Influence of N6-methyladenosine (m6A) modification on cell phenotype in Alzheimer's disease

Recent research has suggested that m6A modification takes on critical significance to Neurodegeneration. As indicated by the genome-wide map of m6A mRNA, genes in Alzheimer's disease model achieved significant m6A methylation. This study aimed to investigate the hub gene and pathway of m6A modification in the pathogenesis of AD. Moreover, possible brain regions with higher gene expression levels and compounds exerting potential therapeutic effects were identified. Thus, this study can provide a novel idea to explore the treatment of AD.

Differential expression genes (DEGs) of GSE5281 and GSE48350 from the Gene Expression Omnibus (GEO) database were screened using the Limma package. Next, the enrichment analysis was conducted on the screened DEGs. Moreover, the functional annotation was given for N6-methyladenosine (m6A) modification gene. The protein-protein interaction network (PPI) analysis and the visualization analysis were conducted using STRING and Cytoscape. The hub gene was identified using CytoHubba. The expression levels of Hub genes in different regions of brain tissue were analyzed based on Human Protein Atlas (HPA) database and Bgee database. Subsequently, the candidate drugs targeting hub genes were screened using cMAP.

A total of 42 m6A modified genes were identified in AD (20 up-regulated and 22 down-regulated genes). The above-described genes played a certain role in biological processes (e.g., retinoic acid, DNA damage response and cysteine-type endopeptidase activity), cellular components (e.g., mitochondrial protein complex), and molecular functions (e.g., RNA methyltransferase activity and ubiquitin protein ligase). KEGG results suggested that the above-mentioned genes were primarily involved in the Hippo signaling pathway of neurodegeneration disease. A total of 10 hub genes were screened using the protein-protein interaction network, and the expression of hub genes in different regions of human brain was studied. Furthermore, 10 compounds with potential therapeutic effects on AD were predicted.

This study revealed the potential role of the m6A modification gene in Alzheimer's disease through the bioinformatics analysis. The biological changes may be correlated with retinoic acid, DNA damage response and cysteine-type endopeptidase activity, which may occur through Hippo signaling pathway. The hub genes (SOX2, KLF4, ITGB4, CD44, MSX1, YAP1, AQP1, EGR2, YWHAZ and TFAP2C) and potential drugs may provide novel research directions for future prognosis and precise treatment.