A series of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, are accompanied with bioenergetic maladaptations and axonopathy with the increasing age. As a key coenzyme in energy metabolism, nicotinamide adenine dinucleotide (NAD) plays a critical role in maintaining axonal health in central neural system.
2.NMNAT2 as the major source of NAD in cortical neurons
NAD is mainly synthesized by nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2). NMNAT2 is pivotal for maintaining NAD redox potential in distal axons, where it provides the adenosine triphosphate (ATP) required for fast axonal transport. Furthermore, NMNAT2 is the main source of NAD in cortical neurons, as evidenced by the reduction of NAD + and NADH levels by approximately 50% in the absence of NMNAT2.
3. The restoring effect of NAD+ supplementation on APP transport via glycolysis in the absence of NMNAT2
Exogenous NAD+ supplementation to NMNAT2-deficient neurons restores glycolysis and resumes fast axonal transport, as manifested by the diminished percentage of stationary/dynamic pause events, the elevated percentage of anterograde and retrograde events, and the restored anterograde and retrograde velocities of APP transport.
4. The molecular mechanism of NAD in protecting axonal health
Remarkably, reducing the activity of SARM1, an NAD degradation enzyme, can reduce axonal transport deficits and suppress axon degeneration in NMNAT2-deficient neurons. SARM1 knockdown prevents the reduction in NAD+/NADH ratio normally caused by NMNAT2 loss. Blocking NAD+ degradation by reducing SARM1 abundance protects axons during NMNAT2 loss in vivo and in vitro.
NAD+ supplementation or repressing the level of SARM1, an NAD + hydrolase, can effectively restore fast axonal transport and prevent the neurodegeneration commonly observed in NMNAT2-deficient axons both in vitro and in vivo, shedding a light on the treatment of neurodegenerative disorders of aging.
Yang S, Niou ZX, Enriquez A, et al. NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport. Preprint. Res Sq. 2023;rs.3.rs-2859584. Published 2023 May 19. doi:10.21203/rs.3.rs-2859584/v1
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