S-Space Graduate School of Convergence Science and Technology (융합과학기술대학원) Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과) Journal Papers (저널논문_분자의학 및 바이오제약학과)
β-Amyloid-induced apoptosis is associated with cyclooxygenase-2 up-regulation via the mitogen-activated protein kinase-NF-κB signaling pathway
- Jang, Jung-Hee; Surh, Young-Joon
- Issue Date
- Free Radical Biology and Medicine, Vol.38 No.12, pp.1604-1613
- beta-amyloid; ERK; COX-2; inflammatory cell death; NF-kappa B; p38 MAPK; PC12 cells; oxidative stress
- 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 (A beta), a neurotoxic peptide that accumulates in senile plaques formed in the brains of AD patients. Rat pheochromocytoma (PC12) cells treated with A beta 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 A beta-induced cell death, which was aggravated by addition of the COX-2 product PGE(2). A beta transiently induced activation of redox-sensitive transcription factor NF-kappa B, and pretreatment of PC12 cells with NF-kappa B inhibitors abolished the A beta-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 A beta-induced NF-kappa B transactivation but also COX-2 expression and PGE(2) production. The above findings suggest that A beta-induced apoptosis in PC12 cells is associated with COX-2 up-regulation through activation of NF-kappa B, which is mediated by upstream kinases including ERK and p38 MAPK. (c) 2005 Elsevier Inc. All rights reserved.
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