Rescue of hippocampal synaptic plasticity and memory performance by Fingolimod (FTY720) in APP/PS1 model of Alzheimer's disease is accompanied by correction in metabolism of sphingolipids, polyamines, and phospholipid saturation composition

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...

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Published inbioRxiv
Main Authors Kalecký, Karel, Buitrago, Luna, Alarcon, Juan Marcos, Singh, Abanish, Bottiglieri, Teodoro, Kaddurah-Daouk, Rima, Hernández, Alejandro Iván
Format Journal Article Paper
LanguageEnglish
Published United States Cold Spring Harbor Laboratory Press 18.01.2025
Cold Spring Harbor Laboratory
Edition1.1
Subjects
Alzheimer's disease
Apoptosis
FTY720
Hippocampal plasticity
Hippocampus
Inflammation
Metabolomics
Mitochondria
Multiple sclerosis
Neurodegenerative diseases
Neuroscience
Patent applications
Phosphatidylethanolamine
Phosphatidylserine
Phosphatidylserine decarboxylase
Phospholipids
Polyamines
Presenilin 1
Protein turnover
Spermidine
Sphingolipids
Sphingomyelin
Synaptic plasticity
Temporal lobe
Therapeutic targets
Transcriptomics
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Summary: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", 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.
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Competing Interest Statement: Karel Kalecky and Teodoro Bottiglieri are authors of the Integrator software, which was used for quantification of chromatographic signal, and which implements an approach described in a patent application (Application # PCT/US24/51426, filed on October 15, 2024) that is currently pending. Dr. Kaddurah-Daouk is an inventor on a series of patents on use of metabolomics for the diagnosis and treatment of CNS diseases and holds equity in Metabolon Inc., Chymia LLC and PsyProtix.
ISSN:2692-8205
2692-8205
DOI:10.1101/2025.01.17.633452