CD38 dependent NAD + depletion contributes to oligodendrocyte loss and inhibition of myelin regeneration
CD38 dependent NAD + depletion contributes to oligodendrocyte loss and inhibition of myelin regeneration
Abstract 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 NAD+ase CD38, and highlight the use of CD38 inhibitors as potential therapeutic candidates to improve myelin regeneration.
Kleppe Laurel、Chini Claudia C.S.、Scarisbrick Isobel A.、Choi Chan-Il、Simon Whitney、Yoon Hyesook、Chini Eduardo N.、Peclat Thais R.、Langley Monica R.
Department of Physical Medicine & Rehabilitation, Rehabilitation Medicine Research Center, Mayo ClinicRobert & Arlene Kogod Center on Aging, Mayo Clinic||Department of Anesthesiology, Mayo ClinicDepartment of Physical Medicine & Rehabilitation, Rehabilitation Medicine Research Center, Mayo Clinic||Department of Physiology and Biomedical Engineering, Mayo ClinicDepartment of Physical Medicine & Rehabilitation, Rehabilitation Medicine Research Center, Mayo ClinicDepartment of Physical Medicine & Rehabilitation, Rehabilitation Medicine Research Center, Mayo ClinicDepartment of Physical Medicine & Rehabilitation, Rehabilitation Medicine Research Center, Mayo Clinic||Department of Physiology and Biomedical Engineering, Mayo ClinicRobert & Arlene Kogod Center on Aging, Mayo Clinic||Department of Anesthesiology, Mayo ClinicRobert & Arlene Kogod Center on Aging, Mayo ClinicDepartment of Physical Medicine & Rehabilitation, Rehabilitation Medicine Research Center, Mayo Clinic
基础医学神经病学、精神病学生物化学
CD38Gliahigh fat dietNAD+remyelination
Kleppe Laurel,Chini Claudia C.S.,Scarisbrick Isobel A.,Choi Chan-Il,Simon Whitney,Yoon Hyesook,Chini Eduardo N.,Peclat Thais R.,Langley Monica R..CD38 dependent NAD + depletion contributes to oligodendrocyte loss and inhibition of myelin regeneration[EB/OL].(2025-03-28)[2025-06-08].https://www.biorxiv.org/content/10.1101/2020.06.10.143941.点此复制
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