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17β-estradiol attenuates glycogen synthase kinase-3β activation and tau hyperphosphorylation in Akt-independent manner

  • Alzheimer's Disease and Related Disorders - Original Article
  • Published:
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An Erratum to this article was published on 06 April 2010

Abstract

Decline of estrogen is associated with high incidence of Alzheimer’s disease (AD) characterized pathologically with tau hyperphosphorylation, and glycogen synthase kinase-3β (GSK-3β) is a major tau kinase. However, the role of estrogen on GSK3β-induced tau hyperphosphorylation is elusive. Here, we treated N2a cells with wortmannin (Wort) and GF-109203X (GFX) or gene transfection to activate GSK-3β and to induce tau hyperphosphorylation and then the effects of 17β-estradiol (βE2) on tau phosphorylation and GSK-3β activity were studied. We found that βE2 could attenuate tau hyperphosphorylation at multiple AD-related sites, including Ser396/404, Thr231, Thr205, and Ser199/202, induced by Wort/GFX or transient overexpression of GSK-3β. Simultaneously, it increased the level of Ser9-phosphorylated (inactive) GSK-3β. To study whether the protective effect of βE2 on GSK-3β and tau phosphorylation involves protein kinase B (Akt), an upstream effector of GSK-3, we transiently expressed the dominant negative Akt (dnAkt) in the cells. We found that βE2 could attenuate Wort/GFX-induced GSK-3β activation and tau hyperphosphorylation with Akt-independent manner. It suggests that βE2 may arrest AD-like tau hyperphosphorylation by directly targeting GSK-3β.

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Abbreviations

βE2:

17β-estradiol

AD:

Alzheimer’s disease

GSK-3:

Glycogen synthase kinase-3

Akt:

Protein kinase B

Wort:

Wortmannin

GFX:

GF-109203X

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Acknowledgments

We thank Dr. JR. Woodgett at University of Toronto for the generous gift of wtGSK-3 plasmid; Dr. K. Marcelo at University of Pennsylvania School of Medicine for HA-pcDNA3.0 plasmid; Dr. K. Walsh at Boston University School of Medicine for dnAkt plasmid; Dr. P. Davies at Albert Einstein College of Medicine for PHF-1 antibody; Dr. H. Xu at Burnham Institute of Neuroscience for N2a cell line; Drs. K. Iqbal, I. Grundke-Iqbal, CX. Gong and F. Liu at NYS Institute for Basic Research for their technical support. This work was supported in part by the National Natural Science Foundation of China (30430270 and 30670738) and the National Science and Technology Committee of China (2006CB500703, 2006AA02Z4A1).

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Authors and Affiliations

  1. Department of Pathophysiology, Key Laboratory of Neurological Disease of Ministry of Education and Hubei Province, Tongji Medical College, HuaZhong University of Science and Technology, Hangkong Road NO.13, Wuhan, 430030, People’s Republic of China

    Hai-Rong Shi, Ling-Qiang Zhu, Shao-Hui Wang, Xin-An Liu, Qing Tian, Qi Zhang, Qun Wang & Jian-Zhi Wang

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  1. Hai-Rong Shi
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  2. Ling-Qiang Zhu
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  3. Shao-Hui Wang
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  8. Jian-Zhi Wang
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Correspondence to Ling-Qiang Zhu or Jian-Zhi Wang.

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Hai-Rong Shi and Ling-Qiang Zhu contributed equally to this work.

An erratum to this article can be found at http://dx.doi.org/10.1007/s00702-010-0399-2

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Shi, HR., Zhu, LQ., Wang, SH. et al. 17β-estradiol attenuates glycogen synthase kinase-3β activation and tau hyperphosphorylation in Akt-independent manner. J Neural Transm 115, 879–888 (2008). https://doi.org/10.1007/s00702-008-0021-z

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