NAD+ reduction in glutamatergic neurons triggers fatty acid catabolism and neuroinflammation in the brain, mitigated by SARM1 deletion

The importance of NAD+ homeostasis for neuronal health has been emphasized by studies on nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2), a NAD+-synthesizing enzyme, and sterile alpha and TIR motif-containing protein 1 (SARM1), a NAD+ hydrolase. NMNAT2 declines caused by neurodegenerative insults activate SARM1 to degenerate axons. To elucidate the impact of the NMNAT2-SARM1 axis on brain energy metabolism, we employed multi-omics approaches to investigate the metabolic effects caused by neuronal NMNAT2 loss. The loss of NMNAT2 in glutamatergic neurons results in a striking metabolic shift in the cerebral cortex from glucose to lipid catabolism, reduced lipid abundance, and pronounced neurodegenerative phenotypes. Proteomic analysis found that neuronal NMNAT2 loss altered levels of glial enzymes central to glucose and lipid metabolism. Genetic deletion of SARM1 in NMNAT2-deficient mice restores lipid metabolism and mitigates neurodegeneration. Taken together, we show that neuronal NAD+ reduction leads to SARM1-dependent maladaptive adaptations in both neurons and glia.