CD38 dependent NAD + depletion contributes to oligodendrocyte loss and inhibition of myelin regeneration

Western-style diets cause disruptions in myelinating cells and astrocytes within the CNS. We identified increased CD38 expression in the mouse spinal cord following chronic high fat consumption or focal demyelinating injury. CD38-catalytically inactive mice are significantly protected from high fat-induced NAD depletion, oligodendrocyte loss, oxidative damage, and astrogliosis. 78c, a CD38 inhibitor, increased NAD and attenuated neuroinflammatory changes in astrocytes induced by saturated fat. Conditioned media from saturated fat-treated astrocytes impaired oligodendrocyte differentiation pointing to indirect mechanisms of oligodendrogliopathy. Combined saturated fat and lysolecithin demyelination in cerebellar slices resulted in additional deficits in myelin proteins that were mitigated by concomitant 78c treatment. Importantly, oral 78c increased counts of oligodendrocytes and remyelinated axons after focal demyelination. Our findings suggest that high fat diet impairs oligodendrocyte survival and differentiation through astrocyte-linked mechanisms mediated by the NADase CD38, and highlight the use of CD38 inhibitors as potential therapeutic candidates to improve myelin regeneration.