Bioinformatics Approaches to Identify Novel Therapeutic Targets of Mixed Dementia

Abstract

Background Mixed dementia (MxD) refers to a patient's coexistence of Alzheimer's disease (AD) and vascular dementia (VaD). Until recently, pharmacological studies have generally focused on pure disease, AD or VaD, and have shed little light on the best therapeutic approaches to MxD. Therefore this study aimed to explore potential targets for MxD. Methods GSE36980 and GSE122063 datasets were downloaded from the Gene Expression Omnibus (GEO). GEO2R was utilized to identify the differentially expressed genes (DEGs) in GSE36980 between MxD and control groups. Then the genes in the top 50% of the median absolute deviation (MAD) with at least MAD greater than 0.01 and phenotypes of samples in GSE36980 were analyzed using R package “weighted gene co-expression network analysis” (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment were analyzed on the selected dark green module genes. Protein-protein interactions analyses were performed in the STRING database and key genes were screened based on the maximal clique centrality (MCC) and maximum neighborhood component (MNC) algorithm of Cytoscape software. Key genes were then verified in external dataset GSE122063. Results There were 162 DEGs identified, including 121 up-regulated and 41 down-regulated genes. And the dark green module was the mostly related to MxD, among which, 43 genes were also DEGs in GSE36980 datasets. The most significantly enriched biological processes were the type I interferon signaling pathway (GO:0060337, P = 1.79E-25) and defense response to virus (GO:0051607, P = 2.34E-22). Due to the highest scores received, STAT1, IFIT3, OAS2, and MX1 may play crucial roles in MxD. Finally, test in external dataset GSE122063, STAT1, and IFIT3 were significantly up-regulated in AD patients. Conclusions In conclusion, STAT1 and IFIT3 may serve as potential targets for the pathogenesis of MxD, which should be further explored in the future.