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We hypothesize that changes in S1P signaling are central to the inflammatory and immune-pathogenesis of AD and the therapeutic benefits of fingolimod, a structural analog of sphingosine that is FDA approved for the treatment of multiple sclerosis. We recently reported that the neuroprotective effects of fingolimod in 5xFAD transgenic AD mice treated from 1\u20133 months of age were greater at 1\u2009mg\/kg\/day than at 5\u2009mg\/kg\/day. Here we performed a dose-response study using fingolimod from 0.03 to 1\u2009mg\/kg\/day in 5xFAD mice treated from 1\u20138 months of age. At 1\u2009mg\/kg\/day, fingolimod decreased both peripheral blood lymphocyte counts and brain A\u03b2 levels, but at the lowest dose tested (0.03\u2009mg\/kg\/day), we detected improved memory, decreased activation of brain microglia and astrocytes, and restored hippocampal levels of GABA and glycerophosphocholine with no effect on circulating lymphocyte counts. These findings suggests that, unlike the case in multiple sclerosis, fingolimod may potentially have therapeutic benefits in AD at low doses that do not affect peripheral lymphocyte function.<\/jats:p>","DOI":"10.1038\/s41598-019-47287-1","type":"journal-article","created":{"date-parts":[[2019,7,29]],"date-time":"2019-07-29T10:21:36Z","timestamp":1564395696000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Dual dose-dependent effects of fingolimod in a mouse model of Alzheimer\u2019s disease"],"prefix":"10.1038","volume":"9","author":[{"given":"Isabel","family":"Carreras","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nurgul","family":"Aytan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Kyung","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5073-8693","authenticated-orcid":false,"given":"Christina M.","family":"Tognoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil W.","family":"Kowall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce G.","family":"Jenkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alpaslan","family":"Dedeoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,7,29]]},"reference":[{"key":"47287_CR1","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.neurobiolaging.2008.05.010","volume":"31","author":"X He","year":"2010","unstructured":"He, X., Huang, Y., Li, B., Gong, C. 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