{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T12:04:52Z","timestamp":1790597092530,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:00:00Z","timestamp":1790380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFF0710402"],"award-info":[{"award-number":["2022YFF0710402"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Plasmalogens (PLS) are a distinctive class of glycerophospholipids with reported neuroprotective properties; however, the mechanisms underlying their potential benefits for age-related cognitive decline remain incompletely understood. Methods: A D-galactose-induced mouse model of aging was used to evaluate the effects of PLS on cognitive performance. Hippocampal synaptic remodeling was assessed by examining the expression of synaptic proteins and receptors. An in vitro BBB model was used to evaluate the transport of PE-PLS 18:0\/20:4. Molecular interaction analyses were conducted to investigate the potential binding of PE-PLS 18:0\/20:4 to the brain-derived neurotrophic factor (BDNF) and its association with BDNF\/TrkB signaling activation. Results: High-dose PLS supplementation significantly improved spatial memory and novel object recognition in D-galactose-treated mice. Molecular interaction analysis indicated that PE-PLS 18:0\/20:4 could interact with BDNF through multiple hydrogen bonds. This interaction was associated with activation of the BDNF\/TrkB signaling pathway, increased synaptic protein expression, and neuroprotective effects. Conclusions: PLS may mitigate age-related cognitive dysfunction by promoting hippocampal synaptic remodeling. PE-PLS 18:0\/20:4 may contribute to these effects through BBB transport and modulation of BDNF\/TrkB signaling, supporting the potential of plasmalogens as a nutritional strategy for promoting healthy brain aging.<\/jats:p>","DOI":"10.3390\/nu18193179","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:35:59Z","timestamp":1790595359000},"page":"3179","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Blood\u2013Brain Barrier (BBB)-Permeable Ethanolamine-Type Plasmalogens 18:0\/20:4 (PE-PLS 18:0\/20:4) Ameliorate Cognitive Impairments in Aged Mice"],"prefix":"10.3390","volume":"18","author":[{"given":"Jiale","family":"Yu","sequence":"first","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, 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Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Fazheng","family":"Ren","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Yanan","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100193, 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leaders","volume":"7","author":"Silcox","year":"2024","journal-title":"npj Digit. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Yang, J., Luo, J., Tian, X., Zhao, Y., Li, Y., and Wu, X. (2024). Progress in Understanding Oxidative Stress, Aging, and Aging-Related Diseases. Antioxidants, 13.","DOI":"10.3390\/antiox13040394"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3506","DOI":"10.1002\/alz.12967","article-title":"Early prediction of Alzheimer\u2019s disease and related dementias using real-world electronic health records","volume":"19","author":"Li","year":"2023","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4094","DOI":"10.1007\/s12035-015-9337-5","article-title":"Oxidative Stress in Neurodegenerative Diseases","volume":"53","author":"Niedzielska","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/s41577-024-01104-7","article-title":"Neuroinflammation in Alzheimer disease","volume":"25","author":"Heneka","year":"2025","journal-title":"Nat. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"Blasco","year":"2013","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.nbd.2011.03.012","article-title":"Hippocampal dysregulation of synaptic plasticity-associated proteins with age-related cognitive decline","volume":"43","author":"VanGuilder","year":"2011","journal-title":"Neurobiol. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.jcis.2021.05.081","article-title":"Conjugated microporous polyarylimides immobilization on carbon nanotubes with improved utilization of carbonyls as cathode materials for lithium\/sodium-ion batteries","volume":"601","author":"Li","year":"2021","journal-title":"J. Colloid Interface Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/nrn3200","article-title":"The ageing cortical synapse: Hallmarks and implications for cognitive decline","volume":"13","author":"Morrison","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Barrantes, F.J. (2024). Cognitive synaptopathy: Synaptic and dendritic spine dysfunction in age-related cognitive disorders. Front. Aging Neurosci., 16.","DOI":"10.3389\/fnagi.2024.1476909"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/ana.410270502","article-title":"Synapse loss in frontal cortex biopsies in Alzheimer\u2019s disease: Correlation with cognitive severity","volume":"27","author":"DeKosky","year":"1990","journal-title":"Ann. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.lfs.2008.12.003","article-title":"Dilinoleoylphosphatidylcholine ameliorates scopolamine-induced impairment of spatial learning and memory by targeting \u03b17 nicotinic ACh receptors","volume":"84","author":"Yaguchi","year":"2009","journal-title":"Life Sci."},{"key":"ref_13","first-page":"197","article-title":"Effect of Phosphatidylserine on Cerebral Glucose Metabolism in Alzheimer\u2019s Disease: (With 1 color plate)","volume":"1","author":"Klinkhammer","year":"1991","journal-title":"Dementia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12944-018-0685-9","article-title":"Plasmalogen lipids: Functional mechanism and their involvement in gastrointestinal cancer","volume":"17","author":"Messias","year":"2018","journal-title":"Lipids Health Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1016\/j.bbadis.2012.05.008","article-title":"Functions of plasmalogen lipids in health and disease","volume":"1822","author":"Braverman","year":"2012","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0163-7827(01)00003-0","article-title":"Plasmalogens: Biosynthesis and functions","volume":"40","author":"Nagan","year":"2001","journal-title":"Prog. Lipid Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Bozelli, J.C., Azher, S., and Epand, R.M. (2021). Plasmalogens and Chronic Inflammatory Diseases. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.730829"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.ebiom.2017.02.012","article-title":"Efficacy and Blood Plasmalogen Changes by Oral Administration of Plasmalogen in Patients with Mild Alzheimer\u2019s Disease and Mild Cognitive Impairment: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial","volume":"17","author":"Fujino","year":"2017","journal-title":"eBioMedicine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"147516","DOI":"10.1016\/j.brainres.2021.147516","article-title":"Neuroprotective effects of Scallop-derived plasmalogen in a mouse model of ischemic stroke","volume":"1766","author":"Feng","year":"2021","journal-title":"Brain Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/s13273-023-00399-2","article-title":"Scallop-derived plasmalogen attenuates amyloid beta-induced inflammation and apoptosis in SH-SY5Y cells","volume":"20","author":"Han","year":"2024","journal-title":"Mol. Cell. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/j.bbrc.2018.01.078","article-title":"Oral ingestion of plasmalogens can attenuate the LPS-induced memory loss and microglial activation","volume":"496","author":"Hossain","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gu, J., Chen, L., Sun, R., Wang, J.-L., Wang, J., Lin, Y., Lei, S., Zhang, Y., Lv, D., and Jiang, F. (2022). Plasmalogens Eliminate Aging-Associated Synaptic Defects and Microglia-Mediated Neuroinflammation in Mice. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.815320"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Li, R., Xiong, W., Li, B., Li, Y., Fang, B., Wang, X., and Ren, F. (2023). Plasmalogen Improves Memory Function by Regulating Neurogenesis in a Mouse Model of Alzheimer\u2019s Diseases. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241512234"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Yamashita, S., Miyazawa, T., Higuchi, O., Kinoshita, M., and Miyazawa, T. (2023). Marine Plasmalogens: A Gift from the Sea with Benefits for Age-Associated Diseases. Molecules, 28.","DOI":"10.3390\/molecules28176328"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s12987-024-00577-x","article-title":"NX210c drug candidate peptide strengthens mouse and human blood-brain barriers","volume":"21","author":"Greene","year":"2024","journal-title":"Fluids Barriers CNS"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s41582-019-0244-7","article-title":"Ageing as a risk factor for neurodegenerative disease","volume":"15","author":"Hou","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.brainres.2014.10.019","article-title":"Regulation of hippocampal synaptic plasticity by BDNF","volume":"1621","author":"Leal","year":"2015","journal-title":"Brain Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.bbr.2010.07.006","article-title":"The role of hippocampal subregions in memory for stimulus associations","volume":"215","author":"Langston","year":"2010","journal-title":"Behav. Brain Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.neuroscience.2015.05.062","article-title":"Pathological changes in hippocampal neuronal circuits underlie age-associated neurodegeneration and memory loss: Positive clue toward SAD","volume":"301","author":"Moorthi","year":"2015","journal-title":"Neuroscience"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1002\/gps.5222","article-title":"Serum levels of glial cell line-derived neurotrophic factor and multiple neurotransmitters: In relation to cognitive performance in Parkinson\u2019s disease with mild cognitive impairment","volume":"35","author":"Liu","year":"2020","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/S0149-7634(99)00067-6","article-title":"5-HT system and cognition","volume":"23","author":"Meneses","year":"1999","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Li, P., Ma, Y., Wang, X., Li, X., Wang, X., Yang, J., and Liu, G. (2024). The protective effect of PL 1-3 on D-galactose-induced aging mice. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1304801"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1007\/s11745-003-1183-9","article-title":"Ingestion of plasmalogen markedly increased plasmalogen levels of blood plasma in rats","volume":"38","author":"Nishimukai","year":"2003","journal-title":"Lipids"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Hossain, M.S., Mawatari, S., and Fujino, T. (2022). Plasmalogens, the Vinyl Ether-Linked Glycerophospholipids, Enhance Learning and Memory by Regulating Brain-Derived Neurotrophic Factor. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.828282"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.neuron.2016.02.033","article-title":"Membrane Lipids in Presynaptic Function and Disease","volume":"90","author":"Lauwers","year":"2016","journal-title":"Neuron"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Takekoshi, H., Fujishima, M., Miyazawa, T., Higuchi, O., Fujikawa, T., and Miyazawa, T. (2024). Simultaneous Intake of Chlorella and Ascidian Ethanolamine Plasmalogen Accelerates Activation of BDNF\u2013TrkB\u2013CREB Signaling in Rats. Molecules, 29.","DOI":"10.3390\/molecules29020357"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/1476-511X-11-109","article-title":"Agonistic effect of polyunsaturated fatty acids (PUFAs) and its metabolites on brain-derived neurotrophic factor (BDNF) through molecular docking simulation","volume":"11","author":"Vetrivel","year":"2012","journal-title":"Lipids Health Dis."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/19\/3179\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:50:27Z","timestamp":1790596227000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/19\/3179"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,26]]},"references-count":37,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["nu18193179"],"URL":"https:\/\/doi.org\/10.3390\/nu18193179","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,26]]}}}