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Inhibition of the microglial voltage-gated proton channel 1 channel ameliorates diabetes-associated cognitive
Chun-Yu Li1,2,3, Shu-Jun Zhang1,2,3, Jia-Lu Xu1,2,3
1Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
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 diabetes-induced 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 was analyzed using electron microscopy.
Results:
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.
Conclusion:
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.
