{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T17:01:11Z","timestamp":1784826071505,"version":"3.55.0"},"reference-count":63,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/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":["2021YFA1101400"],"award-info":[{"award-number":["2021YFA1101400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Alzheimer's disease (AD) is a debilitating neurodegenerative disorder that is difficult to predict and is typically diagnosed only after symptoms manifest. Recently, CD4<jats:sup>+<\/jats:sup> T cell\u2010derived double\u2010negative T (DNT) cells have shown strong immuno\u2010regulatory properties in both in\u00a0vitro and in\u00a0vivo neuronal inflammation studies. However, the effectiveness of DNT cells in treating on AD are not yet fully understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This study's aims were three\u2010fold, to (1) evaluate the efficacy of CD4<jats:sup>+<\/jats:sup> T cell\u2010derived DNT cells treatment on AD mice, (2) understand how DNT treatment make changes in different cell types of 5FAD mice, (3) identify the side effects of DNT treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed tail vein injection of transformed and amplified CD4<jats:sup>+<\/jats:sup> T cell\u2010derived DNT cells into 5\u2009\u00d7\u2009FAD mice, while using WT mice and saline injection 5FAD mice as controls. DNT suspensions or NaCl alone were administered to 5\u2009\u00d7\u2009FAD mice at the 6 months of age. For intravenous injection (<jats:italic>n<\/jats:italic>\u2009=\u200910 for both DNT and control injections), 5\u2009\u00d7\u2009FAD mice were injected with a total of 5\u2009\u00d7\u200910<jats:sup>6<\/jats:sup> DNT cells suspended in 200\u2009\u03bcL of 0.9% NaCl or 0.9% NaCl alone via the lateral tail vein. Behavioral tests and pathology tests were carried out 30\u2009days after cell transplantation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Through qualitative analysis, we identified 6 main themes. DNT from young wild\u2010type mice enhance the capability of spatial learning and memory in AD mice. DNT cell treatment rejuvenates the microglial function. DNT cell treatment improves the state of oligodendrocytes. DNT cell treatment finetunes the activation of the immune system. DNT cell treatment improves the synaptic plasticity and increases the complexity of neurons. DNT cell treatment reduces the density of amyloid Beta plaques deposition in the cortex and hippocampus of 5\u2009\u00d7\u2009FAD mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The findings from this study reveal that DNT treatment improved spatial memory and learning abilities, reduced A\u03b2 deposition, and enhanced synaptic plasticity, contrasting with previous reports on thymus\u2010derived DNT cells. Additionally, CD4<jats:sup>+<\/jats:sup> T cell\u2010derived DNT therapy exhibited anti\u2010inflammatory effects and modulated microglial function, promoting a neuroprotective environment. Notably, DNT treatment also reduced tau pathology by decreasing levels of abnormally phosphorylated tau. These findings suggest that CD4<jats:sup>+<\/jats:sup> T cell\u2010derived DNT cells hold therapeutic potential for AD, effectively targeting both A\u03b2 and tau pathologies.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70187","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T09:24:07Z","timestamp":1737624247000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["<scp>CD4<\/scp>\u2010Derived Double\u2010Negative T Cells Ameliorate Alzheimer's Disease\u2010Like Phenotypes in the 5\u00d7<scp>FAD<\/scp> Mouse Model"],"prefix":"10.1111","volume":"31","author":[{"given":"Yuanzhi","family":"Xie","sequence":"first","affiliation":[{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology Chinese Academy of Sciences  Beijing China"},{"name":"University of Chinese Academy of Sciences  Beijing 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