AbstractCyclooxygenase-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) I₂, 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 PGE₂ and PGI₂. Specifically, PGE₂ accumulation in astrocytes activated the ERK1/2 and NF-κB signaling pathways by phosphorylation, which resulted in IFNγ expression. In contrast, the administration of PGI₂ attenuated the effects of PGE₂ 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 PGE₂ and PGI₂ increased Aβ_1–42 levels. In detail, PGE₂ induced IFNγ expression in an Aβ_1–42-dependent manner, whereas PGI₂-induced Aβ_1–42 production did not alleviate cells from IFNγ inhibition by PGI₂ 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.