Cyclooxygenase-2 stimulates production of amyloid beta-peptide in neuroblastoma x glioma hybrid NG108-15 cells.
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.
Kadoyama
K
K
Department of Pharmacology, Kanazawa University School of Medicine, Kanazawa, Ishikawa 920-8640, Japan.
Takahashi
Y
Y
Higashida
H
H
Tanabe
T
T
Yoshimoto
T
T
D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004274:DNA, Recombinant; D015971:Gene Expression Regulation, Enzymologic; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006822:Hybrid Cells; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009447:Neuroblastoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010080:Oxazoles / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured; D000096926:Benzenesulfonamides
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001557:Benzenesulfonates; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004274:DNA, Recombinant; D007213:Indomethacin; D007527:Isoenzymes; D010080:Oxazoles; D011451:Prostaglandin-Endoperoxide Synthases; D012333:RNA, Messenger; C110453:4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide; D000096926:Benzenesulfonamides