The role of microRNAs in understanding sex-based differences in Alzheimer’s disease

Abstract

Background: Alzheimer's disease (AD) is the most frequent cause of dementia and its incidence is expected to rise as the life expectancy of the population increases. Sex-based differences in AD development have been described, although there are still uncertainties on the role of biological sex in molecular mechanisms of the disease. The study of sex-specific expression profiles of regulatory elements, such as microRNAs (miRNAs), could contribute to a more accurate diagnosis and treatment of the disease. Methods: We conducted a systematic review identifying five studies of microRNA expression in AD that incorporated the biological sex of the samples published in the Gene Expression Omnibus (GEO) repository. Differential expression analyses were performed for each study, considering both disease and biological sex of patients. Subsequently, results were integrated with a meta-analysis methodology. Finally, functional enrichment of the meta-analyses results was performed to establish an association between altered miRNA expression and relevant terms of the Gene Ontology (GO). Results: Meta-analyses of miRNAs expression in blood samples revealed 16 and 22 miRNAs altered in females and males, respectively. Moreover, 9 miRNAs were commonly overexpressed in both sexes, unveiling common miRNAs dysregulation profiles. In contrast, functional enrichment revealed sex-differences in biological processes altered. In males, most of the affected processes were related to ubiquitination, regulation of different kinase activities and apoptotic processes; but in females were linked to RNA splicing and translation. Meta-analyses of brain samples also revealed some alterations in miRNAs expression (6 in females and 4 in males). The unique miRNA altered in both sexes (miR-767-5p) was underexpressed in both males and females. Nonetheless, the functional enrichment analysis did not reveal any affected biological process. Conclusions: Sex-specific meta-analyses allowed for the detection of differentially expressed miRNAs in females and males. Identification of deregulated miRNAs highlighted the relevance of the sex information in biomedical data. Further studies centered on miRNA regulation should meet criteria for comparability and standardization of information.