Calcium Ions Stimulate the Hyperphosphorylation of Tau by Activating Microsomal Prostaglandin E Synthase 1
Calcium Ions Stimulate the Hyperphosphorylation of Tau by Activating Microsomal Prostaglandin E Synthase 1
复制标题
钙离子通过激活微粒体前列腺素 E 合酶 1 刺激 Tau 过度磷酸化
DOI：
10.3389/fnagi.2019.00108
复制
发表时间：
2019-05-09
影响因子：
4.8
通讯作者：
Wang, Pu
中科院分区：
文献类型：
--
作者：
Cao, Long-Long;Guan, Pei-Pei;Wang, Pu
据报道，阿尔茨海默病(AD)与钙离子(Ca~(2+))的积累有关，这种积累与tau的磷酸化有关。尽管有几条证据证明了上述现象，但其内在机制仍不清楚。采用APP/PS1TG小鼠和神经母细胞瘤(N)2a细胞作为体内和体外实验模型，观察到钙离子通过前列腺素(PG)E-2依赖的EP受体激活方式激活微粒体前列腺素E合成酶1(MPGES1)，从而刺激tau的磷酸化。具体来说，大量积累的钙离子刺激了mPGES1的表达和PGE(2)的合成。钙转运蛋白抑制剂NMDAR可抑制S(C)-氯胺酮诱导的APP/PS1TG小鼠mPGE_1的表达和PGE(2)的产生。PGE(2)水平的升高是导致tau过度磷酸化的原因，这种过度磷酸化依赖于EP-1、EP-2和EP-3，而不依赖于EP4依赖的细胞周期蛋白依赖性激酶(CDK)5。反过来，mPGES1表达的下调通过抑制tau的磷酸化来改善APP/PS1 TG小鼠的预期认知能力下降。此外，发现CDK5位于EP1-3的下游，通过切割p35到p25来调节tau的磷酸化。最后，钙离子对tau的磷酸化导致了APP/PS1转基因小鼠的认知功能下降。
Alzheimer's disease (AD) is reportedly associated with the accumulation of calcium ions (Ca2+), 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 in vivo and in vitro experimental models, we observed that Ca2+ stimulated the phosphorylation of tau by activating microsomal PGE synthase 1 (mPGES1) in a prostaglandin (PG) E-2-dependent EP receptor-activating manner. Specifically, the highly accumulated Ca2+ stimulated the expression of mPGES1 and the synthesis of PGE(2). Treatment with the inhibitor of Ca2+ transporter, NMDAR, attenuated the expression of mPGES1 and the production of PGE(2) were attenuated in S(C)-ketamine-treated APP/PS1 Tg mice. Elevated levels of PGE(2) 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 Ca2+ contributed to the cognitive decline of APP/PS1 Tg mice.