ArticleFrontiers in aging neuroscience2025
Treadmill exercise alleviates Alzheimer's disease pathologies in APP/PS1 mice through modulation of microglial glucose metabolic reprogramming.
Article in Frontiers in aging neuroscience, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Exercise and fluoxetine in Alzheimer's disease: Molecular mechanisms of synergistic and antagonistic effects (Review).International journal of molecular medicine · 2026Review
- Forced treadmill running and ladder climbing physical activity attenuates cognitive decline and protein aggregates in aged 3xTg-AD mice.Molecular brain · 2026Article
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4 authors.
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Abstract
Objective: Our preliminary studies have demonstrated that exercise counteracts Alzheimer's disease (AD) by mitigating microglia-mediated neuroinflammation and enhancing microglial Aβ clearance. However, the underlying mechanism remains unclear. Given the crucial role of glucose metabolic reprogramming in regulating microglial functions, this study investigated the effects of treadmill exercise on microglial glucose metabolism and associated AD pathologies. Materials and methods: Three-month-old male APP/PS1 transgenic mice were randomly assigned to a sedentary group (AD-SED) or an exercise group (AD-EXE). Age- and sex-matched C57BL/6 mice served as the wild-type control group (WT-SED). The AD-EXE group underwent a 3-month treadmill exercise intervention. Following the intervention, we assessed spatial learning and memory using the Morris water maze test, measured neuroinflammation and Aβ levels via Western blot and ELISA, and analyzed microglial glucose metabolism using LC-MS/MS targeted metabolomics and Seahorse assays. Results: APP/PS1 mice exhibited longer escape latencies during place navigation trial and fewer platform crossings during the spatial probe trial; these deficits were partially reversed by treadmill exercise. Furthermore, the exercise intervention significantly reduced hippocampal Aβ levels and suppressed neuroinflammation. Notably, microglia from 6-month-old APP/PS1 mice showed significant impairments in both glycolysis and oxidative phosphorylation (OXPHOS), with a metabolic profile primarily reliant on glycolysis. Treadmill exercise enhanced both glycolysis and OXPHOS, and shifted the metabolic phenotype from glycolytic-dominant toward oxidative phosphorylation, and restored metabolic homeostasis. Conclusion: Treadmill exercise promotes microglial glucose metabolic remodeling, which attenuates neuroinflammation and Aβ pathology, and restores spatial learning and memory deficits in APP/PS1 mice.
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