2信号通路对BACE1表达和Aβ生成的调控作用及其分子机制

项目编号： No.81471111

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 苗建亭

作者单位： 中国人民解放军第四军医大学

项目金额： 75万元

中文摘要： 阿尔茨海默病(AD)是最常见的老年痴呆类型，迄今尚无特异性的防治措施。我们近期的初步研究结果表明活化的p38 MAPK在APPswe/PS1dE9小鼠脑内显著增高并分布于淀粉样斑块周围以及胶质细胞和神经元中；其特异性抑制剂可显著减少BACE1表达以及APP裂解产物C99和Aβ生成，提示p38 MAPK激活可能在AD多个病理损害途径中具有重要作用。BACE1裂解野生型和突变型APP代谢导致Aβ过量生成是散发性和家族性AD发病的重要病理学基础，然而p38 MAPK及其活化转录因子2(ATF2)激活在调控BACE1表达以及APP代谢和Aβ生成过程中的关键性作用及其分子机制，目前尚不清楚。本项目将应用多种细胞模型、转基因AD小鼠和快速老化小鼠，通过体外、体内实验，深入阐明p38 MAPK/ATF2信号通路对BACE1表达和Aβ生成的调控作用及其分子机制，有望为研发防治AD新药物提供新的靶点。

中文关键词： 阿尔茨海默病；认知障碍；β-淀粉样蛋白

英文摘要： Alzheimer's disease (AD) is a clinical common form of senile dementia. There is no specific treatment for this disorder so far. The primary results of our recent studies have shown that activated p38 MAPK was markedly increased, distributed aroud amyloid plaque and colocalized with glial cell and neurons in APPswe/PS1dE9 mice; its specific inhibitor might reduce BECE1 expression, APP cleavaged product-C99 and Aβ production; The findings suggest that p38 MAPK activation might play an important role in multiple pathological pathways of AD. Wild-type and mutant APP cleavaged by BACE1 leading to Aβ overproduction is the major pathological basis of sporadic and familial AD, however it remains unclear about the critical role and molecular mechanisms of p38 MAPK activation and its activating transcription factor 2 (ATF2) in regulating BACE1 expression, APP metabolism and Aβ generation. In this study, multiple cell models, transgenic AD mice and senescence accelerated mice were used to investigate the efficacy and molecular mechanisms of p38 MAPK/ATF2 pathway in regulating BACE1 expression and Aβ generation, which would provide new tagart for developing novel drugs against AD.

英文关键词： Alzheimer's disease;Cognitive deficits;Amyloid-beta protein