Th17 cell mediated oligodendrocyte precursor cell arrest drives hippocampal demyelination in diabetic cognitive dysfunction.

Abstract

Demyelination is pivotal in diabetic cognitive dysfunction (DCD), with Th17 cells gaining attention, yet their hippocampal infiltration and mechanisms in diabetes remain unelucidated. Using streptozotocin (STZ)-induced diabetic mice, we demonstrated Th17 cell infiltration and elevated IL-17A in the hippocampus via CD4/IL-17A immunofluorescence and Western blot. Administering IL-17A neutralizing antibodies (NAbs) improved cognitive performance (Morris water maze: reduced escape latency, increased platform crossings/target quadrant time), attenuated neuroinflammation (reduced IL-17A, TNF-α, IL-1β, IL-6; increased IL-10, IL-4; decreased microglial activation/IBA-1), restored blood-brain barrier integrity (increased ZO-1, Occludin), and promoted remyelination (increased MBP, CNPase; decreased NG2, olig2; Luxol fast blue). IL-17A NAbs also enhanced phosphorylated ERK1/2 (p-ERK). Crucially, co-treatment with the ERK inhibitor PD98059 partially reversed the protective effects of IL-17A NAbs on these parameters. These findings indicate that IL-17A, secreted by infiltrating Th17 cells, exacerbates hippocampal demyelination in DCD by inhibiting oligodendrocyte precursor cell (OPC) maturation via suppression of the ERK1/2 pathway and concurrently activating microglia to amplify neuroinflammation, ultimately driving cognitive impairment.