Chronic progressive demyelination induces a microglial state with lysosomal dysfunction.

Chronic demyelination in genetic and toxic mouse models induces a distinct microglial state marked by sustained pro-inflammatory activation, lysosomal lipid sequestration, and reduced lipid droplet formation.

• Why it matters: Immune and metabolic responses to acute myelin injury are known, but how myeloid cells adapt to chronic myelin damage remains unclear, limiting therapeutic targeting for neurodegeneration.
• What they did: The study compared genetic and toxic mouse models of acute versus chronic demyelination using genetic/toxic model analysis and transcriptomics, identifying a metabolic program with upregulated cholesterol synthesis and diminished sterol efflux.
• The result: A desmosterol mimetic with 24-dehydrocholesterol reductase inhibitor activity reversed the 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.