miRNAs, genes e vias regulatórias em comum na doença de Alzheimer e no diabetes mellitus tipo 2: uma análise integrativa de revisão sistemática, bioinformática e aprendizado de máquina.

Abstract

Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) are conditions of significant clinical and epidemiological relevance, primarily affecting adults and the elderly. Evidence suggests that diabetic patients are more predisposed to developing AD, prompting studies aimed at elucidating the shared mechanisms between AD and T2DM. One hypothesis involves the participation of microRNAs (miRNAs), which are key molecules in the regulation of gene expression. This study aimed to identify circulating miRNAs commonly expressed in patients with AD and T2DM, as well as the genes and molecular pathways regulated by these miRNAs and potential therapeutic interventions. Two independent systematic literature reviews (SRs) were conducted to identify differentially expressed miRNAs in AD and T2DM compared to their respective controls. Searches were performed in the EMBASE, Medline/PubMed, Cochrane, Scopus, Cinahl, and Web of Science databases, as well as in grey literature and reference lists. The systematic reviews were conducted in a standardized manner, following the recommendations of the Joanna Briggs Institute’s Manual for Evidence Synthesis and the reporting of results according to PRISMA guidelines. Data were compared to identify miRNAs differentially expressed in both AD and T2DM, and their target genes were extracted using the miRTarBase database. Additionally, biological pathways differentially regulated by these miRNAs were identified using a functional enrichment method (EnrichR). Finally, artificial intelligence was applied to rank the most relevant pathways based on the frequency of involvement of these genes. From the studies included in the AD (49) and T2DM (104) SRs, miRNAs were identified as being downregulated (11) or upregulated (10) in both diseases. Gene extraction revealed targets for downregulated (337) and upregulated (233) miRNAs, along with their associated biological pathways. After ranking, the most relevant pathway among downregulated miRNAs was the T cell receptor signaling cascade via RAS, and for upregulated miRNAs, the extracellular matrix signaling pathway, both of which have approved drugs targeting proteins involved in these mechanisms. These findings suggest that miRNAs may contribute to the understanding of shared pathophysiological mechanisms between AD and T2DM and represent potential targets for therapeutic interventions.