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Updated: Sep 14, 2025
Characterizing RNA Modifications in Single Neurons Using Mass Spectrometry
Published on: April 21, 2022
N6-methyladenosine RNA modification regulates microglial phagocytosis in the APP/PS1 mouse model of Alzheimer's
Xueqi Qu1,2,3, Li Lin1,2,3, Yinhu Li1,2,3
1Chinese 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.
Abstract:
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.
Insights
N6-methyladenosine (m6A) methylation is elevated in Alzheimer
Area of Science:
- Neuroscience
- Epigenetics
- Molecular Biology
Background:
- N6-methyladenosine (m6A) methylation is implicated in neurodegenerative diseases like Alzheimer's disease (AD).
- The precise roles of m6A modification signatures in AD pathogenesis are not fully understood.
Purpose of the Study:
- To investigate the functional significance of m6A modification alterations in an Alzheimer's disease mouse model.
- To identify specific genes and cellular processes affected by differential m6A methylation in AD.
Main Methods:
- Comparative analysis of mRNA m6A modification profiles in the hippocampus of APP/PS1 AD mice and control littermates.
- Bioinformatic enrichment analysis to identify pathways and cellular functions associated with differentially methylated transcripts.
- Validation of m6A association with specific gene expression (CD9, Cebpβ) and assessment of microglial phagocytosis in vitro.
Main Results:
- Elevated m6A abundance was observed in the hippocampus of AD mice.
- Differential m6A modifications were enriched in pathways related to metabolism, immune response, and synaptic function.
- m6A alterations were linked to microglial functions, including phagocytosis, and negatively correlated with microglia-mediated phagocytosis and inflammation.
Conclusions:
- Altered m6A methylation patterns are a feature of Alzheimer's disease progression in mice.
- m6A modification dysregulation impacts gene expression and microglial activity, potentially contributing to AD pathogenesis.
- Targeting m6A pathways may offer novel therapeutic strategies for Alzheimer's disease.
