COX-2 metabolic products, the prostaglandin I(2) and F(2α), mediate the effects of TNF-α and Zn(2+) in stimulating the phosphorylation of Tau

Although the roles of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) in regulating amyloid precursor protein (APP) cleavage and β-amyloid protein (Aβ) production have been the subjects of numerous investigations, their effects on tau phosphorylation have been largely overlooked. Using human Tau(P301S) transgenic (Tg) mice as in vivo model, our results demonstrated that PGI(2) and PGF(2α) mediated the effects of tumor necrosis factor α (TNF-α) and Zinc ions (Zn(2+)) on upregulating the phosphorylation of tau via the PI3-K/AKT, ERK1/2 and JNK/c-Jun signaling pathways. Specifically, we initially found that high level of Zn(2+) upregulates the expression of COX-2 via stimulating the activity of TNF-α in a zinc transporter 3 (ZnT3)-dependent mechanism. COX-2 upregulation then stimulates the phosphorylation of tau at both Ser 202 and Ser 400/Thr 403/Ser 404 via PGI(2) and F(2α) treatment either in i.c.v.-injected mice or in n2a cells. Using n2a cells as in vitro model, we further revealed critical roles for the PI3-K/AKT, ERK1/2 and JNK/c-Jun pathways in mediating the effects of PGI(2) and F(2α) in the phosphorylation of tau. Finally, NS398 treatment delayed the onset of cognitive decline in Tau(P301S) Tg mice according to the nest construction or limb clasping test.