MLK/JNK/c-Jun信号通路调控APP代谢及Aβ生成的效应作用及其机制

Considerable evidence indicates that signaling pathway of c-Jun N-terminal kinase (JNK) might be likely involved in the pathological process of Alzheimer's disease (AD). The primary results of our recent studies have shown that activated JNK was markedly increased and colocalized with senile plaque, glial cell, and neurons in APP/PS1 mice, as well as its inhibitor might reduce APP metabolism, suggesting that JNK activation might play an important role in multiple pathological pathways. Although wild-type and mutant APP over-expression and Aβ over-production are important pathological basis of sporadic and familial AD, it remains unclear about the key role and mechanism of JNK activation in wild-type and mutant APP metabolism and Aβ generation. In this study, JNK knock-out mice, transgenic AD mice, and multiple cell models were used to investigate the effect and mechanism of JNK, its kinase-MLK, and down-stream gene-c-Jun on wild-type and mutant APP metabolism and Aβ generation, as well as the effect and mechanism of JNK and MLK inhibitors in preventing and treating AD. This study would provide new tagarts for developing novel drugs against AD.

研究表明c-Jun氨基末端激酶（JNK）信号转导通路可能参与了阿尔茨海默病（AD）病理过程。我们近期的初步研究结果表明激活的JNK在APP/PS1小鼠脑内显著增高并与老年斑、胶质细胞、神经元共存，其抑制剂可减少APP代谢，提示JNK激活可能在AD多个病理损害途径中具有重要作用。尽管野生型和突变型APP过量表达和Aβ过量生成是散发性和家族性AD的重要病理学基础，然而JNK激活在野生型和突变型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JNK基因敲除小鼠、转基因AD小鼠和多种细胞模型，通过体外、体内实验，深入探讨JNK及其激酶MLK和下游基因c-Jun对野生型和突变型APP代谢和Aβ生成的效应作用及其分子机制；同时探讨JNK及其激酶MLK抑制剂防治AD病程进展的效应作用及其机制。有望为研发防治AD新药物提供新的靶点。