{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:00:22Z","timestamp":1792789222476,"version":"4.5.0"},"reference-count":43,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2022YFA1604503"],"award-info":[{"award-number":["2022YFA1604503"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2022YFA1104302"],"award-info":[{"award-number":["2022YFA1104302"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Foundation of State Key Laboratory of Space Medicine, China Astronaut Research and Training Center","award":["SMFA20A01"],"award-info":[{"award-number":["SMFA20A01"]}],"id":[{"id":"https:\/\/ror.org\/001ycj259","id-type":"ROR","asserted-by":"crossref"}]},{"award":["SMFA20A01"],"award-info":[{"award-number":["SMFA20A01"]}],"id":[{"id":"https:\/\/ror.org\/001ycj259","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Age-related decline in learning and memory functions poses significant challenges in an aging society, with epigenetic dysregulation emerging as a key contributor to cognitive deterioration. As the most prevalent internal RNA modification, N6-methyladenosine (m6A) dynamically orchestrates neural transcriptome plasticity through its \u201cwriters,\u201d \u201cerasers,\u201d and \u201creaders,\u201d yet its role in aging-associated cognitive impairment remains underexplored. This study employs an integrated epitranscriptomic approach to investigate m6A-mediated regulation in hippocampal aging processes. Through comparative m6A-mRNA epitranscriptomic microarray analysis of senescence-accelerated mouse prone 8 (SAMP8) and senescence-resistant SAMR1 hippocampi, we identified neural cell adhesion molecule 1 (NCAM1) as a key m6A-regulated effector whose decreased expression correlates with accelerated cognitive deterioration. Mechanistically, we revealed that Methyltransferase-like 3 (METTL3)-mediated m6A modification governs Ncam1 mRNA stability through insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) reader protein-dependent mechanisms, forming a regulatory axis that modulates cyclic AMP response element-binding protein (CREB) signaling pathway activity. Remarkably, targeting of this METTL3\/IGF2BP1\/NCAM1 axis significantly attenuated cognitive deficits in aged SAMP8 mice. Our findings establish an m6A methylation-dependent paradigm for NCAM1-mediated cognitive preservation during aging, uncovering a novel epitranscriptomic layer in age-related neurodegeneration.<\/jats:p>","DOI":"10.3390\/cells15181662","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T08:16:48Z","timestamp":1789460208000},"page":"1662","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["METTL3\/IGF2BP1 Axis Orchestrates m6A-Dependent NCAM1 Preservation to Combat Age-Related Cognitive Decline"],"prefix":"10.3390","volume":"15","author":[{"given":"Guohua","family":"Ji","sequence":"first","affiliation":[{"name":"State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing 100094, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing 100094, China"},{"name":"Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Forensics, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2687-1695","authenticated-orcid":false,"given":"Xiaopeng","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing 100094, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Lu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing 100094, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengji","family":"Liang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing 100094, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhong","family":"Yuan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing 100094, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuying","family":"Dai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing 100094, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing 100094, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxiang","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Forensics, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Pathology and Forensics, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6374-415X","authenticated-orcid":false,"given":"Lina","family":"Qu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing 100094, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Metwally, N.M., Ragab, O.A.A., Kandil, M.S.H., and Elghareb, L.A. 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