Abstract
Cyclooxygenase (COX) synthesizes bioactive prostaglandins from arachidonic acid, and there are COX-1 and COX-2 isoforms with distinct pathophysiological functions. Recent studies demonstrated that COX-2 expression was up-regulated in the brain of patients with Alzheimer's disease. We established mouse neuroblastoma x rat glioma hybrid NG108-15 cells stably expressing human COX-2. The COX-2-expressing cells showed 3- to 4-fold increases in both COX activity and prostaglandin E(2) production. The mRNA level of amyloid precursor protein (APP) was elevated by approximately 2-fold in the COX-2-expressing cells compared with mock-transfected cells. Amyloid beta-peptide and a secreted form of APP, both derived from APP by proteolysis was also increased. Interestingly, neurite outgrowth was stimulated in the COX-2-expressing cells with concomitant reduction of the cell proliferation rate. A selective COX-2 inhibitor (JTE-522) and a nonselective COX inhibitor (indomethacin) suppressed production of amyloid beta-peptide and a secreted form of APP by inhibition of APP mRNA level, suggesting that COX-2 plays important roles in the neurodegenerative processes of Alzheimer's disease.
Copyright 2001 Academic Press.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid beta-Peptides / drug effects
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Protein Precursor / drug effects
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Amyloid beta-Protein Precursor / genetics
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Animals
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Benzenesulfonates / pharmacology
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Cell Division / drug effects
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Cell Division / genetics
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology
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DNA, Recombinant
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Gene Expression Regulation, Enzymologic
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Genetic Vectors / genetics
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Glioma / enzymology
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Glioma / genetics
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Glioma / pathology
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Hybrid Cells
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Indomethacin / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / genetics
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Isoenzymes / metabolism*
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Mice
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Neurites / drug effects
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Neurites / physiology
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Neuroblastoma / enzymology
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Neuroblastoma / genetics
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Neuroblastoma / pathology
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Oxazoles / pharmacology
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Prostaglandin-Endoperoxide Synthases / genetics
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Prostaglandin-Endoperoxide Synthases / metabolism*
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RNA, Messenger / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Reverse Transcriptase Polymerase Chain Reaction
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Transfection
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Tumor Cells, Cultured
Substances
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4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Benzenesulfonates
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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DNA, Recombinant
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Isoenzymes
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Oxazoles
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RNA, Messenger
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Cyclooxygenase 2
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Prostaglandin-Endoperoxide Synthases
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Indomethacin