Effects of Aerobic Exercise on Endoplasmic Reticulum Stress and Autophagy Coupling in Hippocampus of APP/PS1 Mice

Objective: To explore the effects of 3 months moderate intensity aerobic exercise on AD pathology and endoplasmic reticulum stress autophagy coupling in APP/PS1 mice. Methods: 3-month old male APP/PS1 transgenic mice and wild type mice were randomly divided into wild type control group(WT-Sed), wild type exercise group(WT-Exe), APP/PS1 control group(APP/PS1-Sed) and APP/PS1 exercise group(APP/PS1-Exe). Mice in APP/PS1-Exe group and WT-Exe group were subjected to treadmill exercise for 3 months. After intervention, the immunohistochemistry was used to detect the Aβ plaque, the co-localization of APP and GRP78, CRT and LC3 in hippocampus. Western blotting and Simple western were used to detect the protein levels of PERK, pPERK, eIF2α, p-eIF2α, ATF4, LC3, P62 and CRT in hippocampus. Real-time PCR was used to detect the mRNA levels of ATG5,ATG7, ATG12, BECN1 and CRT in hippocampus. Results: Compared with WT-Sed group, the level of Aβ plaque, the colocalization level of APP/GRP78 and the average fluorescence intensity of APP and GRP78 were significantly increased in APP/PS1-Sed mice; the protein levels of p-PERK, p-eIF2α and ATF4 were significantly increased in APP/PS1-Sed mice; the mRNA levels of BECN1 and ATG7 were significantly decreased, the mRNA level of ATG12 and the protein levels of LC3 Ⅱ and P62 were significantly increased, the mRNA and protein levels of CRT were significantly decreased in APP/PS1-Sed mice; the average fluorescence intensity of CRT was significantly decreased, and the average fluorescence intensity of LC3 was significantly increased in APP/PS1-Sed mice. Compared with APP/PS1-Sed group, the level of Aβ plaque, the co-localization level of APP/GRP78 and the average fluorescence intensity of GRP78 in APP/PS1-Exe mice were significantly decreased; the protein levels of p-PERK, p-eIF2αand ATF4 in APP/PS1-Exe mice were significantly decreased; the mRNA level of ATG12 was significantly increased, and the protein level of P62 was significantly decreased in APP/PS1-Exe mice; the protein level of CRT, and the average fluorescence intensity of CRT was significantly increased in APP/PS1-Exe mice. Conclusion: Treadmill exercise could decrease APP accumulation in endoplasmic reticulum, alleviate endoplasmic reticulum stress and inhibit PERK/eIF2α excessive activation, which improves autophagy activity and upregulate CRT mediated ERS-autophagy coupling, thus may serve as a useful approach in reducing the generation and aggregation of misfolded proteins in AD brain.