Prostaglandin I2 Attenuates Prostaglandin E2-Stimulated Expression of Interferon γ in a β-Amyloid Protein- and NF-κB-Dependent Mechanism

Cyclooxygenase-2 (COX-2) has been recently identified as being involved in the pathogenesis of Alzheimer's disease (AD). However, the role of an important COX-2 metabolic product, prostaglandin (PG)I-2, in AD development remains unknown. Using mouse-derived astrocytes as well as APP/PS1 transgenic mice as model systems, we firstly elucidated the mechanisms of interferon gamma (IFN gamma) regulation by PGE(2) and PGI(2). Specifically, PGE(2) accumulation in astrocytes activated the ERK1/2 and NF-kappa B signaling pathways by phosphorylation, which resulted in IFN gamma expression. In contrast, the administration of PGI(2) attenuated the effects of PGE(2) on stimulating the production of IFN gamma via inhibiting the translocation of NF-kappa B from the cytosol to the nucleus. Due to these observations, we further studied these prostaglandins and found that both PGE(2) and PGI(2) increased A beta(1-42) levels. In detail, PGE(2) induced IFN gamma expression in an A beta(1-42)-dependent manner, whereas PGI(2)-induced A beta(1-42) production did not alleviate cells from IFN gamma inhibition by PGI(2) treatment. More importantly, our data also revealed that not only A beta(1-42) oligomer but also fibrillar have the ability to induce the expression of IFN gamma via stimulation of NF-kappa B nuclear translocation in astrocytes of APP/PS1 mice. The production of IFN gamma finally accelerated the deposition of A beta(1-42) in beta-amyloid plaques.