Chronic progressive demyelination induces a microglial state with lysosomal dysfunction

While immune and metabolic responses to acute myelin injury are well characterized, myeloid cell adaptations to chronic myelin damage remain poorly understood. Comparative analysis of genetic and toxic mouse models of acute and chronic demyelination identified a distinct microglial state associated with chronic demyelination, characterized by sustained pro-inflammatory activation and enhanced myelin-damaging activity.

These microglia exhibited lysosomal lipid sequestration and reduced lipid droplet formation. Transcriptomics profiling further revealed a dysregulated metabolic program marked by upregulated cholesterol synthesis and diminished sterol efflux. Treatment with a desmosterol mimetic possessing 24-dehydrocholesterol reductase inhibitor activity reversed this dysfunctional microglial state, attenuated pro-inflammatory signaling (including C-C Motif Chemokine Ligand 4 expression), reduced myelin damage, and improved motor performance in a mouse model of leukodystrophy.