{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:18:02Z","timestamp":1788999482273,"version":"build-2803163510"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T00:00:00Z","timestamp":1758758400000},"content-version":"vor","delay-in-days":267,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24wm0625303"],"award-info":[{"award-number":["JP24wm0625303"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP20gm1210010"],"award-info":[{"award-number":["JP20gm1210010"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020963","name":"Moonshot Research and Development Program","doi-asserted-by":"publisher","award":["JPMJMS2024"],"award-info":[{"award-number":["JPMJMS2024"]}],"id":[{"id":"10.13039\/501100020963","id-type":"DOI","asserted-by":"publisher"}]},{"name":"JST SPRING Japan","award":["JPMJSP2130"],"award-info":[{"award-number":["JPMJSP2130"]}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20H03564"],"award-info":[{"award-number":["JP20H03564"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24K02354"],"award-info":[{"award-number":["JP24K02354"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP22K06865"],"award-info":[{"award-number":["JP22K06865"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24K18381"],"award-info":[{"award-number":["JP24K18381"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24KJ1888"],"award-info":[{"award-number":["JP24KJ1888"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005694","name":"Hori Sciences and Arts Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005694","id-type":"DOI","asserted-by":"publisher"}]},{"name":"LEGEND Research Grant 2024 from BioLegend"},{"DOI":"10.13039\/501100008883","name":"Nagoya City University","doi-asserted-by":"publisher","award":["2021101"],"award-info":[{"award-number":["2021101"]}],"id":[{"id":"10.13039\/501100008883","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008883","name":"Nagoya City University","doi-asserted-by":"publisher","award":["2401101"],"award-info":[{"award-number":["2401101"]}],"id":[{"id":"10.13039\/501100008883","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>It is known that T cells play an important role in the progression of neurodegenerative disorders, including tauopathies. In this study, we used fingolimod (FTY720), an approved medication for the treatment of multiple sclerosis (MS), to manipulate T cell dynamics in P301S-Tau transgenic (Tau Tg) mice. FTY720 dramatically decreased the population of circulating T cells in blood. However, unexpectedly, we observed a marked increase in the number of CD8+ T cells in the hippocampus of FTY720-treated Tau Tg mice. This increase in CD8+ T cell number was significantly correlated with enhanced tau phosphorylation. Notably, FTY720-treated Tau Tg mice exhibited brain atrophy and neurodegeneration compared with controls. These findings indicate that CD8+ T cells in the brain contribute to the progression of tauopathies, and that brain CD8+ T cells may be a promising target for the treatment of tauopathies. This study provides new insights into the dynamics of brain T cells in neurodegenerative disorders. In addition, these results raise caution regarding FTY720 treatment in individuals predisposed to tauopathies, as it may promote neurodegeneration despite reducing peripheral T cells.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaf330","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T11:53:36Z","timestamp":1756986816000},"source":"Crossref","is-referenced-by-count":5,"title":["Fingolimod treatment exacerbates tau phosphorylation and neurodegeneration in a mouse model of tauopathy with accumulated brain CD8+ T cells"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0152-0819","authenticated-orcid":false,"given":"Ryohei","family":"Uenishi","sequence":"first","affiliation":[{"name":"Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences , Mizuho-cho, Mizuho-ku, Nagoya, 467-8601 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3080-7894","authenticated-orcid":false,"given":"Rinna","family":"Kawata","sequence":"additional","affiliation":[{"name":"Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences , Mizuho-cho, Mizuho-ku, Nagoya, 467-8601 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1424-5688","authenticated-orcid":false,"given":"Tatsuya","family":"Manabe","sequence":"additional","affiliation":[{"name":"Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences , Mizuho-cho, Mizuho-ku, Nagoya, 467-8601 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8103-651X","authenticated-orcid":false,"given":"Toru","family":"Takeo","sequence":"additional","affiliation":[{"name":"Division of Reproductive Engineering, Center for Animal Resources and Development, Kumamoto University , Kumamoto, 860-0811 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6912-3496","authenticated-orcid":false,"given":"Masanori","family":"Hijioka","sequence":"additional","affiliation":[{"name":"Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences , Mizuho-cho, Mizuho-ku, Nagoya, 467-8601 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9659-9251","authenticated-orcid":false,"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences , Mizuho-cho, Mizuho-ku, Nagoya, 467-8601 ,","place":["Japan"]},{"name":"Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University , Nagoya, 464-8601 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,9,25]]},"reference":[{"key":"2025092420012887900_fcaf330-B1","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1146\/annurev-pathmechdis-012418-012936","article-title":"Molecular pathogenesis of the tauopathies","volume":"14","author":"G\u00f6tz","year":"2019","journal-title":"Annu Rev Pathol"},{"issue":"10","key":"2025092420012887900_fcaf330-B2","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1016\/j.neuron.2024.02.017","article-title":"P-tau217 correlates with neurodegeneration in Alzheimer's disease, and targeting p-tau217 with immunotherapy ameliorates murine tauopathy","volume":"112","author":"Zhang","year":"2024","journal-title":"Neuron"},{"issue":"1","key":"2025092420012887900_fcaf330-B3","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1159\/000486200","article-title":"Extravascular CD3+ T cells in brains of Alzheimer disease patients correlate with Tau but not with amyloid pathology: An immunohistochemical study","volume":"18","author":"Merlini","year":"2018","journal-title":"Neurodegener Dis"},{"issue":"1","key":"2025092420012887900_fcaf330-B4","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1093\/brain\/aww270","article-title":"Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy","volume":"140","author":"Laurent","year":"2017","journal-title":"Brain"},{"issue":"13","key":"2025092420012887900_fcaf330-B5","doi-asserted-by":"crossref","first-page":"110158","DOI":"10.1016\/j.celrep.2021.110158","article-title":"TREM2-independent oligodendrocyte, astrocyte, and T cell responses to tau and amyloid pathology in mouse models of Alzheimer disease","volume":"37","author":"Lee","year":"2021","journal-title":"Cell Rep"},{"issue":"2","key":"2025092420012887900_fcaf330-B6","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1093\/brain\/awad309","article-title":"Glial reactivity and T cell infiltration in frontotemporal lobar degeneration with tau pathology","volume":"147","author":"Hartnell","year":"2024","journal-title":"Brain"},{"issue":"7953","key":"2025092420012887900_fcaf330-B7","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/s41586-023-05788-0","article-title":"Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy","volume":"615","author":"Chen","year":"2023","journal-title":"Nature"},{"issue":"16","key":"2025092420012887900_fcaf330-B8","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1212\/01.wnl.0000327609.57688.ea","article-title":"FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis","volume":"71","author":"Mehling","year":"2008","journal-title":"Neurology"},{"issue":"2","key":"2025092420012887900_fcaf330-B9","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1097\/WNF.0b013e3181cbf825","article-title":"Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis","volume":"33","author":"Chun","year":"2010","journal-title":"Clin Neuropharmacol"},{"issue":"3","key":"2025092420012887900_fcaf330-B10","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.neuron.2007.01.010","article-title":"Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model","volume":"53","author":"Yoshiyama","year":"2017","journal-title":"Neuron"},{"issue":"1","key":"2025092420012887900_fcaf330-B11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ab.2003.10.047","article-title":"Visible fluorescent detection of proteins in polyacrylamide gels without staining","volume":"326","author":"Ladner","year":"2004","journal-title":"Anal Biochem"},{"issue":"1","key":"2025092420012887900_fcaf330-B12","doi-asserted-by":"crossref","first-page":"100351","DOI":"10.1016\/j.xpro.2021.100351","article-title":"Analysis of T cells in mouse lymphoid tissue and blood with flow cytometry","volume":"2","author":"Skordos","year":"2021","journal-title":"STAR Protoc"},{"issue":"1","key":"2025092420012887900_fcaf330-B13","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s11481-024-10122-0","article-title":"The effects of fingolimod (FTY720) on leukocyte subset circulation cannot be behaviourally conditioned in rats","volume":"19","author":"Jakobs","year":"2024","journal-title":"J Neuroimmune Pharmacol"},{"issue":"14","key":"2025092420012887900_fcaf330-B14","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1212\/WNL.0b013e3182143564","article-title":"Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS","volume":"76","author":"Kowarik","year":"2011","journal-title":"Neurology"},{"key":"2025092420012887900_fcaf330-B15","doi-asserted-by":"crossref","first-page":"4859","DOI":"10.1038\/ncomms5859","article-title":"Hypothalamic S1P\/S1PR1 axis controls energy homeostasis","volume":"5","author":"Silva","year":"2014","journal-title":"Nat Commun"},{"issue":"10","key":"2025092420012887900_fcaf330-B16","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1523\/JNEUROSCI.5561-03.2004","article-title":"Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia","volume":"24","author":"Planel","year":"2004","journal-title":"J Neurosci"},{"issue":"12","key":"2025092420012887900_fcaf330-B17","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/s41582-023-00883-2","article-title":"Tau-targeting therapies for Alzheimer disease: Current status and future directions","volume":"19","author":"Congdon","year":"2023","journal-title":"Nat Rev Neurol"},{"issue":"1","key":"2025092420012887900_fcaf330-B18","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/s13195-023-01321-7","article-title":"The therapeutic landscape of tauopathies: Challenges and prospects","volume":"15","author":"Cummings","year":"2023","journal-title":"Alzheimers Res Ther"},{"issue":"1","key":"2025092420012887900_fcaf330-B19","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/s41392-023-01563-9","article-title":"Interaction of microglia and T cells: A deadly duo behind Tau-mediated neurodegeneration","volume":"8","author":"Askin","year":"2023","journal-title":"Signal Transduct Target Ther"},{"issue":"1","key":"2025092420012887900_fcaf330-B20","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s41514-024-00145-5","article-title":"Switch of innate to adaptative immune responses in the brain of patients with Alzheimer's disease correlates with tauopathy progression","volume":"10","author":"Costa","year":"2024","journal-title":"NPJ Aging"},{"issue":"19","key":"2025092420012887900_fcaf330-B21","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1212\/01.wnl.0000435293.34351.11","article-title":"Tumefactive MS lesions under fingolimod: A case report and literature review","volume":"81","author":"Pilz","year":"2013","journal-title":"Neurology"},{"issue":"9","key":"2025092420012887900_fcaf330-B22","doi-asserted-by":"crossref","first-page":"2316","DOI":"10.1111\/jnc.16106","article-title":"Infiltration of immune cells to the brain and its relation to the pathogenesis of Alzheimer's and Parkinson's diseases","volume":"168","author":"Netzahualcoyotzi","year":"2024","journal-title":"J Neurochem"},{"issue":"7790","key":"2025092420012887900_fcaf330-B23","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/s41586-019-1895-7","article-title":"Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer\u2019s disease","volume":"577","author":"Gate","year":"2020","journal-title":"Nature"},{"issue":"26","key":"2025092420012887900_fcaf330-B24","doi-asserted-by":"crossref","first-page":"5028","DOI":"10.1016\/j.cell.2022.11.019","article-title":"Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment","volume":"185","author":"Piehl","year":"2022","journal-title":"Cell"},{"issue":"34","key":"2025092420012887900_fcaf330-B25","doi-asserted-by":"crossref","first-page":"eaas9673","DOI":"10.1126\/sciimmunol.aas9673","article-title":"Location, location, location: Tissue resident memory T cells in mice and humans","volume":"4","author":"Szabo","year":"2019","journal-title":"Sci Immunol"},{"issue":"1","key":"2025092420012887900_fcaf330-B26","doi-asserted-by":"crossref","first-page":"4593","DOI":"10.1038\/s41467-018-07053-9","article-title":"Tissue-resident memory T cells populate the human brain","volume":"9","author":"Smolders","year":"2018","journal-title":"Nat Commun"},{"issue":"7","key":"2025092420012887900_fcaf330-B27","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.4049\/jimmunol.2100737","article-title":"Transcriptomic profiling identifies CD8+ T cells in the brain of aged and Alzheimer's disease transgenic mice as tissue-resident memory T cells","volume":"209","author":"Altendorfer","year":"2022","journal-title":"J Immunol"},{"key":"2025092420012887900_fcaf330-B28","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.brainres.2008.02.084","article-title":"Microglial activation in brain lesions with tau deposits: Comparison of human tauopathies and tau transgenic mice TgTauP301L","volume":"1214","author":"Sasaki","year":"2008","journal-title":"Brain Res"},{"issue":"1\u20132","key":"2025092420012887900_fcaf330-B29","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.jim.2010.08.007","article-title":"Novel application of Ki67 to quantify antigen-specific in vitro lymphoproliferation","volume":"362","author":"Soares","year":"2010","journal-title":"J Immunol Methods"},{"issue":"1","key":"2025092420012887900_fcaf330-B30","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s40478-023-01658-y","article-title":"Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau","volume":"11","author":"Schweighauser","year":"2023","journal-title":"Acta Neuropathol Commun"},{"issue":"7880","key":"2025092420012887900_fcaf330-B31","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/s41586-021-03911-7","article-title":"Structure-based classification of tauopathies","volume":"598","author":"Shi","year":"2021","journal-title":"Nature"},{"issue":"1","key":"2025092420012887900_fcaf330-B32","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41467-019-13787-x","article-title":"Transmission of tauopathy strains is independent of their isoform composition","volume":"11","author":"He","year":"2020","journal-title":"Nat Commun"}],"container-title":["Brain Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/7\/5\/fcaf330\/64352393\/fcaf330.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/7\/5\/fcaf330\/64352393\/fcaf330.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T00:01:42Z","timestamp":1758758502000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/braincomms\/article\/doi\/10.1093\/braincomms\/fcaf330\/8262117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025]]},"references-count":32,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,9,1]]}},"URL":"https:\/\/doi.org\/10.1093\/braincomms\/fcaf330","relation":{},"ISSN":["2632-1297"],"issn-type":[{"value":"2632-1297","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025]]},"published":{"date-parts":[[2025]]},"article-number":"fcaf330"}}