Effect Of Treadmill Running On Gut Microbiota And Alzheimer’S Disease Neuropathology In Triple Transgenic Mice

Abstract

The brain-gut-microbiota axis is involved in neurodegenerative disorders such as Alzheimer’s disease (AD). The therapeutic roles of exercise training against AD pathology have been well-established in animal studies. The findings from recent studies show that exercise training induces symbiotic changes in the gut microbiota. PURPOSE: To the effect of exercise training on the gut microbiota and AD neuropathology in triple transgenic (3xTg)-AD mice. METHODS: At 3 months of age, 11 wild type (WT) and 22 transgenic mice were randomly assigned to either WT control (WT, n = 11) or AD control (AD, n = 11) or AD exercise (AD-EXE, n = 11). AD-EXE mice were subjected to treadmill running at a moderate intensity with a frequency of 5 days per week for 20 weeks. Morris water maze (MWM) was conducted to evaluate cognition and memory, and fecal samples were collected to assess the gut environment. Blood and brain samples were collected for biochemical and histological assays, respectively. RESULTS: After 20-week-treadmill running, AD+EXE mice had better MWM-based cognitive performance (p < 0.05) compared to AD mice. AD+EXE mice were characterized by increased Akkermansiaceae and Bacteriodaceae species in conjunction with decreased Clostridaceae and Erysipelotrichaceae species compared to AD mice. In the affected regions of the brain, AD+EXE mice had attenuations in selective loss of tight junction-associated blood barrier proteins (i.e., claudin and ZO1), AD neuropathology (i.e., amyloid precursor protein, β-site APP cleaving enzyme 1, p-tau), neuroinflammation and apoptosis in conjunction with enhanced neurogenesis (i.e., bran-derived neurotrophic factor), better synaptic stability/plasticity and enhanced antioxidation (i.e., anti-oxidant superoxide dismutase, and catalase) compared to AD mice. CONCLUSIONS: The current findings of the study suggested that treadmill running induced changes in the gut microbiota composition and attenuated AD neuropathology in the 3xTg-AD mice. Yet, the exact mechanism(s) by which the brain-gut-microbiota axis leads to the therapeutic effects of treadmill exercise on AD neuropathology remain to be further investigated. This work was supported by the Ministry of Education of the Republic of Korea and the National Research Foundation of Korea (NRF-2020R1A2C1009365).