Nonenzymatic function of DPP4 in diabetes-associated mitochondrial dysfunction and cognitive impairment.
Nonenzymatic function of DPP4 in diabetes-associated mitochondrial dysfunction and cognitive impairment.
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DPP4 在糖尿病相关线粒体功能障碍和认知障碍中的非酶功能。
DOI：
10.1002/alz.12437
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Tianpeng Zheng
中科院分区：
文献类型：
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作者：
Cunwei Sun;YanhuaXiao;Jiaxiu Li;BoGe;XuChen;Hongbo Liu;Tianpeng Zheng
二肽基肽酶-4(DPP4)已被证实通过ENZY-马季奇和非酶途径发挥其功能。DPP4在糖尿病相关认知损害中的非酶作用尚不清楚。我们测定了2型糖尿病患者和db/db小鼠的DPP4蛋白浓度或其酶活性，并测试了DPP4的非酶功能在体内和体外对线粒体功能障碍和认知损害的影响。结果表明，DPP4活性升高是2型糖尿病患者发生轻度认知损害(MCI)的独立危险因素。此外，DPP4在db/db小鼠的海马区高表达，导致线粒体功能障碍和认知损伤。从机制上讲，DPP4可能与海马区的PAR2结合，触发GSK-3β激活，从而下调过氧化体增殖物激活受体γ辅助激活因子1α的表达，导致线粒体功能障碍，从而促进糖尿病认知功能障碍。我们的研究结果表明，DPP4的非酶功能可能促进糖尿病患者线粒体功能障碍和认知功能障碍。
Dipeptidyl peptidase-4 (DPP4) has been proven to exert its functions by both enzy-matic and nonenzymatic pathways. The nonenzymatic function of DPP4 in diabetes-associated cognitive impairment remains unexplored. We determined DPP4 protein concentrations or its enzymatic activity in type 2 diabetic patients and db/dbmice and tested the impact of the non-enzymatic function of DPP4 on mitochondrial dysfunc-tionandcognitive impairment both invivoand invitro. The results showthat increased DPP4 activity was an independent risk factor for incident mild cognitive impairment (MCI) in type 2 diabetic patients. In addition, DPP4 was highly expressed in the hip-pocampus of db/db mice and contributed to mitochondria dysfunction and cognitive.impairment.Mechanistically, DPP4might bind toPAR2 in thehippocampus and trigger GSK-3βactivation, which downregulates peroxisome proliferator-activated receptor gamma coactivator 1 alpha expression and leads tomitochondria dysfunction, thereby promoting cognitive impairment in diabetes. Our findings indicate that the nonen-zymatic function of DPP4 might promote mitochondrial dysfunction and cognitive impairment in diabetes.