Fingolimod normalizes metabolic signatures associated with synaptic plasticity and memory in APP/PS1 model: Sphingosine-1-phosphate receptor a therapeutic target for Alzheimer's.

Overview

1. Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX USA
2. Neural and Behavioral Sciences Program, School of Graduate Studies, Department of Neurology, Physiology and Pharmacology, SUNY Downstate Health Sciences University, Brooklyn, NY USA
3. Neural and Behavioral Sciences Program, School of Graduate Studies, The Robert F. Furchgott Center for Neural and Behavioral Science, Department of Pathology, SUNY Downstate Health Sciences University, Brooklyn, NY USA
4. Department of Psychiatry and Behavioural Sciences, Duke University, Durham, NC USA
5. Department of Medicine, Duke University, Durham, NC USA
6. Duke Institute of Brain Sciences, Duke University, Durham, NC USA

Abstract

Previously, our metabolomic, transcriptomic, and genomic studies characterized the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer’s disease, and we demonstrated that FTY720, a sphingosine-1-phospahate receptor modulator approved for treatment of multiple sclerosis, recovers synaptic plasticity and memory in APP/PS1 mice. 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 “sphingolipid rheostat”, possibly reactivating phosphatidylethanolamine synthesis via mitochondrial phosphatidylserine decarboxylase pathway, and normalizing polyamine levels that are known to 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. Additional mechanistic studies should validate the contribution of the suggested pathways to the treatment effects.

Supplementary Information: The online version contains supplementary material available at 10.1038/s41598-026-42518-8.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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• doi:10.7303/syn64954178, at the source; found in “Data availability”

Data availability

Metabolomic and behavioral data will be available via the Synapse data repository, hosted by Sage Bionetworks, under the digital object identifier address [10.7303/syn64954178]. (https:/doi.org/10.7303/syn64954178) . Provisionally, we include the data file during the manuscript submission process for reviewers.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 4 keywords, 12 MeSH terms, 2 funders, 121 references.

Cite

This paper

Kalecký, K., Buitrago, L., Alarcon, J. M., Singh, A., Bottiglieri, T., Kaddurah-Daouk, R., & Hernández, A. I. (2026). Fingolimod normalizes metabolic signatures associated with synaptic plasticity and memory in APP/PS1 model: Sphingosine-1-phosphate receptor a therapeutic target for Alzheimer's. Scientific reports, 16(1), 12835. https://doi.org/10.1038/s41598-026-42518-8

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