Treadmill Exercise Inhibits Microglial NAMPT Expression and Upregulates NAD+/SIRT1 Pathway to Improve Mitochondrial Function in the Hippocampus of AD Mice
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 co-localization 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.
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