Influence of Exercise Training on Expression of Some Cerebral Proteins Involved in APP Processing in Rat Models of Alzheimer's Disease: A Meta-Analysis

Background and Purpose
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The amyloid-β (Aβ) peptide, derived from the cleavage of amyloid precursor protein (APP), is a key therapeutic target in AD. APP is processed via two pathways: the non-amyloidogenic pathway, mediated by α-secretase (ADAM10), and the amyloidogenic pathway, mediated by β-secretase (BACE1). The balance between these pathways determines Aβ production, with dysregulation contributing to AD pathogenesis.
Exercise on the other hand has been shown to modulate APP processing, shifting it toward the non-amyloidogenic pathway to reduce Aβ production. However, the underlying mechanisms is poorly understood. This study aimed to systematically review and meta-analyze the effects of exercise training on cerebral ADAM10, BACE1, sAPPα, sAPPβ, and Aβ expression, as well as spatial memory function in rat models of AD.
 
Materials and Methods
This systematic review and meta-analysis followed PRISMA guidelines. Animal studies with control groups investigating the effects of at least 3 weeks of exercise training in rat models of AD, published in peer-reviewed journals up to July 2024, were retrieved from PubMed, Google Scholar, SID, and Magiran databases. Studies combining exercise with other interventions, Duplicate publications and review articles were excluded from analysis. Two reviewers independently screened titles and abstracts for eligibility. Disagreements were resolved through consultation with a third reviewer.
Random-effects model was used to calculate standardized mean differences (SMD) and 95% confidence intervals (CIs). Heterogeneity was assessed using the I² statistic, with values >50% indicating high heterogeneity. Publication bias was evaluated using Egger’s regression test. Meta-regression and subgroup analyses were performed to explore the effects of moderators.
 Findings
A total of 14 interventions were included in the meta-analysis. Primary Outcome measure was Cerebral ADAM10 Expression. High heterogeneity (I² > 50%) was observed for all outcomes.
Egger’s regression indicated no significant publication bias. The net effect of exercise training on ADAM10 expression was not statistically significant (SMD = 0.73, 95% CI: -0.43 to 1.91). moreover, subgroup analysis revealed a significant increase in hippocampal ADAM10 expression (SMD = 2.48, p = 0.001).
Secondary Outcomes are listed below:
Cerebral BACE1 Expression: No significant overall effect was observed. Subgroup analysis showed a significant decrease in hippocampal BACE1 expression (SMD = -2.03, p = 0.001).
sAPPα and sAPPβ Expression: Exercise training significantly reduced sAPPβ expression (SMD = -2.59, 95% CI: -3.80 to -1.39). No significant effect was observed for sAPPα.
Aβ Expression: Exercise training significantly reduced Aβ expression (SMD = -4.03, 95% CI: -5.13 to -2.92).
Spatial Memory Function: Exercise training improved spatial memory function, though heterogeneity was high.
 Conclusion
The findings suggest that exercise training modulates APP processing in rat models of AD, favoring an elevated hippocampal non-amyloidogenic pathway, based on a significant increase in ADAM10 expression in this region.
On the other hand, a dimineshed hippocampal BACE1 expression could be indicate on a suppressed amyloidogenic pathway which is thought to can reduced cerebral Aβ burden. Other finding of this study was related to a significant decrease in Aβ expression which is in line with our previous findings to reduce amyloid burden.
The exact mechanisms of exercise training in reduction of cerebral Aβ burden was attributed to induce a shif in APP processing toward the non-amyloidogenic pathway through upregulation of ADAM10 and downregulation of BACE1. Morereover, exercise-induced increases in brain-derived neurotrophic factor (BDNF) may further modulate APP processing and reduce Aβ production. However, this study has some limmitations e.g high heterogeneity across studies that limits the generalizability of the findings. Furthuremore, most of included studies used rodent models, which their results can not be fully generalizable to human patients. Additionally, variability in exercise protocols and outcome measures may contribute to inconsistent results.
Anyway, exercise training shows promise as a non-pharmacological intervention for reducing amyloid burden in AD, however, more clinical trials remain to be provided in human subjects. The observed increases in ADAM10 and converse decreases in BACE1 and Aβ expression, particularly in the hippocampus, suggest that exercise may mitigate amyloid pathology in early AD stages.
For future research it is suggested to conduct longitudinal studies to assess the long-term effects of exercise on APP processing and Aβ levels. Moreover, investigating the straight role of exercise-induced BDNF in modulating APP processing could be instumental. Additionally, it seems exact exploration the effects of different exercise modalities (e.g., aerobic, resistance) on AD biomarkers should be conducted in the future studies in thia area.
Article Message
Increased expression of ADAM10 and decreased expression of BACE1 in the hippocampus, along with reduced sAPPβ and Aβ levels in mixed brain tissue samples of AD modes due to exercise training, herald a potential reduction in cerebral amyloid burden, especially in the early stages of AD; however, these findings still need to be confirmed in human patients.
 Acknowledgments
Thanks, and appreciation are extended to all individuals or groups who collaborated in conducting this research.
 Conflict of interest
The authors declare no competing interests regarding the publication of this article.