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

## TL;DR

Reducing NAD⁺ in glutamatergic neurons shifts brain metabolism to lipids, causing inflammation and neurodegeneration, which can be reversed by removing SARM1.

## Contribution

Shows that SARM1-dependent NAD⁺ depletion in neurons causes metabolic reprogramming linked to neurodegeneration and inflammation.

## Key findings

- Loss of NMNAT2 in glutamatergic neurons shifts brain metabolism from glucose to lipid catabolism.
- SARM1 deletion restores lipid metabolism and reduces neurodegeneration and inflammation.
- Altered glial expression and astrocytic profiles accompany neuronal NAD⁺ depletion.

## 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.

NAD⁺ homeostasis maintains neuronal integrity through opposing actions of NMNAT2 and SARM1. Loss of NMNAT2 in glutamatergic neurons reprograms cortical metabolism from glucose to lipid catabolism, depletes lipid stores, and triggers inflammation and neurodegeneration. Deletion of SARM1 restores lipid metabolism and glial homeostasis, indicating that SARM1‐dependent NAD⁺ depletion drives maladaptive metabolic remodeling in the brain.