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 pathophysiologic al functions, Recent studies demonstrated that COX-2 expression was up-regu lated in the brain of patients with Alzheimer's disease. We established mou se neuroblastoma x rat glioma hybrid NG108-15 cells stably expressing human COX-2, The COX-2-expressing cells showed 3- to Q-fold increases in both CO X activity and prostaglandin E-2 production. The mRNA level of amyloid prec ursor protein (APP) was elevated by approximately 2-fold in the COX-2-expre ssing cells compared with mock-transfected cells, Amyloid beta -peptide and a secreted form of APP, both derived from APP by proteolysis was also incr eased. Interestingly, neurite outgrowth was stimulated in the COX-2-express ing cells with concomitant reduction of the cell proliferation rate, A sele ctive COX-2 inhibitor (JTE-522) and a nonselective COX inhibitor (indometha cin) 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. (C) 2001 A cademic Press.