Prostaglandin I(2) Attenuates Prostaglandin E(2)-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 γ (IFNγ) regulation by PGE(2) and PGI(2). Specifically, PGE(2) accumulation in astrocytes activated the ERK1/2 and NF-κB signaling pathways by phosphorylation, which resulted in IFNγ expression. In contrast, the administration of PGI(2) attenuated the effects of PGE(2) on stimulating the production of IFNγ via inhibiting the translocation of NF-κB 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 Aβ(1–42) levels. In detail, PGE(2) induced IFNγ expression in an Aβ(1–42)-dependent manner, whereas PGI(2)-induced Aβ(1–42) production did not alleviate cells from IFNγ inhibition by PGI(2) treatment. More importantly, our data also revealed that not only Aβ(1–42) oligomer but also fibrillar have the ability to induce the expression of IFNγ via stimulation of NF-κB nuclear translocation in astrocytes of APP/PS1 mice. The production of IFNγ finally accelerated the deposition of Aβ(1–42) in β-amyloid plaques.