NAD⁺ Supplementation Attenuates Neuroinflammation in Mouse Models of Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. DNA damage and mitochondrial dysfunction have been implicated in the aging process and in age-associated neurodegenerative diseases, including AD. We developed a DNA repair-deficient 3xTgAD/Polβ^+/− mouse that exacerbates major features of human AD. Emerging evidence has identified NAD⁺ as a major metabolic factor with anti-aging properties in laboratory animals and humans. NAD⁺ precursor nicotinamide riboside (NR) -treated 3xTgAD/Polβ^+/− mice exhibited reduced DNA damage, normalized behaviors and neuroinflammation (Hou et al., 2018). Microarray analysis of pathways in hippocampus and cortex of our mice showed that immune-related pathways are activated in AD mice and deactivated after NR treatment. However, the molecular mechanisms of the beneficial effects of NAD⁺ supplementation on neuroinflammation in AD pathogenesis remain elusive. Here, we used APP/PS1 AD mice and found that NR increased the NAD⁺/NADH ratio and attenuated brain neuroinflammation by downregulating the NLRP3 inflammasome. NR also attenuated DNA damage and apoptosis in the AD mouse brains. Recent research has provided strong evidence that genomic DNA damage can lead to cyclic GMP-AMP synthase (cGAS) activation which stimulates inflammatory processes. Interestingly, we found that cGAS and stimulator of interferon genes (STING) were increased in AD mice and decreased after NR treatment. These results suggest that the cGAS-STING pathway may contribute to neuroinflammation in AD, which could be a potential novel therapeutic target for AD. Together our results show that NAD⁺ supplementation attenuates neuroinflammation in AD models.

This research was supported by the Intramural Research Program of the NIH, National Institute on Aging.

Ref:

Hou, Y., Lautrup, S., Cordonnier, S., Wang, Y., Croteau, D.L., Zavala, E., Zhang, Y., Moritoh, K., et al. and Bohr, A.V. (2018). NAD(+) supplementation normalizes key Alzheimer`s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A 115, E1876-E1885.