2型糖尿病促进认知功能障碍发生发展，但具体机制不明。近期研究发现高糖环境下二肽基肽酶4（DPP4）酶学活性增高是导致认知功能障碍发生的重要原因，机制与其分解底物GLP-1有关，但现有研究均未探讨DPP4非酶学功能在认知功能障碍中的可能致病作用。本课题组前期研究表明，2型糖尿病小鼠海马DPP4表达增高，抑制海马GLP-1受体表达后，DPP4抑制剂仍可有效改善小鼠海马神经元线粒体功能紊乱、氧化应激损伤和认知功能障碍，机制可能与阻断DPP4非酶学功能介导的PAR2/GSK-3β/PGC-1α信号通路有关。据此，本课题采用病毒转染、透射电镜、蛋白印迹、荧光染色等方法，在活体和细胞水平，阐明DPP4非酶学功能介导的PAR2/GSK-3β/PGC-1α信号通路在海马神经元线粒体生物合成、融合分裂，抗氧化酶，氧化应激，细胞凋亡和认知功能障碍中的作用，旨在为2型糖尿病诱发的认知功能障碍提供早期干预靶点。

The onset and development of cognitive impairment are promoted by type 2 diabetes, however, the underlying mechanism remains unclear. Recent studies found that increased dipeptidyl peptidase-4 (DPP4) enzymatic activities played an important role in the pathogenesis of type 2 diabetes-induced cognitive impairment and the mechanism was related to the degradation of GLP-1, however, to our knowledge, no study has evaluated the pathogenetic role of nonenzymatic function of DPP4 in type 2 diabetes-induced cognitive impairment. Recently, our original findings indicated that DPP4 was overexpressed in the hippocampus of type 2 diabetic mice, after silencing GLP-1 receptor expression in the hippocampus, DPP4 inhibitors treatment still effectively reversed hippocampal mitochondrial dysfunction, oxidative stress damage and cognitive impairment in type 2 diabetic mice via blocking PAR2/GSK-3β/ PGC-1α signaling pathway mediated by the nonenzymatic function of DPP4. Accordingly, in this study we will perform virus transfection, transmission electron microscope, Western blot and immunofluorescent staining, etc, to prove the role of PAR2/GSK-3β/PGC-1α signaling pathway mediated by nonenzymatic function of DPP4 in hippocampal mitochondrial biogenesis, fusion/fission, antioxidant enzymes, oxidative stress and cognitive impaitment in vivo and in vitro. This research aims to provide new therapeutic targets for the early prevention and treatment of cognitive impairment in type 2 diabetes.