# Advances in the Synthesis and Physiological Metabolic Regulation of Nicotinamide Mononucleotide
## 4 NMN Regulates Physiological Metabolism
### Effects on Neurodegeneration  
Older mammals have lower levels of NAD\({}^{+}\) in brain cells, which is correlated with a higher incidence of neurodegeneration [124]. Although it has been observed in age-related neurodegenerative diseases, including Alzheimer's disease [125], Parkinson's disease [126], and amyotrophic lateral sclerosis (ALS) [127], the underlying causes and mechanisms of NAD\({}^{+}\) loss in brain cells in these patients remain largely unknown. Various lines of evidence support a neuroprotective effect of NAD\({}^{+}\)[128; 129]. Rapid depletion of NADhas been found to be a major contributor to axonal degeneration and neuronal derangement [130]. During axonal degeneration, the transport of nicotinamide mononucleotide adenosyltransferase 2 (NMNAT2) along axons is hindered, resulting in rapid degradation of the axonal pool of this protein, leading to significant depletion of NAD\({}^{+}\) levels within axons [131]. Conversely, axonal injury activates the NAD\({}^{+}\)-depleting enzyme SARM1, which facilitates axonal degradation by accelerating NAD\({}^{+}\) breakdown [132]. The role of NMNAT2 and SARM1 in axonal injury has been demonstrated in several models [133]. In mice, Sarm1 knockout can prevent axonal degeneration and rescue severe axonal growth defects as well as related diseases caused by the lack of NMNAT2 [134].  
Furthermore, it has been reported that the expression of the NAD\({}^{+}\)-depleting enzyme CD38 is increased during the development of Alzheimer's disease. Conversely, NAD\({}^{+}\) levels were found to be elevated in the brains of a CD38 knockout mouse model, which also showed a milder disease phenotype [135]. Pro-inflammatory cytokines also induce high levels of CD38 in microglia, astrocytes, neurons, and endothelial cells in the brain [136]. These findings consistently show that CD38 expression is associated with high levels of pro-inflammatory microglia and neuroinflammation in the mouse brain. In addition, activation of the NAD\({}^{+}\)-depleting enzyme PARP1 is also involved in the pathogenesis of [PERSON]'s and Parkinson's disease [136; 137]. In vivo studies using various models of these diseases have shown that the knockdown of PARP1 protects the brain from dysfunction and cognitive decline [138]. As a central metabolite for maintaining a healthy nervous system, NAD\({}^{+}\) can, therefore, affect the biological function of various brain cell types [139; 140]. Accordingly, counteracting the decline of NAD\({}^{+}\) levels associated with aging may be an effective strategy for treating neurodegeneration. It is noteworthy that NMN supplementation to restore NAD\({}^{+}\) levels resulted in demonstrable improvements in neural cell health, memory, and cognitive function in rat and mouse models of Alzheimer's disease [141; 142]. NMN treatment also exhibited neuroprotective effects in a _Drosophila_ model of Parkinson's disease and a mouse model of amyotrophic lateral sclerosis (ALS) [5]. Importantly, clinical trials also tested NMN for the treatment of neurological diseases and the promotion of healthy aging [111]. These experiments will undoubtedly expand our understanding of NMN/NAD\({}^{+}\) metabolism during human neurodegeneration.