Abstract
CD38 is an enzyme that catalyzes the synthesis of cyclic adenosine diphosphate-ribose from nicotinamide adenine dinucleotide (NAD+). We recently reported that this molecule regulates the maturation and differentiation of glial cells such as astrocytes and oligodendrocytes (OLs) in the developing brain. To analyze its role in the demyelinating situation, we employed cuprizone (CPZ)-induced demyelination model in mice, which is characterized by oligodendrocyte-specific apoptosis, followed by the strong glial activation, demyelination, and repopulation of OLs. By using this model, we found that CD38 was upregulated in both astrocytes and microglia after CPZ administration. Experiments using wild-type and CD38 knockout (KO) mice, together with those using cultured glial cells, revealed that CD38 deficiency did not affect the initial decrease of the number of OLs, while it attenuated CPZ-induced demyelination, and neurodegeneration. Importantly, the clearance of the degraded myelin and oligodendrocyte repopulation were also reduced in CD38 KO mice. Further experiments revealed that these observations were associated with reduced levels of glial activation and inflammatory responses including phagocytosis, most likely through the enhanced level of NAD+ in CD38-deleted condition. Our results suggest that CD38 and NAD+ in the glial cells play a critical role in the demyelination and subsequent oligodendrocyte remodeling through the modulation of glial activity and neuroinflammation.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and degenerative disease of the central nervous system (CNS), and has been one of the leading causes of neurological disability among young adults
Recent studies demonstrated that ablation of astrocytes or astrocytetargeted production of interleukin-6 led to a reduction in the activation and invasion of microglia into demyelinating lesions, which resulted in delayed demyelination and subsequently delayed oligodendrocyte precursor cell (OPC) proliferation, and remyelination (Skripuletz et al, 2013; Petkovic et al, 2016)
We examined the role of CD38 in CPZ-induced demyelination model in mice
Summary
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and degenerative disease of the central nervous system (CNS), and has been one of the leading causes of neurological disability among young adults. Cuprizone (CPZ)-induced experimental demyelination is a suitable rodent model to study the mechanisms leading to demyelination and subsequent remyelination in the CNS without a significant autoimmune lymphocytic response (Remington et al, 2007). In this model, the first pathological event is the selective apoptotic death of mature oligodendrocytes (OLs) in particular brain regions such as the corpus callosum (CC), which results in primary demyelination (Blakemore, 1972). Some in vitro data suggest that CPZ-induced OL apoptosis requires the presence of microglia-derived proinflammatory mediators such as TNFα and inducible nitric oxide synthase (iNOS) (Pasquini et al, 2007; Raposo et al, 2013)
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