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P1–090: FTY720/Fingolimod, a sphingosine analogue, reduces beta‐amyloid production in neurons
Author(s) -
Takasugi Nobumasa,
Sasaki Tomoki,
Tomita Taisuke,
Iwatsubo Takeshi
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.05.311
Subject(s) - sphingosine kinase , sphingosine , fingolimod , lipid signaling , chemistry , microbiology and biotechnology , sphingolipid , sphingosine 1 phosphate , biology , pharmacology , receptor , biochemistry , immunology , multiple sclerosis
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-b peptide (Ab), a pathogenic proteins causative for Alzheimer disease (AD), in cultured neuronal cells. Pharmacological analyses suggested that the mechanism of FTY720-mediated Ab 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 Ab40, but an increase in Ab42 levels in brains. These results suggest that S1PR modulators are novel type of regulators for Ab metabolisms that are active in vitro and in vivo.