NMN alleviates cognitive impairment in Alzheimer's disease by regulating the gut microbiota through the Nrf2/HO-1 pathway

Background Alzheimer's disease (AD) is a complex neurodegenerative disorder, with clinical manifestations mainly including gradual deterioration of cognitive and memory functions, progressive decline in daily living abilities, and neuropsychiatric symptoms and behavioral disorders. Increasing evidence suggests that the gut microbiota plays a role in its pathogenesis. Nicotinamide mononucleotide (NMN), a powerful NAD + precursor, has shown potential in combating age-related pathologies, particularly in neurodegenerative decline. Methods This study explores the potential of NMN in alleviating age-related dementia through in vivo experiments.An aging mouse model was established by D-gal injection for 6 weeks, and NMN oral supplementation intervention was conducted. Behavioral tests (crossed elevated plus maze, Y-maze) and oxidative stress indicators (CAT, GSH, SOD, MDA), as well as inflammatory factors (TNF-α, IL-6, IL-1β) were analyzed simultaneously. The gut microbiota (fecal 16srRNA sequencing) and brain tissue morphology (immunohistochemical staining, fluorescence staining) were evaluated, and the Nrf2/HO-1 pathway was verified by Western blot. Results NMN restored the spatial memory ability of D-gal mice but did not alleviate anxiety responses. Mechanistically, NMN synergistically alleviated oxidative stress and systemic inflammation, increased the level of antioxidant enzymes (SOD), and simultaneously inhibited MDA levels and pro-inflammatory cytokines (TNF-α, IL-6). Hippocampal analysis showed that NMN maintained the normal morphology of brain tissue and alleviated aging dementia caused by D-gal. Fecal 16srRNA sequencing of the gut microbiota revealed changes in the gut microbiota after treatment. The effects observed by WB were related to the expression levels of Nrf2, HO-1. Therefore, the Nrf2/HO-1 signaling pathway is a key mechanism by which NMN exerts protective effects in aging dementia. Conclusion Our research findings establish NMN as a therapeutic agent that maintains neurocognitive function in aging models by regulating the gut microbiota and microglia and coordinating antioxidant, anti-inflammatory, and anti-apoptotic responses. Our research indicates that NMN alleviates inflammation through the Nrf2/HO-1 pathway, inhibits gut microbiota-mediated D-gal-induced aging dementia, and exerts an impact on Alzheimer's disease mice.