Neuroprotection through adiponectin receptor agonist: an updated meta-analysis of preclinical Alzheimer’s disease studies

Abstract

Background: Alzheimer’s disease (AD) is a leading cause of dementia, imposing a substantial burden on individuals and society. While existing therapies can reduce the symptoms of AD, they do not offer genuine therapeutic effectiveness. Adiponectin Receptor Agonist (ADN-R Ag) has been proposed as a novel therapeutic agent for AD. This study aims to evaluate its efficacy in treating AD model mice. Methods: A systematic search of PubMed, Scopus, Cochrane Library, and Web of Science was conducted up to May 3, 2025. Research investigating the impact of ADN-R Ag on cognitive performance and associated molecular pathways in Alzheimer’s disease models, specifically APP/PS1, P301S, and 5XFAD mice, was incorporated. The Alzheimer’s disease models in the study were male and ranged in age from 5.5 to 8 months. Studies evaluating the effect of ADN-R Ag on AD model mice through cognitive function tests and related molecular mechanisms were included. Methodological quality assessment was performed using the CAMARADES tool for animal studies. The meta-analysis was performed following Cochrane guidelines. Results: Six articles were included for the review. ADN-R Ag significantly improved cognitive function in the meta-analysis. The weighted mean difference of ADN-R Ag was 21.75 (95% CI: 16.61–26.88; p < 0.001) for alternation rate percentage in the Y-maze, 20.46 (95% CI: 11.41–29.51, p < 0.001) for novel object exploration time percentage in the novel object recognition (NOR) test, -15.83 (95% CI: -23.33 to -8.32, p < 0.001) for escape latency in the Morris water maze (MWM), and 13.89 (95% CI: 8.84–18.94; p < 0.001) for target quadrant time in the probe test. Additionally, ADN-R Ag was reported to mitigate AD pathology by reducing Aβ depositions through inhibition of GSK3β/BACE1/NF-κB pathway, suppressing neuronal inflammation by suppressing microglial and astrocytes activity and reducing and IL1β and TNFα levels, enhancing autophagy, and improving mitochondrial function with significant involvement of the AMPK pathway. Conclusion: Based on the current study, ADN-R Ag has therapeutic effects on AD. However, considering the complex underlying molecular mechanisms and limited prior studies, further research is needed.