NAD⁺ Reduction in Glutamatergic Neurons Induces Lipid Catabolism and Neuroinflammation in the Brain via SARM1

Abstract NAD⁺ homeostasis is vital for neuronal health, as demonstrated by the opposing roles of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), a NAD⁺‐synthesizing enzyme, and sterile alpha and TIR motif‐containing protein 1 (SARM1), a NAD⁺ hydrolase. Neurodegenerative insults that decrease NMNAT2 activate SARM1, leading to axon loss. To understand how the NMNAT2–SARM1 axis influences brain energy metabolism, multi‐omics approaches are used to investigate the metabolic changes resulting from neuronal NMNAT2 loss. Loss of NMNAT2 in glutamatergic neurons leads to a significant metabolic shift in the cerebral cortex from glucose to lipid catabolism, reduced lipid abundance, and pronounced neurodegenerative phenotypes and motor behavioral deficits. These metabolic disturbances are accompanied by altered glial expression of enzymes regulating glucose and lipid metabolism, enhanced inflammatory signaling, and disrupted astrocytic transcriptomic profiles related to cholesterol synthesis and immune activation. Notably, SARM1 deletion in NMNAT2‐deficient mice restored lipid metabolism, astrocyte transcriptomic profiles, and mitigated neurodegeneration and motor behaviors. These findings suggest that neuronal NAD⁺ depletion triggers maladaptive, SARM1‐dependent metabolic reprogramming, shifting energy use from glucose to lipids, which in turn promotes inflammation and neurodegeneration.