Affiliations: College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China
Correspondence:
[*]
Correspondence to: Pu Wang and Xue-Shi Huang, PhD, College of Life and Health Sciences, Northeastern
University, No. 3-11. Wenhua Road, Shenyang, 110819, P. R. China. Tel.: +86-13998827106; E-mail: [email protected] (P. Wang) and Tel.: +86-13386886029; E-mail: [email protected] (X.-S. Huang).
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 tauP301S 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 tauP301S 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.
Keywords: Alzheimer’s disease, cyclooxygenase-2, EP receptors, prostaglandin
E2
, tau
