PHYSICAL EXERCISE PROMOTES INTEGRATED MUSCLE AND MOTOR CORTEX PLASTICITY THROUGH SYNAPTIC REMODELING AND GLIAL REGULATION IN 3XTG-AD MICE

Alzheimer’s disease (AD) is the leading cause of dementia, affecting around 60 million people worldwide. Beyond its characteristic cognitive decline, motor impairments and structural changes in motor-related brain regions are also frequent. The 3xTg-AD mouse model reproduces multiple pathological features of AD, including motor deficits. Physical exercise represents a promising non-pharmacological strategy capable of modulating both central and peripheral mechanisms; however, its effects on the muscle–brain axis and motor cortical plasticity remain poorly understood. Here, we evaluated whether a mixed exercise paradigm could enhance motor performance, muscle structure, and cortical remodeling in 3xTg-AD mice. Sixty-four 12-month-old male mice were assigned to four groups (n = 16): Non-Tg sedentary, Non-Tg exercise, 3xTg-AD sedentary, and 3xTg-AD exercise. The exercise groups completed 16 weeks of training combining voluntary wheel running (3 sessions/week) and treadmill exercise (2 sessions/week). Motor function was evaluated through open field, four-limb pressure, beam walk, and gait tests, while recognition memory was assessed using the novel object recognition task. Body composition and muscle histology were analyzed alongside mitochondrial complex activity in brain and muscle. In the motor cortex, synaptic and glial plasticity were evaluated by Golgi staining and immunolabeling for synaptophysin, PSD95, Iba1, and GFAP. Exercise attenuated motor deficits, preserved muscle mass, reduced fiber atrophy, and partially restored mitochondrial function. In parallel, it enhanced synaptic integrity and modulated microglial and astrocytic activation. These findings suggest that physical exercise promotes coordinated muscle and cortical remodeling, supporting motor function and neuroplasticity in advanced stages of Alzheimer’s disease.