Deletion of microsomal prostaglandin E synthase-1 protects neuronal cells from cytotoxic effects of β-amyloid peptide fragment 31-35

Epidemiological studies have suggested that the long-term use of nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX) activity moderates the onset or progression of Alzheimer's disease (AD). Thus it has been suggested that prostaglandin E-2 (PGE(2)), a major end-product of COX, may play a pathogenic role in AD, but the involvement of PGE synthase (PGES), a terminal enzyme downstream from COX, has not been fully elucidated. To examine the involvement in AD pathology of microsomal PGES-1 (mPGES-1), a PGES enzyme, we here prepared primary cerebral neuronal cells from the cerebri of wildtype and mPGES-1-deficient mice and then treated them with beta-amyloid (A beta) fragment 31-35 (A beta(31-35)), which represents the shortest sequence of native A beta peptide required for neurotoxicity. Treatment of wild-type neuronal cells with A beta(31-35) induced mPGES-1 gene expression and PGE2 production, followed by significant apoptotic cell death, but apoptosis was not induced in mPGES-1-deficient cells. Furthermore, the combined treatment of A beta(31-35) and PGE2 induced apoptosis in mPGES-1-deficient neuronal cells. These results indicated that mPGES-1 is induced during A beta-mediated neuronal cell death and is involved in A beta-induced neurotoxicity associated with AD pathology. (C) 2012 Elsevier Inc. All rights reserved.