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To further investigate how FTY720 rescues the pathology, we performed metabolomic analysis in brain, plasma, and liver of trained APP\/PS1 and wild-type mice. APP\/PS1 mice showed area-specific brain disturbances in polyamines, phospholipids, and sphingolipids. Most changes were completely or partially normalized in FTY720-treated subjects, indicating rebalancing the \u201csphingolipid rheostat\u201d, reactivating phosphatidylethanolamine synthesis via mitochondrial phosphatidylserine decarboxylase pathway, and normalizing polyamine levels that support mitochondrial activity. Synaptic plasticity and memory were rescued, with spermidine synthesis in temporal cortex best corresponding to hippocampal CA3-CA1 plasticity normalization. FTY720 effects, also reflected in other pathways, are consistent with promotion of mitochondrial function, synaptic plasticity, and anti-inflammatory environment, while reducing pro-apoptotic and pro-inflammatory signals.<\/jats:p>","DOI":"10.1101\/2025.01.17.633452","type":"posted-content","created":{"date-parts":[[2025,1,18]],"date-time":"2025-01-18T22:15:12Z","timestamp":1737238512000},"source":"Crossref","is-referenced-by-count":2,"title":["Rescue of hippocampal synaptic plasticity and memory performance by Fingolimod (FTY720) in APP\/PS1 model of Alzheimer\u2019s disease is accompanied by correction in metabolism of sphingolipids, polyamines, and phospholipid saturation composition"],"prefix":"10.64898","author":[{"given":"Karel","family":"Kaleck\u00fd","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luna","family":"Buitrago","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Marcos","family":"Alarcon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abanish","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teodoro","family":"Bottiglieri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rima","family":"Kaddurah-Daouk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro Iv\u00e1n","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Alzheimer\u2019s Disease Metabolomics Consortium","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025012109252868000_2025.01.17.633452v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30403-4"},{"key":"2025012109252868000_2025.01.17.633452v1.2","doi-asserted-by":"publisher","DOI":"10.1042\/bse0330117"},{"key":"2025012109252868000_2025.01.17.633452v1.3","unstructured":"Florence, A. 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