Qu Xueqi, Lin Li, Li Yinhu, Chen Yuewen, Chen Yu
Chinese Academy of Sciences Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Translational Research for Brain Diseases, the Brain Cognition and Brain Disease Institute; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen Institutes of Advanced Technology, Shenzhen, Guangdong, China.
Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen, Guangdong, China.
Genes Immun. 2025 Jul 24. doi: 10.1038/s41435-025-00347-1.
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.
N6-甲基腺苷（m6A）甲基化与异常细胞过程参与包括阿尔茨海默病（AD）在内的神经退行性疾病。然而，AD中与m6A修饰相关的分子特征的功能仍不清楚。在此，我们表明在6月龄的AD小鼠模型APP/PS1小鼠的海马体中m6A丰度升高。对mRNA m6A修饰谱的比较分析揭示了AD小鼠和对照小鼠之间m6A修饰存在显著差异。在神经系统和免疫系统中，具有差异m6A修饰（高甲基化或低甲基化）的转录本在细胞过程的调控中富集，包括代谢改变、免疫反应、突触传递和对刺激的反应。此外，与m6A相关的免疫特征参与了小胶质细胞特征，包括细胞因子信号传导、小胶质细胞稳态和小胶质细胞吞噬作用。重要的是，我们在AD小鼠中鉴定出m6A修饰显著富集的基因。其中，我们证实m6A甲基化与CD9和Cebpβ的基因表达水平相关。此外，这些改变在体外与小胶质细胞介导的吞噬作用呈负相关，进而损害活化小胶质细胞诱导的炎症。综上所述，这些发现表明m6A修饰的改变通过调节基因表达和小胶质细胞功能促进AD的进展。
