{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T22:50:49Z","timestamp":1789858249012,"version":"4.0.1"},"reference-count":25,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T00:00:00Z","timestamp":1663200000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Shorai Foundation for Science and Technology, KAKENHI grant-in-aid for scientific research","award":["21K05303"],"award-info":[{"award-number":["21K05303"]}]},{"name":"the Shorai Foundation for Science and Technology, KAKENHI grant-in-aid for scientific research","award":["19H02836"],"award-info":[{"award-number":["19H02836"]}]},{"name":"the Shorai Foundation for Science and Technology, KAKENHI grant-in-aid for scientific research","award":["8607011"],"award-info":[{"award-number":["8607011"]}]},{"name":"the Shorai Foundation for Science and Technology, KAKENHI grant-in-aid for scientific research","award":["PCS8617001"],"award-info":[{"award-number":["PCS8617001"]}]},{"name":"Industry Creation Departments Funding","award":["21K05303"],"award-info":[{"award-number":["21K05303"]}]},{"name":"Industry Creation Departments Funding","award":["19H02836"],"award-info":[{"award-number":["19H02836"]}]},{"name":"Industry Creation Departments Funding","award":["8607011"],"award-info":[{"award-number":["8607011"]}]},{"name":"Industry Creation Departments Funding","award":["PCS8617001"],"award-info":[{"award-number":["PCS8617001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The extracellular accumulation of aggregated amyloid-\u03b2 (A\u03b2) in the brain leads to the early pathology of Alzheimer\u2019s disease (AD). The administration of exogenous plant-type ceramides into AD model mice can promote the release of neuronal exosomes, a subtype of extracellular vesicles, that can mediate A\u03b2 clearance. In vitro studies showed that the length of fatty acids in mammalian-type ceramides is crucial for promoting neuronal exosome release. Therefore, investigating the structures of plant ceramides is important for evaluating the potential in releasing exosomes to remove A\u03b2. In this study, we assessed plant ceramide species with D-erythro-(4E,8Z)-sphingadienine and D-erythro-(8Z)-phytosphingenine as sphingoid bases that differ from mammalian-type species. Some plant ceramides were more effective than mammalian ceramides at stimulating exosome release. In addition, using deuterium chemistry-based lipidomics, most exogenous plant ceramides were confirmed to be derived from exosomes. These results suggest that the ceramide-dependent upregulation of exosome release may promote the release of exogenous ceramides from cells, and plant ceramides with long-chain fatty acids can effectively release neuronal exosomes and prevent AD pathology.<\/jats:p>","DOI":"10.3390\/ijms231810751","type":"journal-article","created":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T22:11:10Z","timestamp":1663279870000},"page":"10751","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Evaluation of Plant Ceramide Species-Induced Exosome Release from Neuronal Cells and Exosome Loading Using Deuterium Chemistry"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9115-6478","authenticated-orcid":false,"given":"Yuta","family":"Murai","sequence":"first","affiliation":[{"name":"Graduate School of Life Science, Hokkaido University, Kita 21 Nishi 11, Sapporo 001-0021, Japan"},{"name":"Faculty of Advanced Life Science, Hokkaido University, Kita 21 Nishi 11, Sapporo 001-0021, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takumi","family":"Honda","sequence":"additional","affiliation":[{"name":"Graduate School of Life Science, Hokkaido University, Kita 21 Nishi 11, Sapporo 001-0021, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Yuyama","sequence":"additional","affiliation":[{"name":"Lipid Biofunction Section, Faculty of Advanced Life Science, Hokkaido University, Kita 21, Nishi 11, Sapporo 001-0021, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Mikami","sequence":"additional","affiliation":[{"name":"Lipid Biofunction Section, Faculty of Advanced Life Science, Hokkaido University, Kita 21, Nishi 11, Sapporo 001-0021, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Eguchi","sequence":"additional","affiliation":[{"name":"Innovation and Business Development Headquarters, Daicel Corporation, Niigata 944-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Ukawa","sequence":"additional","affiliation":[{"name":"Healthcare SBU Business Strategy, Daicel Corporation, Tokyo 108-8259, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seigo","family":"Usuki","sequence":"additional","affiliation":[{"name":"Lipid Biofunction Section, Faculty of Advanced Life Science, Hokkaido University, Kita 21, Nishi 11, Sapporo 001-0021, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyuki","family":"Igarashi","sequence":"additional","affiliation":[{"name":"Lipid Biofunction Section, Faculty of Advanced Life Science, Hokkaido University, Kita 21, Nishi 11, Sapporo 001-0021, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1424-1054","authenticated-orcid":false,"given":"Kenji","family":"Monde","sequence":"additional","affiliation":[{"name":"Graduate School of Life Science, Hokkaido University, Kita 21 Nishi 11, Sapporo 001-0021, Japan"},{"name":"Faculty of Advanced Life Science, Hokkaido University, Kita 21 Nishi 11, Sapporo 001-0021, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1126\/science.1197623","article-title":"Decreased clearance of CNS beta-amyloid in Alzheimer\u2019s disease","volume":"330","author":"Mawuenyega","year":"2010","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.jalz.2011.03.003","article-title":"Toward defining the preclinical stages of Alzheimer\u2019s disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"Sperling","year":"2011","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1001\/archneur.60.7.940","article-title":"Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease","volume":"60","author":"Martha","year":"2003","journal-title":"Arch Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"16827","DOI":"10.1038\/s41598-019-53394-w","article-title":"Plant sphingolipids promote extracellular vesicle release and alleviate amyloid-\u03b2 pathologies in a mouse model of Alzheimer\u2019s disease","volume":"9","author":"Yuyama","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Yuyama, K., and Igarahsi, Y. (Glycoconjugate J., 2022). Linking glycosphingolipids to Alzheimer\u2019s amyloid-\u03b2: Extracellular vesicles and functional plant materials, Glycoconjugate J., in press.","DOI":"10.1007\/s10719-022-10066-8"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"10977","DOI":"10.1074\/jbc.M111.324616","article-title":"Sphingolipid-modulated exosome secretion promotes clearance of amyloid-\u03b2 by microglia","volume":"287","author":"Yuyama","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"24488","DOI":"10.1074\/jbc.M114.577213","article-title":"Decreased amyloid-\u03b2 pathologies by intracerebral loading of glycosphingolipid-enriched exosomes in Alzheimer model mice","volume":"289","author":"Yuyama","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.febslet.2014.11.027","article-title":"A potential function for neuronal exosomes: Sequestering intracerebral amyloid-\u03b2 peptide","volume":"589","author":"Yuyama","year":"2015","journal-title":"FEBS Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3389\/fnins.2017.00229","article-title":"Exosomes as Carriers of Alzheimer\u2019s Amyloid-\u03b2","volume":"11","author":"Yuyama","year":"2017","journal-title":"Front. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"16022","DOI":"10.1096\/fj.202001599R","article-title":"Lysosomal-associated transmembrane protein 4B regulates ceramide-induced exosome release","volume":"34","author":"Yuyama","year":"2020","journal-title":"FASEB J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1271\/bbb.70463","article-title":"Analysis of sphingolipid classes and their contents in meals","volume":"72","author":"Yunoki","year":"2008","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_12","first-page":"160","article-title":"Chemoenzymatically prepared konjac ceramide inhibits NGF-induced neurite outgrowth by a semaphoring 3A-like action","volume":"5","author":"Usuki","year":"2016","journal-title":"Biochem. Biophys. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"33935","DOI":"10.1038\/srep33935","article-title":"A novel affinity-based method for the isolation of highly purified extracellular vesicles","volume":"6","author":"Nakai","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"105202","DOI":"10.1016\/j.chemphyslip.2022.105202","article-title":"Penta-deuterium-labeled 4E,8Z-sphingadienine for rapid analysis in sphingolipidomics study","volume":"245","author":"Murai","year":"2022","journal-title":"Chem. Phys. Lipids"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/nchembio.1889","article-title":"LAPTM4B facilitates late endosomal ceramide export to control cell death pathways","volume":"11","author":"Blom","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1021\/acscentsci.7b00582","article-title":"A ceramide-regulated element in the late endosomal protein LAPTM4B controls amino acid transporter interaction","volume":"4","author":"Zhou","year":"2018","journal-title":"ACS Central Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1002\/chir.23179","article-title":"Chiral combinatorial preparation and biological evaluation of unique ceramides for inhibition of sphingomyelin synthase","volume":"32","author":"Koolath","year":"2020","journal-title":"Chirality"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1042\/bj20020205","article-title":"Lysosome-associated protein transmembrane 4 alpha (LAPTM4 alpha) requires two tandemly arranged tyrosine-based signals for sorting to lysosomes","volume":"365","author":"Hogue","year":"2002","journal-title":"Biochem. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5060","DOI":"10.1038\/sj.onc.1206832","article-title":"Molecular cloning and characterization of LAPTM4B, a novel gene upregulated in hepatocellular carcinoma","volume":"22","author":"Shao","year":"2003","journal-title":"Oncogene"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.jdermsci.2006.08.005","article-title":"Dietary glucosylceramide improves skin barrier function in hairless mice","volume":"44","author":"Tsuji","year":"2006","journal-title":"J. Dermatol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/0005-2760(69)90138-6","article-title":"Metabolism of cerebroside in the intestinal tract of the rat","volume":"187","author":"Nilsson","year":"1969","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s12944-021-01448-2","article-title":"Structure-dependent absorption of atypical sphingoid long-chain bases from digestive tract into lymph","volume":"20","author":"Mikami","year":"2021","journal-title":"Lipids Health Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1093\/jn\/124.5.702","article-title":"Uptake and metabolism of sphingolipids in isolated intestinal loops of mice","volume":"124","author":"Schmelz","year":"1994","journal-title":"J. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.jdermsci.2009.09.002","article-title":"Dietary glucosylceramide is absorbed into the lymph and increases levels of epidermal sphingolipids","volume":"56","author":"Ishikawa","year":"2009","journal-title":"J. Dermatol. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Eguchi, K., Mikami, D., Sun, H., Tsumita, T., Takahashi, K., Mukai, K., Yuyama, K., and Igarashi, Y. (2020). Blood-brain barrier permeability analysis of plant ceramides. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0241640"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10751\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:31:49Z","timestamp":1760142709000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/18\/10751"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,15]]},"references-count":25,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms231810751"],"URL":"https:\/\/doi.org\/10.3390\/ijms231810751","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,15]]}}}