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Cited by 85Alzheimer's disease research and treatmentsSphingolipid Metabolism and SignalingLysosomal Storage Disorders Research

FTY720/fingolimod, a sphingosine analogue, reduces amyloid-β production in neurons

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Takasugi, Nobumasa, Sasaki, Tomoki, Ebinuma, Ihori, Osawa, Satoko, Isshiki, Hayato, Takeo, Koji, Tomita, Taisuke, Iwatsubo, Takeshi·2013·PLoS ONE
DOI 10.1371/journal.pone.0064050PMC PMC3646787
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Abstract

Sphingosine-1-phosphate (S1P) is a pluripotent lipophilic mediator working as a ligand for G-protein coupled S1P receptors (S1PR), which is currently highlighted as a therapeutic target for autoimmune diseases including relapsing forms of multiple sclerosis. Sphingosine related compounds, FTY720 and KRP203 known as S1PR modulators, are phosphorylated by sphingosine kinase 2 (SphK2) to yield the active metabolites FTY720-P and KRP203-P, which work as functional antagonists for S1PRs. Here we report that FTY720 and KRP203 decreased production of Amyloid-β peptide (Aβ), a pathogenic proteins causative for Alzheimer disease (AD), in cultured neuronal cells. Pharmacological analyses suggested that the mechanism of FTY720-mediated Aβ decrease in cells was independent of known downstream signaling pathways of S1PRs. Unexpectedly, 6-days treatment of APP transgenic mice with FTY720 resulted in a decrease in Aβ40, but an increase in Aβ42 levels in brains. These results suggest that S1PR modulators are novel type of regulators for Aβ metabolisms that are active in vitro and in vivo.

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Authors
Takasugi, N., Sasaki, T., Ebinuma, I., Osawa, S., Isshiki, H., Takeo, K., Tomita, T., & Iwatsubo, T.
Affiliations
  • Japan Science and Technology Agency (JP)
  • The University of Tokyo (JP)
Corresponding author
Tomita, Taisuke
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-05-07
Volume
8
Issue
5
Pages
e64050
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0064050
PMC
PMC3646787
OpenAlex
W2074300020
Cited by
85
References
2
Citations by year
2026: 2 · 2025: 6 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 2 · 2020: 9 · 2019: 9 · 2018: 8 · 2017: 9 · 2016: 6 · 2015: 6 · 2014: 12 · 2013: 1
FWCI
5.18
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Washington University in St. Louis
  • Karolinska Institutet
  • Japan Society for the Promotion of Science
  • Core Research for Evolutional Science and Technology
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
fingolimod, sphingosine-1-phosphate, S1P receptors, sphingosine kinase 2, amyloid-beta production, Alzheimer's disease, APP transgenic mice, amyloid-beta 42, Aβ40, neurons, multiple sclerosis
MeSH terms
Fingolimod Hydrochloride, Sphingosine Kinase, Animals, Brain, Disease Models, Animal, Humans, Mice, Inbred BALB C, Neurons, Propylene Glycols, Sphingosine, Sulfhydryl Compounds, Signal Transduction, Amyloid beta-Peptides, Phosphotransferases (Alcohol Group Acceptor), Mice, Amyloid Precursor Protein Secretases

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