Abstract: Objective: To investigate the effect of 12-week aerobic treadmill exercise on microglial NAMPT and its role in improving mitochondrial dysfunction through upregulating the NAD⁺/SIRT1/FOXO1/3a signaling pathway in hippocampus of APP/PS1 mice.Methods: 3-month-old wild type C57BL/6 mice and APP/PS1 mice were randomly divided into wild type control group（WT-sed）,wild type exercise group（WT-exe）, APP/PS1control group（AD-sed）, and APP/PS1 exercise group（AD-exe）. Mice in exercise group was conducted 12-week aerobic treadmill exercise intervention. After the intervention, morris water maze was used to detect the learning and memory abilities of mice. Immunofluorescence was used to measure the expression of Iba-1 expression and colocalization level of NAMPT and Iba-1 in hippocampal microglia. The hippocampal mitochondrial ultrastructure was detected by the transmission electron microscopy. Western blot was used to detect the protein expression levels of SIRT1, Ace-FOXO1/3a, PARP1,and CD38 in the hippocampus. RT-PCR was used to detect the mRNA expression levels of mtDNA, PARP1, and CD38. ELISA and kit were used to detect the content of NAD⁺, NADH, IL-6, IL-1β, TNF-α, ATP, and H₂O₂. Results: Compared with WT-sed, the levels of NAMPT and Iba-1 co-localization, PARP1, CD38, Ace-FOXO1/3a, IL-6, IL-1β, TNF-α, H₂O₂ and the number of damaged mitochondria were significantly increased, but the NAD⁺ content, NAD⁺/NADH ratio, SIRT1, mtDNA copy number, ATP content and learning and memory ability were significantly decreased in AD-sed mice. However, the 12-week aerobic treadmill exercise significantly improved the aforementioned abnormal changes in the hippocampus of APP/PS1 mice. Conclusions: 12-week aerobic treadmill exercise intervention could inhibit the overexpression of NAMPT in microglia, reduce neuroinflammatory response,decrease the consumption of NAD⁺ by inhibiting PARP1 and CD38, and then upregulate the NAD⁺/SIRT1/FOXO1/3a signaling pathway, improve mitochondrial dysfunction, and ultimately alleviate the decline of learning and memory in APP/PS1 mice.