Effects of m6A methylation of MAT2A mRNA regulated by METTL16 on learning and memory, hippocampal synaptic plasticity and Aβ1–42 in 5 × FAD mice

作者：Huan Chen, Fangzhen Guo, Yan Zhao, Wei Liu, Bingyu Chen, Chang Wang, Lining Huang, Sufang Jiang, Xiaowei Ma, Huiling Ren, Sha Li, Huixian Cui · 发表于：Frontiers in Aging Neuroscience · 年份：2025 · DOI：10.3389/fnagi.2025.1572976 · 被引用次数：5 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、Peptidase Inhibition and Analysis

Background Alzheimer’s disease (AD) is a common neurodegenerative disorder affecting older adults, characterized by progressive cognitive decline and pathological features such as amyloid plaque deposition, neuronal loss, and synaptic reduction. RNA N6-methyladenosine (m 6 A) methylation is prevalent in the brain and is intricately linked to synaptic plasticity, learning, and memory in AD. However, the precise mechanisms underlying these associations remain elusive. Methods This study employed the overexpression of methyltransferase-like protein 16 (METTL16), or overexpression of methionine adenosyltransferase 2A (MAT2A), or a combination of METTL16 overexpression with MAT2A knockdown to explore the influence of METTL16 on the regulation of MAT2A in cognitive function, hippocampal synaptic plasticity, and amyloid-beta (Aβ 1–42 ) metabolism in 5 × FAD mice. Results Our findings indicated a reduction in m 6 A methylation levels and the expression of METTL16 and MAT2A in the hippocampus of 5 × FAD mice. Overexpression of METTL16 led to an increase in overall m 6 A methylation levels, furthermore, overexpression of either METTL16 or MAT2A enhanced learning and memory in 5 × FAD mice, elevated the expression levels of postsynaptic density 95 (PSD95) and synaptophysin (Syp), increased dendritic spine density, and decreased the accumulation of Aβ 1–42 in the hippocampus. In the hippocampus of 5 × FAD mice, METTL16 was found to upregulate both the protein and mRNA levels of MAT2A, as...