Physical Exercise As a Therapeutic Strategy in Animal Models of Alzheimer's Disease: Molecular, Behavioral, and Histopathological Evidence Publisher



Behrouzfar H ; Gholami M ; Hassani S ; Maghsoudi A S ; Bekheir S A
Source: Biochemistry and Biophysics Reports Published:2026

Abstract

Background Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide, imposing a substantial economic burden. As the population ages and cases rise, interest in early identification, prevention, and treatment has intensified. After establishing that pathology involves neurofibrillary tangles, neuroinflammation, and neuronal loss, interventions have been tested in laboratory animals to slow disease progression. One commonly tested intervention is physical exercise, an economical approach. Laboratory animal models of AD aim to demonstrate how different types and intensities of exercise affect disease pathology. This review aims to categorize and elucidate the mechanisms and their outcomes. Materials and methods Original manuscripts concerning the impact of exercise, with or without medicinal intervention, on Alzheimer's dementia progression modeled in laboratory animals from 2020 onwards were included. The routes through which exercise exerts its impact at molecular, behavioral, and histomorphological levels were categorized. Results The most frequent modeling approach was Aβ injection into the hippocampus of Wistar rats, followed by Streptozocin and other chemicals, and transgenic models. Exercise mainly consisted of treadmill or swimming. Interventions were categorized into short-, medium-, and long-term protocols, ranging from 3 to 24 weeks, with most at 4 weeks, 30–60 min per session, 5 days/week. Molecular tests primarily measured Reactive Oxygen Species (ROS), while the most common behavioral test was the Morris Water Maze (MWM), assessing learning and memory. Histopathological assessments focused on β-Amyloid plaque formation, dark cells, and glial activation. Most studies agreed on AD modeling methods, but exercise protocols varied in intensity, duration, and type. The combined use of molecular, behavioral, and histological tests to assess intervention effects was consistent. Conclusion Physical exercise has been linked to lower oxidative stress and neuroinflammation, enhanced cognitive function, and fewer pathological changes in animal models of AD. However, variability in disease models and exercise protocols makes it difficult to identify the best exercise approach. © 2026 The Authors.