Li Chun-Yu, Zhang Shu-Jun, Xu Jia-Lu, Yang Yan, Zeng Zhi-Xuan, Ma De-Lin
Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
Hubei Clinical Medical Research Center for Endocrinology and Metabolic Diseases, Wuhan 430030, Hubei Province, China.
World J Psychiatry. 2025 Mar 19;15(3):101178. doi: 10.5498/wjp.v15.i3.101178.
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 diabetes-induced cognitive dysfunction is unclear.
To investigate the role of Hv1 in cognitive impairment induced by diabetes and its potential mechanisms, focusing on neuroinflammation, oligodendrocyte apoptosis, and axonal demyelination.
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 behavioral tests and neuroinflammation using immunofluorescence. Oligodendrocyte apoptosis was assessed with the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, and axonal demyelination was analyzed using electron microscopy.
Hv1 expression was significantly increased in the corpus callosum of diabetic mice. Hv1 KO alleviated cognitive impairment, reduced oligodendrocyte apoptosis, and decreased the expression of inflammatory factors, including interleukin-1 and tumor necrosis factor-α, in diabetic mice. Electron microscopy revealed a reduction in myelin thickness and an increased g-ratio in diabetic mice, which were reversed by Hv1 KO.
Hv1 plays a role in diabetes-induced cognitive dysfunction by modulating neuroinflammation and myelin integrity. Hv1 KO demonstrates therapeutic potential in mitigating diabetes-related cognitive decline and associated complications.
糖尿病与认知功能下降和痴呆症增加有关，这是由于有髓神经纤维功能丧失，而这与少突胶质细胞功能障碍有关。电压门控质子通道1（Hv1）对细胞质子排出机制很重要。然而，其在调节糖尿病诱导的认知功能障碍中的作用尚不清楚。
研究Hv1在糖尿病诱导的认知障碍中的作用及其潜在机制，重点关注神经炎症、少突胶质细胞凋亡和轴突脱髓鞘。
通过给小鼠喂食高脂饮食并注射链脲佐菌素建立糖尿病模型。使用Hv1基因敲除（KO）小鼠和野生型小鼠，通过行为测试评估认知功能，并使用免疫荧光法检测神经炎症。用末端脱氧核苷酸转移酶脱氧尿苷三磷酸缺口末端标记法评估少突胶质细胞凋亡，并用电子显微镜分析轴突脱髓鞘情况。
糖尿病小鼠胼胝体中Hv1表达显著增加。Hv1基因敲除减轻了糖尿病小鼠的认知障碍，减少了少突胶质细胞凋亡，并降低了包括白细胞介素-1和肿瘤坏死因子-α在内的炎症因子的表达。电子显微镜显示糖尿病小鼠的髓鞘厚度减少且g比值增加，而Hv1基因敲除可使其逆转。
Hv1通过调节神经炎症和髓鞘完整性在糖尿病诱导的认知功能障碍中起作用。Hv1基因敲除在减轻糖尿病相关认知下降及相关并发症方面显示出治疗潜力。
