Distinct effects of long-term resistance exercise on cognitive deficits,neurotrophins,and amyloid pathology in male and female APP/PS1 mice

Abstract

Background

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by cognitive decline, memory impairment, and neuronal and vascular dysfunction. Men and women respond differently to AD progression, with women at higher risk due to hormonal, metabolic, and immune differences that increase brain vulnerability. Physical exercise benefits brain health by improving cognition, modulating inflammation, and promoting vascular and neurotrophic activity. However, the long-term effects of resistance exercise (RE) on brain health, particularly regarding sex differences, remain unclear.

Objective

This study investigated the effects of a long-term RE protocol on the APP/PS1 transgenic mouse model, evaluating behavior, neurotrophic factor levels, and amyloid pathology in males and females.

Methods

Male and female APP/PS1 and wild-type (WT) mice underwent a 4-month RE protocol using a ladder-climbing paradigm. Behavioral tests included open field, object recognition, and T-maze tests. Hippocampal tissue was analyzed via ELISA (VEGF, IGF-1, BDNF, Aβ) and immunohistochemistry (amyloid plaques).

Results

RE had sex-dependent effects. In female APP/PS1 mice, RE reduced hyperlocomotion, rescued short-term memory, increased VEGF levels, and reduced brain Aβ and plaque burden. In male APP/PS1 mice, RE rescued learning and long-term memory, increased IGF-1 and BDNF levels, and reduced hyperlocomotion, although no significant reduction in Aβ or plaque burden was observed.

Conclusions

These findings highlight sex-specific effects of RE in AD and suggest potential personalized exercise-based interventions for delaying disease progression.