NAD+ Precursor Enhances Adult Brain Cell Production and Motor Function in ALS Mice

Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s disease, is caused by the progressive deterioration of cells throughout the nervous system called motor neurons that control our muscle movements, prompting muscle weakness and eventual paralysis. Still, there is a lack of effective drugs for treating ALS. The decline in levels of a vital molecule called nicotinamide adenine dinucleotide (NAD+) is seen in many neurological diseases. In adult mice, boosting NAD+ levels promotes the maintenance of brain stem cells, which are affected in ALS and are critical for neurogenesis, the process of forming new neurons. Yet, the effects of NAD+ levels on the nervous system in ALS has been unclear.

Researchers from the Affiliated People’s Hospital of Nanchang University in China published an article in the International Journal of Biological Sciences revealing that mice treated with the NAD+ precursor nicotinamide riboside (NR) in their drinking water exhibited better motor function. They observed that supplementation with 400 mg/kg/day of NR enhanced the proliferation and migration of neural stem cells in the brain of ALS mice but did not postpone the onset of disease or extend their lifespan. “NR may be a viable clinical therapeutic scheme of translational medicine for ALS and other neurodegenerative diseases,” said the authors in their study.

The regulation of proteins in the mitochondria, the primary site of energy acquisition in cells, has been proposed to be important in the age-related decline. Recent studies have implicated a mitochondrial stress response as a connection between mitochondria and aging in different organisms. The consumption of NAD+ is a related pathway to mitochondrial damage in many situations, and replenishment of NAD+ can counteract mitochondrial stress.

Research shows that brain stem cells, which are necessary for forming new neurons, are affected in ALS mice, and there are several lines of proof supporting the role of NAD+ supplementation for reestablishing the function of brain stem cells during aging. Collectively, this suggests that boosting NAD+ levels by administering NAD+ precursors might be therapeutic against ALS disease by affecting mitochondrial dysfunction and adult neurogenesis.

NR Clears Toxic Proteins and Promotes Neurogenesis

In this study, the investigators showed that aging ALS mice had declining levels of NAD+ and that treatment with NR had several therapeutic effects, such as improved motor function. They observed that the NR treatment significantly attenuated the ALS-induced loss of neural stem cells. In the meantime, the NR administration also continually renewed the pool of immature neurons, jointly suggesting the promotion of the proliferation and migration of neural stem cells was improved by NR in the brain of ALS mice.

The investigators observed that the balance of proteins in mitochondria, which indicates its functionality, was disrupted in the brain of ALS mice. They observed that the protein that is mutated in ALS called hSOD1 (human superoxide dismutase 1) aggregated in the mitochondria of the nervous system and that NR supplementation promoted the clearance of the mutant hSOD1 toxic protein from the nervous system in ALS mice. They found that mitochondrial stress response proteins were increased in the brain of ALS mice after the NR treatment. “Our observations provided evidence that the recharging of intracellular NAD+ by providing NR might decrease the neurotoxic impacts of protein aggregates of mitochondria in the brain of ALS mice,” said the investigators in their study.

Although the investigators saw enhanced motor function, clearance of the neurotoxic protein hSOD1, and mitochondrial stress response, NR treatment did not delay tremors, an indicator of disease onset, or extend the lifespan of ALS mice. The investigators propose that, although studies have shown that NAD+ intervention increases the lifespan of mice, they did not observe an increased lifespan in ALS mice treated with NR due to insufficient supplementation or a difference in the treatment regimen.

In summary, these findings reveal that the administration of NR activates the mitochondrial stress response to clear toxic proteins and improves the adult neurogenesis in the brains of ALS mice as well as some motor function. “We conclude that the NR…improves adult neurogenesis in the brain of [ALS] mice, and NR may be a viable clinical therapeutic scheme of translational medicine for ALS and other neurodegenerative diseases,” said the investigators in their study.