This study reveals that NMNAT2 deficiency disrupts NAD+ metabolism and triggers accumulation of toxic APP protein fragments in neurons, driving neurodegenerative pathology through SARM1 activation. The research demonstrates a mechanistic link between metabolic stress (NAD+ depletion) and protein misfolding characteristic of Alzheimer’s disease. Critically, SARM1 knockdown—but not NAD+ supplementation alone—restored metabolic function and normalized pathology, suggesting SARM1 inhibition may be more therapeutic than simple NAD+ replenishment. This repositions NMN and NAD+-boosting strategies in the context of neurodegenerative disease prevention and treatment.
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SARM1 activation may limit NAD+ repletion strategies; NMN supplementation alone may be insufficient without addressing upstream signaling.