Neuregulin-1 facilitates myelin regeneration through microglia-mediated mechanisms in a mouse model of chronic demyelination

Failure in remyelination is a key feature of progressive multiple sclerosis (MS) that drive neurodegeneration and accumulation of disabilities. Microglia crucially facilitate oligodendrocyte remyelination in MS lesions through myelin phagocytosis, and subsequent cholesterol metabolism and release. However, microglia lose this capacity in chronic demyelinated lesions, as they acquire a dysfunctional phenotype characterized by intracellular accumulation of lipid droplets due to impaired cholesterol processing of myelin debris. Given the abundance of microglia in chronic MS lesions, revitalizing their pro-remyelination capacity represents a critical repair strategy for progressive MS. Here, we reveal that dysregulation of neuregulin-1 underlies impaired remyelination in chronically demyelinated brain lesions. Therapeutic restoration of neuregulin-1 supports remarkable myelin regeneration by augmenting microglia capacity for clearance of myelin debris, cholesterol metabolism and efflux. Altogether, we demonstrate the promise of neuregulin-1 as an endogenous target to facilitate microglia reparative functions in progressive MS in which there is an unmet critical need for new treatments.