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  • Title: Beta-amyloid-induced apoptosis is associated with cyclooxygenase-2 up-regulation via the mitogen-activated protein kinase-NF-kappaB signaling pathway.
    Author: Jang JH, Surh YJ.
    Journal: Free Radic Biol Med; 2005 Jun 15; 38(12):1604-13. PubMed ID: 15917189.
    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.
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