Prostaglandin I(2) is responsible for ameliorating prostaglandin E(2) stress in stimulating the expression of tumor necrosis factor α in a β-amyloid protein -dependent mechanism

Cyclooxygenase-2 (COX-2) has been found to be induced during the early stage of Alzheimer’s disease (AD). Using mouse-derived astrocyte and APP/PS1 transgenic (Tg) mice as model systems, we firstly elucidated the mechanisms underlying COX-2 metabolic production including prostaglandin (PG)E(2)- and PGI(2)-mediated tumor necrosis factor α (TNF-α) regulation. Specifically, PGE(2) accumulation in astrocyte activated the p38 and JNK/c-Jun signaling pathways via phosphorylation, resulting in TNF-α expression. In contrast, the administration of PGI(2) attenuated the effects of PGE(2) in stimulating the production of TNF-α by inhibiting the activity of TNF-α promoter and the binding activity of AP1 on the promoter of TNF-α. Moreover, our data also showed that not only Aβ(1-42) oligomers but also Aβ(1-42) fibrils have the ability to involve in mediating the antagonistic effects of PGE(2) and PGI(2) on regulating the expression of TNF-α via a p38- and JNK/c-Jun-dependent, AP1-transactivating mechanism. Reciprocally, the production of TNF-α finally accelerated the deposition of β-amyloid protein (Aβ)(1-42) in β-amyloid plaques (APs), which contribute to the cognitive decline of AD.