Dual Regulatory Effects on Autophagy and Apoptosis: a Preliminary Exploration into the Mechanisms by Which Aerobic Exercise Improves Cognitive Function in APP/PS1 Mice

FAN Congxian^1#, SONG Hehe^2#, JIANG Xu³, ZHANG Meng⁴, TANG Jie¹, GAO Qianfei¹, LIU Tao²*

(¹College of Physical Education and Health, Anhui University of Applied Technology, Hefei 230000, China; ²College of Sports and Health Sciences, Xi’an Physical Education University, Xi’an 710068, China; ³Department of Traditional Chinese Medicine Health, Zaozhuang Vocational College of Appled Techology, Zaozhuang 277000, China; ⁴School of Exercise and Health, Shanghai University of Sport, Shanghai 200438, China)

Abstract:

This study aims to investigate the effects of 8‑week aerobic exercise on cognitive function in a mouse model of AD (Alzheimer’s disease) and analyze whether the underlying mechanisms involve the regula tion of autophagy and apoptosis via the AMPK/ULK1 and PI3K/AKT/mTOR signaling pathways. A total of 48 mice were used in this study, including 24 male C57BL/6 mice and 24 APP/PS1 transgenic mice. Mice of each type (C57BL/6 and APP/PS1) were randomly assigned to either an exercise group or a sedentary control group, resulting in four experimental groups: the control group (Control), the control+exercise group (Control+Ex), the APP/PS1 model control group (APP/PS1), and the APP/PS1+exercise group (APP/PS1+Ex). The Control+Ex and APP/PS1+Ex groups underwent eight weeks of treadmill training. Cognitive function was assessed using the Morris water maze; autophagosome morphology and quantity were observed via transmission electron micros copy; neuronal morphology was evaluated by HE staining and Nissl staining; the expression and localization of autophagy‑related proteins LC3‑II and Beclin1 were detected by immunofluorescence; apoptotic levels were analyzed with TUNEL staining; the deposition levels of Aβ40 and Aβ42 were determined by ELISA; and the ex pression of key proteins in the AMPK/ULK1 and PI3K/AKT/mTOR signaling pathways was quantitatively ana lyzed by Western blot. Compared with the Control group, the APP/PS1 group showed prolonged escape latency (P<0.01), decreased time spent in the target quadrant (P<0.01) and fewer platform crossings (P<0.05), abnormal neuronal structure, reduced autophagic structures, weakened fluorescence intensity of Beclin1 (P<0.05), and de creased protein expression of AMPK, ULK1, PI3K, AKT, and mTOR (P<0.01 or P<0.05). Compared with the APP/PS1 group, the APP/PS1+Ex group showed significant improvement in all the aforementioned indicators (P<0.05 or P<0.01), increased autophagosomes and lysosomes, enhanced fluorescence intensity of LC3‑II and Beclin1 (P<0.05), and significantly upregulated expression of all pathway‑associated proteins (P<0.05). This study preliminarily demonstrates that eight weeks of aerobic exercise can effectively improve cognitive function in APP/PS1 mice. The underlying mechanism may be related to the exercise‑induced coordinated modulation of the AMPK/ULK1 and PI3K/AKT/mTOR signaling pathways in hippocampal neurons: on one hand, by activat ing the AMPK/ULK1 pathway to enhance autophagy and promote Aβ clearance; on the other hand, by maintain ing PI3K/AKT/mTOR pathway activity to inhibit apoptosis and potentially prevent neuronal damage caused by excessive autophagy. This dual‑effect regulatory mode of “enhanced autophagy‑inhibited apoptosis” provides a synergistic neuroprotective approach for exercise intervention in AD, distinct from simple autophagy activators, thereby collectively ameliorating AD pathology and promoting neuronal survival.

CSTR: 32200.14.cjcb.2026.03.0011