N6-methyladenosine RNA modification regulates microglial phagocytosis in the APP/PS1 mouse model of Alzheimer's disease.

N6-methyladenosine (m6A) methylation and abnormal cellular processes are involved in neurodegenerative diseases, including Alzheimer's disease (AD). However, the functions of molecular signatures associated with m6A modification in AD remain unclear. Here, we show that m6A abundance is elevated in the hippocampus in 6-month-old APP/PS1 mice, an AD mouse model. Comparative analysis of mRNA m6A modification profiles revealed substantial variation in m6A modifications between AD and control mice. Transcripts with differential m6A modification (either hyper- or hypomethylation) were enriched in the regulation of cellular processes, including metabolic alterations, immune responses, synaptic transmission, and responses to stimuli, in both the nervous and immune systems. Moreover, the m6A-associated immune features were involved in microglial signatures, including cytokine signaling, microglial homeostasis, and microglial phagocytosis. Importantly, we identified genes with significant enrichment of m6A modifications in AD mice. Among these, we confirmed that m6A methylation was associated with the gene expression levels of CD9 and Cebpβ. Moreover, these alterations were negatively associated with microglia-mediated phagocytosis in vitro, which in turn impaired activated microglia-induced inflammation. Taken together, these findings suggest that the alteration of m6A modification contributes to the progression of AD by regulating gene expression and microglial function.