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

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.

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。

国内外研究表明p38丝裂原活化蛋白激酶（p38 MAPK）及其活化转录因子2（ATF2）信号通路激活可能参与了阿尔茨海默病（AD）多个病理过程。然而p38 MAPK激活在APP代谢和Aβ生成过程中的关键性作用及机制，目前尚不清楚。本项目将应用多种细胞模型和转基因AD小鼠，通过体外、体内实验，深入探讨p38 MAPK激活对APP代谢和Aβ生成的效应作用及其分子机制；同时探讨p38 MAPK抑制剂防治AD病程进展的效应作用及其机制。. 主要研究内容和结果：（1）应用培养的人类神经母细胞瘤细胞（SH‐SYSY细胞）和转染人类瑞典突变型APP695cDNA的细胞株（SH-SYSY-APPsw细胞），采用多种实验技术方法，研究表明特异性抑制p38 MAPK/ATF2信号通路激活可能通过减少Aβ裂解酶BACE1和PS1活性表达而减少野生型和突变型Aβ生成，提示p38 MAPK/ATF2信号通路激活在人类野生型和突变型Aβ生成过程中具有关键性作用。（2）应用6月龄APPswe/PS1dE9（APP/PS1）转基因AD模型小鼠及同龄野生型小鼠；治疗组予以连续腹腔注射p38 MAPK抑制剂（SB239063）12周，对照组注射等量的安慰剂；主要结果表明p38 MAPK抑制剂-SB239063显著抑制了APP/PS1小鼠大脑皮层和海马组织中p-APP和p-p38 MAPK的含量；SB239063显著改善了APP/PS1小鼠的空间学习记忆障碍；SB239063治疗显著降低APP/PS1小鼠大脑皮质和海马中可溶性及不可溶性Aβ1-40、Aβ1-42和Aβ寡聚体的含量及其沉积；SB239063治疗显著增加APP/PS1小鼠大脑皮层和海马组织中ADAM10表达，显著降低BACE1和PS1的表达；进而明显增加α-分泌酶裂解产物—可溶性APPα（sAPPα）的含量，同时显著降低β-分泌酶裂解产物—可溶性APPβ（sAPPβ）的含量；SB239063治疗通过抑制p38 MAPK、GSK3β和Cdk5的异常活化而减少tau蛋白磷酸化水平，并上调突触相关蛋白PSD-95和SYP的表达。. 综上结果，该项研究提示p38 MAPK信号通路激活在AD病理损害过程中具有关键性作用，而其特异性抑制剂-SB239063可做为一种治疗AD的新型药物，有望为研发防治AD新药物提供新的靶点