A066: Aerobic Exercise Regulates miR3473e/EphB2 Signal Pathway in Improving Synaptic Plasticity in APP/PS1 Mice

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment, with evidence suggesting that exercise can improve cognitive function. Our previous studies demonstrated that aerobic exercise improves cognitive dysfunction and enhances synaptic plasticity in APP/PS1 mice, while identifying the endogenous microRNA-3473e as a potential regulator of neuronal activity and cognitive function. However, the precise mechanism underlying this regulation remains unclear. This study aimed to investigate the mechanism by which aerobic exercise regulates miR3473e to improve synaptic plasticity and cognitive dysfunction in APP/PS1 mice. Exercise intervention was performed on 3-month-old C57BL/6J and APP/PS1 mice with a 12-week moderate-intensity aerobic treadmill training program. The Morris water maze test was employed to assess learning and memory capabilities. Golgi staining was used to evaluate dendritic spine density. Transcriptomic profiling was performed using RNA sequencing (RNA-Seq), followed by bioinformatics analysis and target gene screening. Quantitative reverse transcription PCR (qRT-PCR) was utilized to validate the expression levels of miR-3473e and its downstream targets EphB2 and Slc1a1, as well as synaptic plasticity-related genes CREB, SYN, and PSD95. Western blotting was conducted to examine the protein expression levels of EphB2, PSD95, GluN1, GRIA1, GluN2B, and p-GluN2B. 1) Morris water maze tests revealed that 12 weeks of moderate-intensity aerobic exercise significantly enhanced learning and memory in APP/PS1 mice. 2) Aerobic exercise increased dendritic spine density in the cortex and hippocampus of APP/PS1 mice, accompanied by elevated expression of synaptic plasticity-related genes CREB, SYN, and PSD95. 3) Transcriptomic analysis identified miR-3473e as a candidate target, which was found to be overexpressed in the brains of APP/PS1 mice. Notably, miR-3473e expression was significantly downregulated in aerobic exercise. 4) Aerobic exercise upregulated the expression of miR-3473e downstream targets EphB2 and Slc1a1 in APP/PS1 mice. Furthermore, exercise increased the protein levels of NMDA receptor subunits GluN1 and GluN2B, as well as their phosphorylation (p-GluN2B), and the AMPA receptor subunit GRIA1 in APP/PS1 mice. Conclusion: 1) Aerobic exercise increased dendritic spine density in the cortex and hippocampus of APP/PS1 mice, thereby enhancing synaptic plasticity and ameliorating cognitive deficits. 2) The cognitive and synaptic improvements in APP/PS1 mice following aerobic exercise were mediated through the miR-3473e/EphB2 signaling pathway.