{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:04:21Z","timestamp":1791900261927,"version":"4.3.4"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T00:00:00Z","timestamp":1744761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171582"],"award-info":[{"award-number":["82171582"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Alzheimer\u2019s 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<jats:sup>6<\/jats:sup>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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 (A\u03b2<jats:sub>1\u201342<\/jats:sub>) metabolism in 5\u202f\u00d7\u202fFAD mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our findings indicated a reduction in m<jats:sup>6<\/jats:sup>A methylation levels and the expression of METTL16 and MAT2A in the hippocampus of 5\u202f\u00d7\u202fFAD mice. Overexpression of METTL16 led to an increase in overall m<jats:sup>6<\/jats:sup>A methylation levels, furthermore, overexpression of either METTL16 or MAT2A enhanced learning and memory in 5\u202f\u00d7\u202fFAD mice, elevated the expression levels of postsynaptic density 95 (PSD95) and synaptophysin (Syp), increased dendritic spine density, and decreased the accumulation of A\u03b2<jats:sub>1\u201342<\/jats:sub> in the hippocampus. In the hippocampus of 5\u202f\u00d7\u202fFAD mice, METTL16 was found to upregulate both the protein and mRNA levels of MAT2A, as well as enhance MAT2A mRNA m<jats:sup>6<\/jats:sup>A methylation levels. Concurrent, overexpression of METTL16 and knockdown of MAT2A in the hippocampus resulted in impaired learning and memory in 5\u202f\u00d7\u202fFAD mice, alongside a reduction in synaptic protein expression and dendritic spine density, and an increase in A\u03b2<jats:sub>1\u201342<\/jats:sub> accumulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The present study demonstrated that METTL16 enhances learning and memory in 5\u202f\u00d7\u202fFAD mice by regulating MAT2A mRNA m<jats:sup>6<\/jats:sup>A methylation, which leads to increased expression levels of PSD95 and Syp, greater dendritic spine density, and reduced A\u03b2<jats:sub>1\u201342<\/jats:sub> accumulation in the hippocampus. These findings reveal a novel approach for investigating the pathophysiological role of METTL16 in AD and offer new insights for developing of potential therapeutic targets for AD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2025.1572976","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T05:26:29Z","timestamp":1744781189000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Effects of m6A methylation of MAT2A mRNA regulated by METTL16 on learning and memory, hippocampal synaptic plasticity and A\u03b21\u201342 in 5\u202f\u00d7\u202fFAD mice"],"prefix":"10.3389","volume":"17","author":[{"given":"Huan","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangzhen","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lining","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sufang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiling","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huixian","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,16]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/0006-8993(90)91009-6","article-title":"Morphological adaptive response of the synaptic junctional zones in the human dentate gyrus during aging and Alzheimer\u2019s disease","volume":"517","author":"Bertoni-Freddari","year":"1990","journal-title":"Brain Res."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1016\/S0021-9258(18)64899-9","article-title":"Activation of methionine for transmethylation. II. The methionine-activating enzyme; studies on the mechanism of the reaction","volume":"225","author":"Cantoni","year":"1957","journal-title":"J. Biol. Chem."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2441","DOI":"10.1523\/JNEUROSCI.2121-18.2019","article-title":"Conditional BDNF delivery from astrocytes rescues memory deficits, spine density, and synaptic properties in the 5\u202f\u00d7\u202fFAD mouse model of Alzheimer disease","volume":"39","author":"de Pins","year":"2019","journal-title":"J. Neurosci."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1186\/s13578-024-01286-6","article-title":"Insights into the m6A demethylases FTO and ALKBH5: structural, biological function, and inhibitor development","volume":"14","author":"Gao","year":"2024","journal-title":"Cell Biosci."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3233\/JAD-220720","article-title":"Alzheimer\u2019s disease: a systems view provides a unifying explanation of its development","volume":"91","author":"Grobler","year":"2023","journal-title":"J. Alzheimers Dis."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"2128","DOI":"10.1093\/brain\/awae015","article-title":"Maf1 loss regulates spinogenesis and attenuates cognitive impairment in Alzheimer\u2019s disease","volume":"147","author":"Han","year":"2024","journal-title":"Brain"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"98","DOI":"10.3389\/fnins.2020.00098","article-title":"Abnormality of m6A mRNA methylation is involved in Alzheimer\u2019s disease","volume":"14","author":"Han","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"2998301","DOI":"10.1155\/2022\/2998301","article-title":"The effects of moxibustion on learning and memory and m6A RNA methylation in APP\/PS1 mice","volume":"2022","author":"Huang","year":"2022","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1016\/j.neuron.2013.12.003","article-title":"Biomarker modeling of Alzheimer\u2019s disease","volume":"80","author":"Jack","year":"2013","journal-title":"Neuron"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/s41392-020-00450-x","article-title":"The role of m6A modification in the biological functions and diseases","volume":"6","author":"Jiang","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"71","DOI":"10.3233\/JAD-220873","article-title":"The role of caspases in Alzheimer\u2019s disease: pathophysiology implications and pharmacologic modulation","volume":"91","author":"Khezri","year":"2023","journal-title":"J. Alzheimers Dis."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.neuron.2018.06.007","article-title":"Mettl14 is essential for epitranscriptomic regulation of striatal function and learning","volume":"99","author":"Koranda","year":"2018","journal-title":"Neuron"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1111\/ene.13439","article-title":"Alzheimer\u2019s disease","volume":"25","author":"Lane","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.bbrc.2018.02.201","article-title":"FTO is involved in Alzheimer\u2019s disease by targeting TSC1-mTOR-tau signaling","volume":"498","author":"Li","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s13578-019-0330-y","article-title":"The role of mRNA m6A methylation in the nervous system","volume":"9","author":"Li","year":"2019","journal-title":"Cell Biosci."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"3141","DOI":"10.1038\/s41380-024-02574-w","article-title":"Integration of multi-omics summary data reveals the role of N6-methyladenosine in neuropsychiatric disorders","volume":"29","author":"Liufu","year":"2024","journal-title":"Mol. Psychiatry"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s13020-021-00425-2","article-title":"Suan-Zao-Ren decoction ameliorates synaptic plasticity through inhibition of the A\u03b2 deposition and JAK2\/STAT3 signaling pathway in AD model of APP\/PS1 transgenic mice","volume":"16","author":"Long","year":"2021","journal-title":"Chin. Med."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/s13059-018-1435-z","article-title":"RNA m6A methylation participates in regulation of postnatal development of the mouse cerebellum","volume":"19","author":"Ma","year":"2018","journal-title":"Genome Biol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"7141","DOI":"10.1038\/s41380-021-01282-z","article-title":"Modifying the m6A brain methylome by ALKBH5-mediated demethylation: a new contender for synaptic tagging","volume":"26","author":"Martinez De La Cruz","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1212\/wnl.56.1.127","article-title":"Altered expression of synaptic proteins occurs early during progression of Alzheimer\u2019s disease","volume":"56","author":"Masliah","year":"2001","journal-title":"Neurology"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1038\/s41593-018-0173-6","article-title":"Synaptic N6-methyladenosine (m6A) epitranscriptome reveals functional partitioning of localized transcripts","volume":"21","author":"Merkurjev","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"e0227647","DOI":"10.1371\/journal.pone.0227647","article-title":"Characterization of METTL16 as a cytoplasmic RNA binding protein","volume":"15","author":"Nance","year":"2020","journal-title":"PLoS One"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1016\/j.cell.2017.05.003","article-title":"The U6 snRNA m6A methyltransferase METTL16 regulates SAM synthetase intron retention","volume":"169","author":"Pendleton","year":"2017","journal-title":"Cell"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"2176","DOI":"10.3390\/ijms22042176","article-title":"METTL16, methyltransferase-like protein 16: current insights into structure and function","volume":"22","author":"Ruszkowska","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"e1681","DOI":"10.1002\/wrna.1681","article-title":"RNA methyltransferase METTL16: targets and function","volume":"13","author":"Satterwhite","year":"2022","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/s41586-018-0666-1","article-title":"m6A facilitates hippocampus-dependent learning and memory through YTHDF1","volume":"563","author":"Shi","year":"2018","journal-title":"Nature"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"3354","DOI":"10.1016\/j.celrep.2017.11.092","article-title":"S-adenosylmethionine synthesis is regulated by selective N6-adenosine methylation and mRNA degradation involving METTL16 and YTHDC1","volume":"21","author":"Shima","year":"2017","journal-title":"Cell Rep."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1038\/s41556-021-00835-2","article-title":"METTL16 exerts an m6A-independent function to facilitate translation and tumorigenesis","volume":"24","author":"Su","year":"2022","journal-title":"Nat. Cell Biol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1002\/ana.410300410","article-title":"Physical basis of cognitive alterations in Alzheimer\u2019s disease: synapse loss is the major correlate of cognitive impairment","volume":"30","author":"Terry","year":"1991","journal-title":"Ann. Neurol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.1038\/npp.2017.31","article-title":"The role of the RNA demethylase FTO (fat mass and obesity-associated) and mRNA methylation in hippocampal memory formation","volume":"42","author":"Walters","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"2198","DOI":"10.7150\/ijbs.79651","article-title":"Crosstalk between N6-methyladenosine (m6A) modification and noncoding RNA in tumor microenvironment","volume":"19","author":"Wang","year":"2023","journal-title":"Int. J. Biol. Sci."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/s41593-017-0057-1","article-title":"N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications","volume":"21","author":"Wang","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/s40035-023-00386-6","article-title":"N6-methyladenosine-modified circRIMS2 mediates synaptic and memory impairments by activating GluN2B ubiquitination in Alzheimer\u2019s disease","volume":"12","author":"Wang","year":"2023","journal-title":"Transl. Neurodegener."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.neuron.2017.12.036","article-title":"Epitranscriptomic m6A regulation of axon regeneration in the adult mammalian nervous system","volume":"97","author":"Weng","year":"2018","journal-title":"Neuron"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"10111","DOI":"10.3390\/ijms241210111","article-title":"An exploration of the coherent effects between METTL3 and NDUFA10 on Alzheimer\u2019s disease","volume":"24","author":"Yang","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"e3002017","DOI":"10.1371\/journal.pbio.3002017","article-title":"Loss of the m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer\u2019s disease pathology in mice","volume":"21","author":"Yin","year":"2023","journal-title":"PLoS Biol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"9516","DOI":"10.1021\/acs.jmedchem.4c00599","article-title":"Structure-based design of a potent and selective YTHDC1 ligand","volume":"67","author":"Z\u00e1le\u0161\u00e1k","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1925","DOI":"10.1007\/s12035-022-02739-0","article-title":"N6-methyladenosine and neurological diseases","volume":"59","author":"Zhang","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1050","DOI":"10.1038\/s41422-018-0092-9","article-title":"METTL3-mediated N6-methyladenosine mRNA modification enhances long-term memory consolidation","volume":"28","author":"Zhang","year":"2018","journal-title":"Cell Res."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"e1006663","DOI":"10.1371\/journal.pcbi.1006663","article-title":"Global analysis of N6-methyladenosine functions and its disease association using deep learning and network-based methods","volume":"15","author":"Zhang","year":"2019","journal-title":"PLoS Comput. Biol."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1038\/s41420-022-01220-0","article-title":"Knockdown of METTL16 disrupts learning and memory by reducing the stability of MAT2A mRNA","volume":"8","author":"Zhang","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1186\/s13024-021-00484-x","article-title":"METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer\u2019s disease through aberrant cell cycle events","volume":"16","author":"Zhao","year":"2021","journal-title":"Mol. Neurodegener."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2025.1572976\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T05:26:30Z","timestamp":1744781190000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2025.1572976\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,16]]},"references-count":42,"alternative-id":["10.3389\/fnagi.2025.1572976"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2025.1572976","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,16]]},"article-number":"1572976"}}