Chronic progressive demyelination induces a microglial state with lysosomal dysfunction

Dysfunctional immune responses impair remyelination and contribute to neurodegeneration. While immune and metabolic responses to acute myelin injury are well characterized, myeloid cell adaptations to chronic myelin damage remain poorly understood. Here we performed a comparative analysis of genetic and toxic mouse models of acute and chronic demyelination, which identified a distinct microglial state associated with chronic demyelination, characterized by sustained pro-inflammatory activation, lysosomal lipid sequestration and reduced lipid droplet formation. Transcriptomics profiling further revealed a metabolic program marked by upregulated cholesterol synthesis and diminished sterol efflux. Treatment with a desmosterol mimetic possessing 24-dehydrocholesterol reductase inhibitor activity reversed this 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. Our findings uncover a pro-inflammatory microglial state characterized by lysosomal dysfunction and increased myelin reactivity, highlighting a novel therapeutic target for chronic demyelinating disorders.