Glycogen synthase kinase 3β links neuroprotection by 17β-estradiol to key Alzheimer processes
Glycogen synthase kinase 3β links neuroprotection by 17β-estradiol to key Alzheimer processes
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DOI：
10.1016/j.neuroscience.2004.12.029
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发表时间：
2005-01-01
期刊：
影响因子：
3.3
通讯作者：
Behl, C
中科院分区：
文献类型：
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作者：
Goodenough, S;Schleusner, D;Behl, C
雌激素通过激活多种细胞内信号转导途径，包括丝裂原激活蛋白激酶（MAPK）、磷酸肌醇-3激酶和蛋白激酶C途径，发挥多种受体介导的神经保护功能。本研究利用凯尼克酸诱导的神经毒性细胞死亡海马切片培养模型，证明雌激素对氧化性细胞死亡具有保护作用。我们之前已经证明MAPK和糖原合成酶激酶3 β (GSK-3 β)参与了kainic酸诱导的细胞死亡/细胞存活。在这个模型和其他细胞和体内模型中，我们已经表明雌激素也可以引起GSK-3 β的磷酸化并因此失活，GSK-3 β是一种已知的神经元细胞死亡介质。雌激素对GSK-3 β活性的影响是由雌激素受体介导的。此外，这种雌激素/GSK-3 β相互作用可能在与阿尔茨海默病相关的一些关键致病途径的细胞模型中具有功能后果。更具体地说，雌激素影响已知被GSK-3 β磷酸化的位点的tau磷酸化的基础水平。综上所述，这些数据表明雌激素和GSK-3 β之间存在一种新的分子和功能联系，可能对雌激素受体调节作为预防神经退行性疾病的靶点具有启示意义。(c) 2005年由Elsevier Ltd代表IBRO出版。
Estrogen exerts many of its receptor-mediated neuroprotective functions through the activation of various intracellular signal transduction pathways including the mitogen activating protein kinase (MAPK), phospho inositol-3 kinase and protein kinase C pathways. Here we have used a hippocampal slice culture model of kainic acid-induced neurotoxic cell death to show that estrogen can protect against oxidative cell death. We have previously shown that MAPK and glycogen synthase kinase-3 beta (GSK-3 beta) are involved in the cell death/cell survival induced by kainic acid. In this model and other cellular and in vivo models we have shown that estrogen can also cause the phosphorylation and hence inactivation of GSK-3 beta, a known mediator of neuronal cell death. The effect of estrogen on GSK-3 beta activity is estrogen receptor mediated. Further, this estrogen/GSK-3 beta interaction may have functional consequences in cellular models of some key pathogenic pathways associated with Alzheimer's disease. More specifically, estrogen affects the basal levels of tau phosphorylation at a site known to be phosphorylated by GSK-3 beta. Taken together, these data indicate a novel molecular and functional link between estrogen and GSK-3 beta and may have implications for estrogen receptor modulation as a target for the prevention of neurodegenerative disorders. (c) 2005 Published by Elsevier Ltd on behalf of IBRO.