Effects of Aerobic Exercise on Intestinal Mucosal Barrier Function and Anxiety-Like Behavior in APP/PS1 Mice

YUAN Shunling^1,2, LIN Wei¹, DAI Shengyu^1,2, XU Diqun³*, LIU Yiping^1,4*

(¹Provincial University Key Laboratory of Sport and Health Science, School of Physical Education and Sport Sciences, Fujian Normal University, Fuzhou 350117, China; ²School of Kinesiology and Health, Capital University of Physical Education and Sports, Beijing 100191, China; ³School of Physical Education, Minnan Normal University, Zhangzhou 363000, China; ⁴National Sports General Administration Key Laboratory of Motor Function Evaluation, Fuzhou 350117, China)

Abstract:

This study aimed to explore the effects of aerobic exercise on intestinal mucosal barrier function, anxiety-like behavior, and the TLR4/NF-κB signaling pathway in APP/PS1 transgenic AD (Alzheimer’s disease) mouse models. APP/PS1 double transgenic mice were randomly divided into the sedentary group (SE-AD) and the aerobic exercise group (EX-AD), while C57BL/6J mice were raised as the control group (WT). After 12 weeks of aerobic exercise intervention in the mice of the EX-AD group, the open field test was used to evaluate anxiety-like behavior. ELISA was used to measure plasma levels of DAO, D-LA, and LPS. Histological analysis of the colon was performed with HE (hematoxylin-eosin) staining. Immunofluorescence was used to detect ZO-1 and Occludin in the colon. Western blot was performed to determine the expression levels of tight junction proteins, TLR4/MyD88/NF-κB pathway-associated proteins, as well as inflammatory cytokines in the colon. The results showed that aerobic exercise significantly reduced the distance of AD mice in the open field (P<0.01), and significantly increased not only the time spent moving in the central area, but also the percentage of distance traveled (P<0.05, P<0.01). Furthermore, aerobic exercise significantly decreased the plasma levels of DAO, D-LA, and LPS in AD mice (P<0.05, P<0.01). In the SE-AD group, the colon cells had fewer nuclei, a thinner mucosal layer which was loose and porous with epithelial damage, and the columnar cells were fewer and arranged irregularly. In contrast, the EX-AD group showed more colonic cell nuclei, regular arrangement of mucosal columnar cells, and thicker mucosal epithelium. Aerobic exercise significantly increased the fluorescence area of ZO-1 and Occludin in the colon of AD mice (P<0.01), up-regulated the expression levels of Claudin-1, ZO-1 and Occludin (P<0.05, P<0.01), and down-regulated the expression of TLR4, MyD88, NF-κB, TNF-α, and IL-1β (P<0.05, P<0.01). These results suggest that aerobic exercise can improve the intestinal mucosal barrier function and alleviate anxiety-like behavior of AD mice. Its mechanism of action is related to the up-regulation of intestinal tight junction proteins, the reduction of LPS displacement, and the inhibition of the TLR4/MyD88/NF-κB signaling pathway, which in turn reduces the release of inflammatory factors.

CSTR: 32200.14.cjcb.2025.08.0018