title: Beta-amyloid-induced apoptosis is associated with cyclooxygenase-2 up-regulation via the mitogen-activated protein kinase-NF-kappaB signaling pathway.
abstract: Inflammatory cell death as well as oxidative stress has been implicated in some neurodegenerative disorders such as Alzheimer's disease (AD). Expression of cyclooxygenase-2 (COX-2) and production of prostaglandins have been frequently elevated in AD. In this study, we have investigated the molecular mechanisms underlying inflammatory cell death induced by beta-amyloid (Abeta), a neurotoxic peptide that accumulates in senile plaques formed in the brains of AD patients. Rat pheochromocytoma (PC12) cells treated with Abeta exhibited increased mRNA and protein expression of COX-2 and production of prostaglandin E(2) (PGE(2)) and underwent apoptotic death as determined by positive in situ terminal end-labeling, decreased mitochondrial membrane potential, increased Bax/Bcl-X(L) ratio, activation of c-Jun N-terminal kinase, and cleavage of poly(ADP-ribose)polymerase. Pretreatment with celecoxib, a selective COX-2 inhibitor, attenuated Abeta-induced cell death, which was aggravated by addition of the COX-2 product PGE(2). Abeta transiently induced activation of redox-sensitive transcription factor NF-kappaB, and pretreatment of PC12 cells with NF-kappaB inhibitors abolished the Abeta-induced COX-2 expression. Pharmacologic inhibition of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) and dominant-negative mutation of both enzymes suppressed not only Abeta-induced NF-kappaB transactivation but also COX-2 expression and PGE(2) production. The above findings suggest that Abeta-induced apoptosis in PC12 cells is associated with COX-2 up-regulation through activation of NF-kappaB, which is mediated by upstream kinases including ERK and p38 MAPK.
authors.affiliation: National Research Laboratory, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Jung-Hee
authors.initials: JH
authors.lastname: Jang
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D002070:Butadienes / Q000494:pharmacology; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D002070:Butadienes; D007093:Imidazoles; D016328:NF-kappa B; D009570:Nitriles; D010446:Peptide Fragments; D011720:Pyrazoles; D011725:Pyridines; D013449:Sulfonamides; C113580:U 0126; C074636:amyloid beta-protein (25-35); D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011065:Poly(ADP-ribose) Polymerases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000068579:Celecoxib; D015232:Dinoprostone; C093642:SB 203580