Tth NAD+ is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD+-dependent enzymes are involved in synaptic plasticity and neuronal stress resistance. Here, we review emerging findings that reveal key roles for NAD+ and related metabolites in the adaptation of neurons to a wide range of physiological stressors and in counteracting processes in neurodegenerative diseases, such as those occurring in Alzheimer’s, Parkinson’s, and Huntington diseases, and amyotrophic lateral sclerosis. Advances in understanding the molecular and cellular mechanisms of NAD+-based neuronal resilience will lead to novel approaches for facilitating healthy brain aging and for the treatment of a range of neurological disorders.
NAD+ Synthesis and Metabolism
Nicotinamide adenine dinucleotide (NAD+) is essential for cellular functions. It is synthesized via three main pathways: de novo biosynthesis (kynurenine pathway), Preiss-Handler pathway, and the salvage pathway. The kynurenine pathway, starting with tryptophan, is the primary de novo pathway in mammals, influencing neuronal functions and producing both neuroprotective and neurotoxic metabolites.
The Preiss-Handler pathway converts nicotinic acid (NA) to NAD+, while the salvage pathway recycles nicotinamide (NAM) and nicotinamide riboside (NR) into NAD+. Enzymes like NMNATs and NAMPT are key to these processes. NAD+ cannot cross cell membranes directly and must be converted to smaller molecules like NMN or NR for cellular uptake.
NAD+ Functions in Cells
NAD+ is crucial for metabolism, ATP production, and as a substrate for enzymes involved in longevity and health. It is important in glycolysis, the TCA cycle, and oxidative phosphorylation. The NAD+/NADH ratio affects metabolic homeostasis.
NAD+-consuming enzymes include sirtuins (SIRTs), poly(ADP-ribose) polymerases (PARPs), CD38/CD157, and SARM1. SIRTs regulate metabolism and neuronal survival. PARPs, especially PARP1, are involved in DNA repair and cell death. Excessive PARP1 activation depletes NAD+ and ATP, leading to neuronal loss.
CD38 influences immunity, metabolism, and social behaviors, and its activity increases with age, depleting NAD+. SARM1, an NADase, is implicated in axonal degeneration and is a potential therapeutic target for neurodegenerative diseases. These enzymes compete for NAD+, affecting cellular health.
