Combined effects of tactile stimulation and aerobic exercise on BDNF-related pathways and neurofunctional outcomes in an early-stage 5xFAD mouse model of Alzheimer's disease.

Alzheimer's disease (AD) lacks effective early-stage non-pharmacological interventions capable of simultaneously targeting neurotrophic signaling and neurofunctional decline. This study examined the early-stage effects of tactile stimulation (TS), aerobic exercise (Ex), and their combination (TS + Ex) on behavioral, molecular, and histopathological outcomes in 5xFAD mouse model of AD. Twenty-eight male transgenic 5xFAD mice (7-8 weeks old) were randomly assigned to four groups: control (n = 7), TS (n = 7), Ex (n = 7), and TS + Ex (n = 7). Interventions were applied for eight weeks, 5 days per week, with daily 30-minute sessions. Behavioral assessments were conducted, and biochemical analyses measured brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), fibroblast growth factor-2 (FGF-2), irisin, lactate, total antioxidant status (TAS), total oxidant status (TOS), and myeloperoxidase (MPO) levels in brain, muscle, skin, and serum tissues. Histological, immunofluorescent, and ultrastructural evaluations were performed in the hippocampus. Compared to control, the TS + Ex group showed significant improvements in motor performance, neurotrophic factor levels, irisin and lactate concentrations, and antioxidant capacity in 5xFAD mice (p = 0.05-<0.001, partial η²=0.498-0.902). Additionally, increased doublecortin expression (p = 0.032, partial η²=0.571) and improved histopathological architecture were observed. Aerobic exercise alone improved motor function, anxiety-related behaviors, modulated several biochemical and histological outcomes compared with the control (p = 0.05 - 0.004, partial η²=0.332-0.498). TS alone produced limited effects, with notable increases only in hippocampal BDNF (p < 0.001, partial η²=0.712) and lactate levels (p = 0.015, partial η²=0.605) compared with the control group. The combination of TS and Ex may exert synergistic neuroprotective effects, suggesting that multimodal non-pharmacological strategies could represent promising early-stage interventions for mitigating AD-related pathology.