Zhang Quan-Guang, Wang Ruimin, Khan Mohammad, Mahesh Virendra, Brann Darrell W
Developmental Neurobiology Program, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, USA.
J Neurosci. 2008 Aug 20;28(34):8430-41. doi: 10.1523/JNEUROSCI.2752-08.2008.
17beta-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/beta-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-beta-catenin and elevation of nuclear beta-catenin levels, as well as enhancement of Wnt-3, suggesting E2 activation of the Wnt/beta-catenin signaling pathway. In agreement, the beta-catenin downstream prosurvival factor, survivin, was induced by E2 at 24 and 48 h after cerebral ischemia, an effect observed only in surviving neurons because degenerating neurons lacked survivin expression. E2 suppression of Dkk1 elevation was found to be caused by attenuation of upstream c-Jun N-terminal protein kinase (JNK)/c-Jun signaling, as E2 attenuation 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 intracerebroventricular administration completely reversed E2-induced neuroprotection, nuclear beta-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 after cerebral ischemia.
17β-雌二醇（E2）已被认为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。当前的研究通过证明低生理水平的E2可通过防止Dickkopf-1（Dkk1）升高来保护海马CA1区免受全脑缺血的影响，从而阐明了这一问题。Dkk1是Wnt/β-连环蛋白信号通路的拮抗剂，而该信号通路是脑缺血和阿尔茨海默病中神经退行性变的主要介导因子。E2对Dkk1升高的抑制作用与磷酸化β-连环蛋白的减少、核β-连环蛋白水平的升高以及Wnt-3的增强相关，提示E2激活了Wnt/β-连环蛋白信号通路。与此一致的是，β-连环蛋白下游的促生存因子survivin在脑缺血后24小时和48小时被E2诱导，这种效应仅在存活的神经元中观察到，因为退化的神经元缺乏survivin表达。发现E2对Dkk1升高的抑制是由上游c-Jun氨基末端蛋白激酶（JNK）/c-Jun信号通路的减弱引起的，因为E2对JNK/c-Jun激活的减弱以及一种JNK抑制剂显著阻断了Dkk1的诱导。tau蛋白过度磷酸化在阿尔茨海默病和脑缺血中被认为具有促死亡作用，而E2可减轻tau蛋白过度磷酸化。我们的研究表明，全脑缺血后tau蛋白过度磷酸化被强烈诱导，并且E2通过抑制JNK/c-Jun/Dkk1信号通路的激活来抑制tau蛋白过度磷酸化。最后，通过脑室内注射外源性Dkk1完全逆转了E2诱导的神经保护作用、核β-连环蛋白的诱导以及磷酸化tau蛋白的减弱，进一步表明E2对Dkk1的抑制是其在脑缺血后神经保护和磷酸化tau蛋白调节作用的关键机制。
