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The immune modulator FTY720 targets sphingosine–kinase‐dependent migration of human monocytes in response to amyloid beta‐protein and its precursor
Author(s) -
Kaneider Nicole C.,
Lindner Julia,
Feistritzer Clemens,
Sturn Daniel H.,
Mosheimer Birgit A.,
Djanani Angela M.,
Wiedermann Christian J.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-1050fje
Subject(s) - sphingosine , sphingosine kinase , amyloid beta , amyloid precursor protein , p3 peptide , amyloid (mycology) , neurodegeneration , microbiology and biotechnology , senile plaques , biochemistry of alzheimer's disease , alzheimer's disease , biology , chemistry , receptor , sphingosine 1 phosphate , biochemistry , medicine , peptide , botany , disease
Accumulation of inflammatory mononuclear phagocytes in Alzheimer's senile plaques, a hallmark of the innate immune response to β‐amyloid fibrils, can initiate and propagate neurodegeneration characteristic of Alzheimer's disease. Phagocytes migrate toward amyloid β‐ protein involving formyl peptide receptor like‐1‐dependent signaling. Using human peripheral blood monocytes in Boyden chamber micropore filter assays, we show that the amyloid β‐ protein‐ and amyloid β‐precursor protein‐induced migration was abrogated by dimethylsphingosine, a sphingosine kinase inhibitor. Amyloid β‐protein stimulated in monocytes the gene expression for sphingosine‐1‐phosphate receptors 2 and 5, but not 1, 3, and 4. FTY720 that acts as a sphingosine‐1‐phosphate receptor agonist after endogenous phosphorylation by sphingosine kinase, as well as various neuropeptides that are known to be monocyte chemoattractants, dose‐dependently inhibited amyloid β‐protein‐induced migration. These data demonstrate that the migratory effects of β‐amyloid in human monocytes involve spingosine‐1‐ phosphate signaling. Whereas endogenous neuropeptides may arrest and activate monocytes at sites of high β‐amyloid concentrations, interference with the amyloid β‐protein‐dependent sphingosine‐1‐phosphate pathway in monocytes by FTY720, a novel immunomodulatory drug, suggests that FTY720 may be efficacious in β‐amyloid‐related inflammatory diseases.