Preliminary exploration of the co-regulation of Alzheimer’s disease pathogenic genes by microRNAs and transcription factors

Abstract

BackgroundAlzheimer’s disease (AD) is the most common form of age-related neurodegenerative disease. Unfortunately, due to the complexity of pathological types and clinical heterogeneity of AD, there is a lack of satisfactory treatment for AD. Previous studies have shown that microRNAs and transcription factors can modulate genes associated with AD, but the underlying pathophysiology remains unclear.MethodsThe datasets GSE1297 and GSE5281 were downloaded from the gene expression omnibus (GEO) database and analyzed to obtain the differentially expressed genes (DEGs) through the “R” language “limma” package. The GSE1297 dataset was analyzed by weighted correlation network analysis (WGCNA), and the key gene modules were selected. Next, gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis for the key gene modules were performed. Then, the protein-protein interaction (PPI) network was constructed and the hub genes were identified using the STRING database and Cytoscape software. Finally, for the GSE150693 dataset, the “R” package “survivation” was used to integrate the data of survival time, AD transformation status and 35 characteristics, and the key microRNAs (miRNAs) were selected by Cox method. We also performed regression analysis using least absolute shrinkage and selection operator (Lasso)-Cox to construct and validate prognostic features associated with the four key genes using different databases. We also tried to find drugs targeting key genes through DrugBank database.ResultsGO and KEGG enrichment analysis showed that DEGs were mainly enriched in pathways regulating chemical synaptic transmission, glutamatergic synapses and Huntington’s disease. In addition, 10 hub genes were selected from the PPI network by using the algorithm Between Centrality. Then, four core genes (TBP, CDK7, GRM5, and GRIA1) were selected by correlation with clinical information, and the established model had very good prognosis in different databases. Finally, hsa-miR-425-5p and hsa-miR-186-5p were determined by COX regression, AD transformation status and aberrant miRNAs.ConclusionIn conclusion, we tried to construct a network in which miRNAs and transcription factors jointly regulate pathogenic genes, and described the process that abnormal miRNAs and abnormal transcription factors TBP and CDK7 jointly regulate the transcription of AD central genes GRM5 and GRIA1. The insights gained from this study offer the potential AD biomarkers, which may be of assistance to the diagnose and therapy of AD.

MiR-15b and let-7a as Non-invasive Diagnostic Biomarkers of Alzheimer’s Disease Using an Artificial Neural Network

“…Furthermore, the KEGG pathway analysis indicated that retrograde endocannabinoid signaling, GABAergic synapse, nicotine addiction, neuroactive ligand-receptor interaction, staphylococcus aureus infection, cholinergic synapse, glutamatergic synapse, calcium signaling pathway, synaptic vesicle cycle, and morphine addiction terms were significantly enriched. The results of related studies in the molecular mechanism of AD showed that GABAergic synapse (44), retrograde endocannabinoid signaling (45), nicotine addiction, morphine addiction (46), Staphylococcus aureus infection (47), cholinergic synapse (48), glutamatergic synapse pathway (49), calcium signaling pathway (50), and synaptic vesicle cycle (51) were significantly enriched.…”

A review and analysis of key biomarkers in Alzheimer’s disease

“…The interaction between differential long noncoding RNA (lncRNA) and/or targeted microRNA (miRNA) and messenger RNA (mRNA) has been demonstrated in AD and AD pathogenesis. Zhang et al (2022b) identified four AD genes and two miRNAs and constructed a network in which miRNAs and transcription factors jointly regulate pathogenic genes. Zhang T. et al (2020) integrated genomic transcriptome datasets through biomolecular networks, found 9 genes, as well as 6 common transcription factors, 10 miRNAs, and identified 10 AD candidate biomolecules by protein-drug interactions.…”

The Features Analysis of Hemoglobin Expression on Visual Information Transmission Pathway in Early Stage of Alzheimer's Disease

“…Method: This paper includes both the methods the authors have used in the past year [43][44][45][46][47][48] and the new methods proposed in this paper. The new methods include the calculation of the correlation between different brain regions along the V-H pathway.…”