Inhibition of the microglial voltage-gated proton channel 1 channel ameliorates diabetes-associated cognitive dysfunction by regulating axon demyelination  

作　　者：Chun-Yu Li Shu-Jun Zhang Jia-Lu Xu Yan Yang Zhi-Xuan Zeng De-Lin Ma 

机构地区：[1]Division of Endocrinology,Department of Internal Medicine,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,Hubei Province,China [2]Hubei Clinical Medical Research Center for Endocrinology and Metabolic Diseases,Wuhan 430030,Hubei Province,China [3]Branch of National Clinical Research Center for Metabolic Diseases,Wuhan 430030,Hubei Province,China

出　　处：《World Journal of Psychiatry》2025年第3期288-301,共14页世界精神病学杂志(英文)

基　　金：Supported by the National Natural Science Foundation of China,No.82300894.

摘　　要：BACKGROUND Diabetes is associated with increased cognitive decline and dementia due to the loss of myelinated nerve fiber function,which is linked to oligodendrocyte dysfunction.The voltage-gated proton channel 1(Hv1)is important for the cellular proton extrusion machinery.However,its role in regulating diabetesinduced cognitive dysfunction is unclear.AIM To investigate the role of Hv1 in cognitive impairment induced by diabetes and its potential mechanisms,focusing on neuroinflammation,oligodendrocyte apoptosis,and axonal demyelination.METHODS A diabetes model was established by administering a high-fat diet and streptozotocin injections in mice.Hv1 knockout(KO)and wild-type mice were used to evaluate cognitive function via behavioral tests and neuroinflammation using immunofluorescence.Oligodendrocyte apoptosis was assessed with the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, and axonal demyelination wasanalyzed using electron microscopy.RESULTSHv1 expression was significantly increased in the corpus callosum of diabetic mice. Hv1 KO alleviated cognitiveimpairment, reduced oligodendrocyte apoptosis, and decreased the expression of inflammatory factors, includinginterleukin-1 and tumor necrosis factor-α, in diabetic mice. Electron microscopy revealed a reduction in myelinthickness and an increased g-ratio in diabetic mice, which were reversed by Hv1 KO.CONCLUSIONHv1 plays a role in diabetes-induced cognitive dysfunction by modulating neuroinflammation and myelinintegrity. Hv1 KO demonstrates therapeutic potential in mitigating diabetes-related cognitive decline andassociated complications.

关 键 词：Diabetes Cognitive dysfunction Voltage-gated proton channel 1 Neuroinflammation Myelin regeneration 

分 类 号：R73[医药卫生—肿瘤]