糖尿病增加阿尔茨海默病（AD）发生风险，但糖尿病合并AD发生机制不明确且缺乏有效药物。本课题组已证实GLP-1受体激动剂抑制糖原合成酶激酶-3β（GSK-3β）异常活化改善糖尿病相关AD动物、细胞模型病变，但糖尿病合并AD中GLP-1对蛋白磷酸酯酶2A（PP2A）的作用，特别是稳定GSK3β/PP2A平衡的机制尚不清楚，基于GSK3β/PP2A失衡是AD发生的关键因素，本项目首先观察糖尿病合并AD致GSK-3β/PP2A失衡及GLP-1干预作用；然后采用转染、RNAi等技术考察GSK-3β和PP2A激活或抑制在AD发病中的作用及GLP-1的调节；最后分析GSK-3β/核转录因子CREB、胰岛素/PI3K、mTOR途径在GLP-1调节GSK-3β/PP2A中的作用，旨在阐明GLP-1受体介导GSK-3β/PP2A平衡的分子机制，为GLP-1受体激动剂治疗糖尿病合并AD及新靶点提供实验依据。

Diabetes mellitus is considered to be a risk factor for Alzheimer's disease (AD), but the pathogenesis is still unclear. Diabetes-related AD is lack of effective drugs. In our previous study, we have found the amelioration effect of neurodegenerative changes in cellular and rat models of diabetes-related AD by glucagon-like peptide-1 (GLP-1) receptor agonist through reversal abnormal activation of glycogen synthase kinase 3β (GSK-3β), but the effect and mechanism of GLP-1 on protein phosphatase 2A (PP2A) in diabetes-related AD especially the mechanism in regulation of the equilibrium between GSK3β and PP2A is unclear. Based on the unbalance in GSK3β/PP2A is a key risk factor for AD, in this project, first we will investigate the mechanism of deregulation of the equilibrium between GSK3β and PP2A in diabetes-related AD and the effect of GLP-1 receptor agonist; then we will intervene GSK3β/PP2A by using the transfection, RNA interference (RNAi) technologies and so on to explore the roles of GSK3β and PP2A activation/inactivation in AD and the regulation effect of GLP-1; finally we will clarify the roles of GSK-3β/cAMP response element binding protein (GSK-3β/CREB), insulin/phosphoinositide 3-kinase (insulin/PI3K) and mammalian target of rapamycin (mTOR) pathways in the regulation of the equilibrium between GSK3β and PP2A by GLP-1 receptor agonist. The aim of this project is to clarify the mechanism of GSK3β/PP2A equilibrium mediated by GLP-1 receptor and provide new experimental evidence for the potential targets of GLP-1 receptor agonist treatment of diabetes-related AD.