Author(s): PEREIRA, A., OTAVIANO, S., FIGUEIREDO, E., CAMPOS, H., PEDROSA, V., SHECAIRA, T., NASCIMENTO, A., DE ANGELIS, K., ARIDA, R., LONGO, B., Institution: FEDERAL UNIVERSITY OF SAO PAULO - UNIFESP, Country: BRAZIL, Abstract-ID: 1639

INTRODUCTION:
Alzheimer’s disease (AD) is the leading cause of dementia in older adults and is characterized by progressive cognitive decline, memory impairment, and neuronal dysfunction. Resistance exercise (RE) supports brain and muscle health by improving cognitive function and protecting against age-related sarcopenia. However, the long-term effects of RE in AD brain and skeletal muscle remain unknown, particularly when initiated early in life and before symptom onset. Here, we investigated the effects of a long-term RE protocol initiated during the pre-symptomatic stage in APP/PS1 mice, an established model of AD, assessing behavioral outcomes, amyloid pathology and neurogenesis in the hippocampus, and oxidative stress markers in skeletal muscle.
METHODS:
Two-month-old male APP/PS1 and wild-type (WT) mice were assigned to four groups: WT sedentary (WT-SED; n=12), WT resistance exercise (WT-RE; n=10), APP/PS1 sedentary (AD-SED; n=11), and APP/PS1 resistance exercise (AD-RE; n=11). Trained groups performed 26 consecutive weeks (6 months) of RE using a ladder-climbing paradigm with increasing progressive load. At the end of the RE program, mice underwent behavioral testing to evaluate locomotor activity, and learning and memory function. Immunohistochemistry was processed for hippocampal analyses to quantify amyloid-β (Aβ) plaque burden (6E10) and neurogenesis in the dentate gyrus (DCX), and oxidative stress markers were assessed in the gastrocnemius muscle.
RESULTS:
In APP/PS1 mice, RE reduced hyperlocomotion (p<0.001) and rescued spatial learning and memory deficits (p<0.001; p=0.002, respectively), restoring performance to WT levels. RE also maintained dentate gyrus neurogenesis at WT-like levels (p=0.027) and reduced hippocampal Aβ plaque burden (p=0.007). In the gastrocnemius muscle, RE modulated oxidative stress-related markers, reducing protein carbonyls (p=0.007) and hydrogen peroxide levels (p=0.014) while increasing total antioxidant capacity (FRAP; p=0.015) when compared to WT SED.
CONCLUSION:
Long-term RE initiated before symptom onset produced robust central and peripheral benefits in APP/PS1 mice, improving behavior, enhancing hippocampal neurogenesis, reducing amyloid pathology, and reducing muscle oxidative stress. These findings support RE as a promising non-pharmacological strategy to delay AD-related disease progression and preserve central and peripheral functions.