Calcium Ions Stimulate the Hyperphosphorylation of Tau by Activating Microsomal Prostaglandin E Synthase 1.

Alzheimer's disease (AD) is reportedly associated with the accumulation of calcium ions (Ca), and this accumulation is responsible for the phosphorylation of tau. Although several lines of evidence demonstrate the above phenomenon, the inherent mechanisms remain unknown. Using APP/PS1 Tg mice and neuroblastoma (N)2a cells as and experimental models, we observed that Ca stimulated the phosphorylation of tau by activating microsomal PGE synthase 1 (mPGES1) in a prostaglandin (PG) E-dependent EP receptor-activating manner. Specifically, the highly accumulated Ca stimulated the expression of mPGES1 and the synthesis of PGE. Treatment with the inhibitor of Ca transporter, NMDAR, attenuated the expression of mPGES1 and the production of PGE were attenuated in S(+)-ketamine-treated APP/PS1 Tg mice. Elevated levels of PGE were responsible for the hyperphosphorylation of tau in an EP-1-, EP-2-, and EP-3-dependent but not EP4-dependent cyclin-dependent kinase (Cdk) 5-activating manner. Reciprocally, the knockdown of the expression of mPGES1 ameliorated the expected cognitive decline by inhibiting the phosphorylation of tau in APP/PS1 Tg mice. Moreover, CDK5 was found to be located downstream of EP1-3 to regulate the phosphorylation of tau though the cleavage of p35 to p25. Finally, the phosphorylation of tau by Ca contributed to the cognitive decline of APP/PS1 Tg mice.