Abstract
Accumulation of inflammatory mononuclear phagocytes in Alzheimer's senile plaques, a hallmark of the innate immune response to beta-amyloid fibrils, can initiate and propagate neurodegeneration characteristic of Alzheimer's disease. Phagocytes migrate toward amyloid beta-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 beta-protein- and amyloid beta-precursor protein-induced migration was abrogated by dimethylsphingosine, a sphingosine kinase inhibitor. Amyloid beta-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 beta-protein-induced migration. These data demonstrate that the migratory effects of beta-amyloid in human monocytes involve spingosine-1-phosphate signaling. Whereas endogenous neuropeptides may arrest and activate monocytes at sites of high beta-amyloid concentrations, interference with the amyloid beta-protein-dependent sphingosine-1-phosphate pathway in monocytes by FTY720, a novel immunomodulatory drug, suggests that FTY720 may be efficacious in beta-amyloid-related inflammatory diseases.
MeSH terms
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1-Methyl-3-isobutylxanthine / pharmacology
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Amyloid beta-Peptides / pharmacology*
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Amyloid beta-Protein Precursor / pharmacology*
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Androstadienes / pharmacology
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Bombesin / pharmacology
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Calcitonin Gene-Related Peptide / pharmacology
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Cell Movement / drug effects
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Chemotaxis, Leukocyte / drug effects
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Cholera Toxin / pharmacology
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / pharmacology
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Fingolimod Hydrochloride
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Gene Expression Regulation / drug effects
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Heterotrimeric GTP-Binding Proteins / physiology
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Humans
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Immunologic Factors / pharmacology*
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Indoles / pharmacology
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Leukocytes, Mononuclear / cytology
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Leukocytes, Mononuclear / drug effects*
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Maleimides / pharmacology
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N-Formylmethionine Leucyl-Phenylalanine / pharmacology
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Neuropeptides / pharmacology
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Pertussis Toxin / pharmacology
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
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Phosphotransferases (Alcohol Group Acceptor) / physiology*
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Propylene Glycols / pharmacology*
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Protein Kinase Inhibitors / pharmacology
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Protein Processing, Post-Translational / drug effects
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RNA, Messenger / biosynthesis
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Receptors, Lysosphingolipid / agonists
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Receptors, Lysosphingolipid / biosynthesis*
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Receptors, Lysosphingolipid / genetics
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Receptors, Lysosphingolipid / physiology
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Secretogranin II
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Sphingosine / analogs & derivatives*
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Sphingosine / pharmacology
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Staurosporine / pharmacology
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Tyrphostins / pharmacology
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Vasoactive Intestinal Peptide / pharmacology
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Wortmannin
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Androstadienes
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Enzyme Inhibitors
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Immunologic Factors
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Indoles
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Maleimides
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Neuropeptides
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Phosphoinositide-3 Kinase Inhibitors
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Propylene Glycols
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Protein Kinase Inhibitors
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RNA, Messenger
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Receptors, Lysosphingolipid
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Secretogranin II
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Tyrphostins
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secretoneurin
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Vasoactive Intestinal Peptide
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N-Formylmethionine Leucyl-Phenylalanine
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Cholera Toxin
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Pertussis Toxin
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase
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Heterotrimeric GTP-Binding Proteins
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Fingolimod Hydrochloride
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Staurosporine
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Calcitonin Gene-Related Peptide
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bisindolylmaleimide I
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N,N-dimethylsphingosine
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Sphingosine
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safingol
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Bombesin
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tyrphostin A23
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1-Methyl-3-isobutylxanthine
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Wortmannin