NAD metabolism regulates diverse biological processes, including ageing, circadian rhythm and axon survival. Axons depend on the activity of the central enzyme in NAD biosynthesis, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), for their maintenance and degenerate rapidly when this activity is lost. However, whether axon survival is regulated by the supply of NAD or by another action of this enzyme remains unclear. Here we show that the nucleotide precursor of NAD, nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration. Inhibitors of NMN-synthesising enzyme NAMPT confer robust morphological and functional protection of injured axons and synapses despite lowering NAD. Exogenous NMN abolishes this protection, suggesting that NMN accumulation within axons after NMNAT2 degradation could promote degeneration. Ectopic expression of NMN deamidase, a bacterial NMN-scavenging enzyme, prolongs survival of injured axons, providing genetic evidence to support such a mechanism. NMN rises prior to degeneration and both the NAMPT inhibitor FK866 and the axon protective protein WldS prevent this rise. These data indicate that the mechanism by which NMNAT and the related WldS protein promote axon survival is by limiting NMN accumulation. They indicate a novel physiological function for NMN in mammals and reveal an unexpected link between new strategies for cancer chemotherapy and the treatment of axonopathies.

Even though considerable research studies suggest pivotal functional outcomes induced by statin therapy, additional investigation is required to better determine the pharmacological effectiveness of statins in the brain, and support their clinical use in the management of different neuropathologies.

The brain’s white matter is highly vulnerable to reductions in cerebral blood flow via mechanisms that may involve elevated microgliosis and pro-inflammatory pathways. In the present study, the effects of severe cerebral hypoperfusion were investigated on white matter function and inflammation. Male C57Bl/6J mice underwent bilateral common carotid artery stenosis and white matter function was assessed at seven days with electrophysiology in response to evoked compound action potentials (CAPs) in the corpus callosum. The peak latency of CAPs and axonal refractoriness was increased following hypoperfusion, indicating a marked functional impairment in white matter, which was paralleled by axonal and myelin pathology and increased density and numbers of microglia/macrophages. The functional impairment in peak latency was significantly correlated with increased microglia/macrophages. Dimethyl fumarate (DMF; 100 mg/kg), a drug with anti-inflammatory properties, was found to reduce peak latency but not axonal refractoriness. DMF had no effect on hypoperfusion-induced axonal and myelin pathology. The density of microglia/macrophages was significantly increased in vehicle-treated hypoperfused mice, whereas DMF-treated hypoperfused mice had similar levels to that of sham-treated mice. The study suggests that increased microglia/macrophages following cerebral hypoperfusion contributes to the functional impairment in white matter that may be amenable to modulation by DMF.