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Pretreatment of PC12 Cells with 17β-estradiol Prevents Aβ-Induced Down-Regulation of CREB Phosphorylation and Prolongs Inhibition of GSK-3β

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Abstract

It is believed that estrogen protects neurons against various toxicities like that from amyloid β (Aβ) in Alzheimer’s disease (AD). In the present study, we investigated the effects of Aβ1–42 on the activities of cyclic-AMP response element-binding protein (CREB) and glycogen synthase kinase-3β (GSK-3β), two key proteins associated with learning and memory, and the effects of 17β-estradiol on Aβ1–42-induced changes of CREB and GSK-3β in PC12 cells. We found that Aβ1–42 induced a decrease in phosphorylation of CREB at Ser133 (CREB pS133) and caused a transient (30 min) up-regulation of the inhibitory GSK-3β phosphorylation at Ser9 (GSK-3β pS9), followed by down-regulation of GSK-3β pS9. Pretreatment of 17β-estradiol is needed for its protection against Aβ1–42-induced changes of CREB. The protective role of 17β-estradiol against Aβ1–42-induced down-regulation of CREB pS133 was abolished by the mitogen-activated protein kinase (MAPK) pathway inhibitor U0126. Furthermore, 17β-estradiol also prolonged the up-regulation of GSK-3β pS9 for at least 8 h. However, this action of 17β-estradiol was abrogated by PKA inhibitor H-89, AKT inhibitor LY294002, and MAPK inhibitor U0126. These results suggest that, while the protection of 17β-estradiol on CREB is MAPK dependent, its effect on GSK-3β integrates several pathways. These studies provide new insights into the role of estrogen in memory and AD.

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Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (30901386), the Wuhan Science and Technology Bureau, China (200960323132), and the Research Fund for the Doctoral Program of Higher Education of China (200804871026). We thank Dr. Fei Liu of New York State Institute for Basic Research in Developmental Disabilities for providing PC12 cells and reagents.

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The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei, China

    Yanxing Chen, Ying Su, Zhou Sun, Tao Wang, Shenggang Sun & Zhihou Liang

  2. Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei, China

    Xiaoqin Run

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  1. Yanxing Chen
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Correspondence to Zhihou Liang.

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Yanxing Chen and Ying Su contributed equally to this work.

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Chen, Y., Su, Y., Run, X. et al. Pretreatment of PC12 Cells with 17β-estradiol Prevents Aβ-Induced Down-Regulation of CREB Phosphorylation and Prolongs Inhibition of GSK-3β. J Mol Neurosci 50, 394–401 (2013). https://doi.org/10.1007/s12031-012-9938-7

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