Role of Dickkopf-1, an antagonist of the Wnt/beta-catenin signaling pathway, in estrogen-induced neuroprotection and attenuation of tau phosphorylation.
Role of Dickkopf-1, an antagonist of the Wnt/beta-catenin signaling pathway, in estrogen-induced neuroprotection and attenuation of tau phosphorylation.
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DOI：
10.1523/jneurosci.2752-08.2008
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发表时间：
2008-08-20
影响因子：
5.3
通讯作者：
Brann, Darrell W.
中科院分区：
文献类型：
--
作者：
Zhang, Quan-Guang;Wang, Ruimin;Khan, Mohammad;Mahesh, Virendra;Brann, Darrell W.
17β-雌二醇（E2）在多种神经退行性疾病中具有神经保护作用，但其机制仍知之甚少。目前的研究揭示了这个问题，通过证明低生理水平的E2通过防止dickkopf-1（Dkk 1）的升高来保护海马CA 1免受全脑缺血的影响，Dkk 1是Wnt-β-Catenin信号通路的拮抗剂，Wnt-β-Catenin信号通路是脑缺血和阿尔茨海默病中神经变性的主要介质。E2对Dkk 1升高的抑制与磷酸化β-连环蛋白的减少和核β-连环蛋白水平的升高以及Wnt-3的增强相关，表明E2激活了Wnt-β-连环蛋白信号通路。与此一致的是，β-连环蛋白下游促生存因子生存素在脑缺血后24小时和48小时被E2诱导，这种作用仅在存活的神经元中观察到，因为变性的神经元缺乏生存素表达。发现E2抑制Dkk 1升高是由于上游JNK/c-Jun信号转导的减弱，因为E2减弱了JNK/c-Jun活化，并且JNK抑制剂显著阻断了Dkk 1诱导。Tau蛋白过度磷酸化在阿尔茨海默病和脑缺血中具有促死亡作用，而E2可减弱Tau蛋白过度磷酸化。我们的研究表明，tau蛋白过度磷酸化强烈诱导全脑缺血后，E2抑制tau蛋白过度磷酸化通过抑制JNK/c-Jun/Dkk 1信号通路的激活。最后，通过icv施用的外源性Dkk 1替代完全逆转了E2诱导的神经保护、核β-连环蛋白诱导和磷酸化tau衰减，进一步表明E2对Dkk 1的抑制是脑缺血后其神经保护和磷酸化tau调节作用的关键机制。
17β-Estradiol (E2) has been implicated to be neuroprotective in a variety of neurodegenerative disorders, although the mechanism remains poorly understood. The current study sheds light on this issue by demonstrating that low physiological levels of E2 protects the hippocampus CA1 against global cerebral ischemia by preventing elevation of dickkopf-1 (Dkk1), an antagonist of the Wnt-β-Catenin signaling pathway, which is a principal mediator of neurodegeneration in cerebral ischemia and Alzheimer’s disease. E2 inhibition of Dkk1 elevation correlated with a reduction of phospho-β-Catenin and elevation of nuclear β-Catenin levels, as well as enhancement of Wnt-3, suggesting E2 activation of the Wnt-β-Catenin signaling pathway. In agreement, the β-Catenin-downstream prosurvival factor, survivin was induced by E2 at 24 hr and 48 hr after cerebral ischemia, an effect observed only in surviving neurons, as degenerating neurons lacked survivin expression. E2 suppression of Dkk1 elevation was found to be due to attenuation of upstream JNK/c-Jun signaling, as E2 attenuated of JNK/c-Jun activation and a JNK inhibitor significantly blocked Dkk1 induction. Tau hyperphosphorylation has been implicated to have a prodeath role in Alzheimer’s disease and cerebral ischemia, and E2 attenuates tau hyperphosphorylation. Our study demonstrates that tau hyperphosphorylation is strongly induced after global cerebral ischemia, and that E2 inhibits tau hyperphosphorylation by suppressing activation of the JNK/c-Jun/Dkk1 signaling pathway. Finally, exogenous Dkk1 replacement via icv administration completely reversed E2 induced-neuroprotection, nuclear β-Catenin induction and phospho-tau attenuation, further suggesting that E2 inhibition of Dkk1 is a critical mechanism underlying its neuroprotective and phospho-tau regulatory effects following cerebral ischemia.