Comprehensive analysis ofmRNAs in the cerebral cortex inAPP/PS1 double-transgenic mice withAlzheimer's disease based onhigh-throughput sequencing ofN4-acetylcytidine.

Abstract

N4-acetylcytidine (ac4C), a significant modified nucleoside, participates in the development of many diseases. Messenger RNAs (mRNAs) contain most of the information of the genome and are the molecules that transmit information from genes to proteins. Alzheimer's disease (AD) is a progressive neurodegenerative disease in which fibrillar amyloid plaques are present. However, it remains unknown how mRNA ac4C modification affects the development of AD. In the current study, ac4C-modified mRNAs were comprehensively analyzed in AD mice by ac4C-RIP-seq and RNA-seq. Next, a protein-protein interaction (PPI) network was constructed to examine the relationships between the genes with differential ac4C modification levels and their RNA expression levels. The differentially expressed genes (DEGs) acquired above were subjected to Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to further analyze the molecular mechanisms in AD. In total, 3312 significant ac4C peaks were found on 2512 mRNAs, 1241 of which were hyperacetylated and 1271 of which were hypoacetylated. In addition, 956 mRNAs with differential expression were found, including 520 upregulated mRNAs and 436 downregulated mRNAs. Overall, 134 mRNAs with simultaneous changes at the ac4C levels as well as RNA expression levels were identified via joint analysis. Then, through PPI network construction and functional enrichment analysis, 37 key mRNAs were screened, which were predominantly enriched in GABAergic synapses and the PI3K/AKT signaling pathway. The significant difference in the abundance of mRNA ac4C modification indicates that this modification is associated with AD progression, which may provide insight for more investigations of the potential mechanisms.