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Novel roles for the ectoenzyme CD38 in the maintenance of transcriptional and metabolic homeostasis in astrocytes

ABSTRACT: CD38 is an ectoenzyme that converts NAD+ to NAM and helps to maintain bioenergetic homeostasis. A better understanding of CD38 biology in the brain is needed, considering the evidence for CD38 dysregulation and/or gene variation in neurodegenerative conditions such as Parkinson’s Disease (PD) and Alzheimer’s Disease (AD). Here, we demonstrate enrichment of Cd38 in midbrain astrocytes and describe how CD38 deficiency influences brain metabolism, astrocytic gene expression, and bioenergetics. We demonstrate increased NAD content, decreased NAM content, and increased NAD/NAM in the midbrain and striatum of CD38-deficient (Cd38-/-) mice, indicating the dependence on CD38 for NAD to NAM conversion. RNA-sequencing of isolated astrocytes revealed numerous differentially expressed genes in Cd38+/- and Cd38-/- mice, with alterations in mitochondrial, metabolic, and senescence-related genes and several genes involved in PD and AD etiology. Interestingly, Seahorse XFe24 mitochondrial functional evaluation in primary astrocyte cultures from Cd38+/+, Cd38+/-, and Cd38-/- mice revealed enhanced oxygen consumption, with an increase in glycolytic rate with Cd38 deficiency. These findings indicate a novel role for astrocytes in the regulation of CD38-dependent NAD/NAM homeostasis in the brain and provide the framework for future studies evaluating the relationship between CD38 dysfunction, aging, and vulnerability of neuronal populations in neurodegenerative disease. Also, these studies highlight the need to better elucidate the impact of CD38 deficiency on brain metabolism, considering ongoing clinical trials using CD38 inhibitors for the treatment of multiple myeloma and other cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE272765 | GEO | 2025/12/30

REPOSITORIES: GEO

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Project description:Alzheimer's disease (AD) is a severe neurodegenerative disorder. Clinical trials to identify agents to treat AD have failed, and its underlying molecular pathology and etiology remain elusive. Neuroinflammation is thought to play a key role in the progression of AD. Emerging evidence has identified lower Nicotinamide adenine dinucleotide (NAD+) levels as a major factor in neurodegeneration, especially in AD. NAD+ is an important metabolite in all human cells, as it is at the convergence of many central processes in cellular and mitochondrial maintenance, including DNA repair and mitophagy (the degradation of damaged mitochondria). Our previous work found that treatment of 3xTgAD mice with an NAD+ precursor, nicotinamide riboside (NR), can improve key AD features including tau phosphorylation and learning deficits in mice. Here we used the APP/PS1 AD mouse model to interrogate the effect of NR on neuroinflammation. Microarray analysis revealed major changes in pathways and genes associated with inflammation and the APP/PS1 mice had lower NAD+ levels than WT mice. Thus, seven months old mice were treated with NR for five months and their NAD+/NADH ratio increased. Brain neuroinflammation decreased as determined by decreased activation of astrocytes and microglia, decreased pro-inflammatory cytokines and chemokines in the brains of the APP/PS1 mice. NR decreased neuroinflammation by lowering the NLRP3 inflammasome and NF-κB pathways. NR also attenuated DNA damage and apoptosis in the AD mouse brains. NR dramatically decreased senescence in the hippocampus and cortex of AD mice, relative to controls. Recent studies suggest that cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) activation are associated with DNA damage and senescence. cGAS-STING was activated in AD mice and decreases after NR treatment. Suggesting that NR can diminish neuroinflammation and senescence through the cGAS-STING pathway. NR treatment also greatly improved cognition and synaptic function in the APP/PS1 mice. We propose that the cGAS-STING pathway should be evaluated as a potential novel therapeutic target in AD.

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Novel roles for the ectoenzyme CD38 in the maintenance of transcriptional and metabolic homeostasis in astrocytes

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