Nicotinamide Adenine Dinucleotide Metabolism and Neurodegeneration

Antioxid Redox Signal. 2018 Jun 20;28(18):1652-1668. doi: 10.1089/ars.2017.7145. Epub 2017 Jun 27.


Significance: Nicotinamide adenine dinucleotide (NAD+) participates in redox reactions and NAD+-dependent signaling processes, which involve the cleavage of NAD+ coupled to posttranslational modifications of proteins or the production of second messengers. Either as a primary cause or as a secondary component of the pathogenic process, mitochondrial dysfunction and oxidative stress are prominent features of several neurodegenerative diseases. Activation of NAD+-dependent signaling pathways has a major effect in the capacity of the cell to modulate mitochondrial function and counteract the deleterious effects of increased oxidative stress. Recent Advances: Progress in the understanding of the biological functions and compartmentalization of NAD+-synthesizing and NAD+-consuming enzymes have led to the emergence of NAD+ metabolism as a major therapeutic target for age-related diseases.

Critical issues: Three distinct families of enzymes consume NAD+ as substrate: poly(ADP-ribose) polymerases (PARPs), ADP-ribosyl cyclases (CD38/CD157) and sirtuins. Two main strategies to increase NAD+ availability have arisen. These strategies are based on the utilization of NAD+ intermediates/precursors or the inhibition of the NAD+-consuming enzymes, PARPs and CD38. An increase in endogenous sirtuin activity seems to mediate the protective effect that enhancing NAD+ availability confers in several models of neurodegeneration and age-related diseases.

Future directions: A growing body of evidence suggests the beneficial role of enhancing NAD+ availability in models of neurodegeneration. The challenge ahead is to establish the value and safety of the long-term use of these strategies for the treatment of neurodegenerative diseases. Antioxid. Redox Signal. 28, 1652-1668.

Keywords: CD38; NAD; PARP; mitochondria; neurodegeneration; oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Humans
  • NAD / metabolism*
  • Neurodegenerative Diseases / metabolism*


  • NAD