Microglial voltage-gated proton channel 1 ablation in diabetic mice mitigates diabetes-driven demyelination and cognitive decline.

Abstract

This article discusses a study by Li et al, which investigates the role of the microglial voltage-gated proton channel 1 (Hv1) in diabetes-related cognitive decline. The authors showed that Hv1 is upregulated in the corpus callosum of diabetic mice and that its knockout improves working memory, reduces microglial production of interleukin-1β and tumour necrosis factor alpha, and decreases apoptosis of oligodendrocyte progenitor cells. Furthermore, electron microscopy revealed that the myelin thickness and the g-ratio were preserved in Hv1 knockout mice, remaining within normal limits. In addition, Hv1 knockdown mitigated interleukin-1β secretion and suppressed ferroptosis markers (ferritin heavy chain/ferritin light chain, CCAAT/enhancer binding protein homologous protein, glucose-regulated protein 78, etc.) in vitro, suggesting the involvement of an Hv1-reactive oxygen species-glucose-regulated protein 78 axis in diabetic demyelination. We highlight the translational implications of these findings and recommend future studies employing microglia-specific Hv1 deletion models, longitudinal cognitive assessments and preclinical evaluation of pharmacological Hv1 inhibitors.