Figure 8. Signaling cascade of IFNγ upregulation during the course of AD development.

COX-2 metabolic products including PGE₂ and PGI₂ displayed opposing effects on regulating the expression of IFNγ in vitro and in vivo. Specifically, PGE₂ upregulated the expression of IFNγ via an Aβ-dependent NF-κB activating pathways. Although PGI₂ can stimulate the expression of IFNγ via an Aβ-dependent NF-κB mechanism, PGI₂ predominantly suppresses the expression of IFNγ via NF-κB-deactivating pathways, which is independent of Aβ_1–42. Due to the role of PGE₂ and PGI₂ in inducing the production of Aβ_1–42, we further found that Aβ_1–42 oligomers stimulated the expression of IFNγ during the early stage of AD and that Aβ_1–42 fibrils upregulated the expression of IFNγ at the late stage of AD. Highly expressed IFNγ accelerates the aggregation of Aβ_1–42 in APs by inducing the expression of BACE-1 and PS2. These findings are instrumental for understanding the mechanisms of IFNγ upregulation in APP/PS1 transgenic mice and the roles of IFNγ in Aβ_1–42 deposition in APs during the course of AD progression.