Cyclooxygenase-2 is Essential for Mediating the Effects of Calcium Ions on Stimulating Phosphorylation of Tau at the Sites of Ser 396 and Ser 404

Abstract

Alzheimer’s disease (AD) is reported to be associated with the accumulation of calcium ions (Ca²⁺), which is responsible for the phosphorylation of tau. Although a series of evidence have demonstrated this phenomenon, the inherent mechanisms remain unknown. Using tau^P301S and cyclooxygenase-2 (COX-2) transgenic mice and neuroblastoma (n)2a cells as in vivo and in vitro experimental models, we found that Ca²⁺ stimulates the phosphorylation of tau by activating COX-2 in a prostaglandin (PG) E₂-dependent EP receptor-activating manner. Specifically, Ca²⁺ incubation stimulated COX-2 and PGE₂ synthase activity, microsomal PGE synthase 1 and the synthesis of PGE₂ by activating the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in n2a cells. Elevated levels of PGE₂ were responsible for phosphorylating tau in an EP-1, -2, and -3 but not EP4-dependent glycogen synthase kinase 3-activating manner. These observations were corroborated by results that showed tau was phosphorylated when it colocalized with activated COX-2 in tau^P301S and COX-2 transgenic mice or n2a cells. To further validate these observations, treatment of mice with the COX-2 inhibitor rofecoxib decreased the phosphorylation of tau via EP1-3 but not EP4. Collectively, our observations fill the gaps between Ca²⁺ and the phosphorylation of tau in a COX-2-dependent mechanism, which potentially provides therapeutic targets for combating AD.