Journal of Molecular Neuroscience

, Volume 61, Issue 3, pp 436–448 | Cite as

Estrogen Modulates ubc9 Expression and Synaptic Redistribution in the Brain of APP/PS1 Mice and Cortical Neurons

  • Yu-Jie Lai
  • Lu Liu
  • Xiao-Tong Hu
  • Ling He
  • Guo-Jun Chen
Article

Abstract

Estrogen exerts multiple actions in the brain and is an important neuroprotective factor in a number of neuronal disorders. However, the underlying mechanism remains unknown. Studies demonstrate that ubiquitin-conjugating enzyme 9 (ubc9) has an integral role in synaptic plasticity and may contribute to the pathology of neuronal disorders. We aimed to investigate the effects of estrogen on ubc9 and in the Alzheimer’s disease brain. Ubc9 protein and mRNA were significantly increased in the cortex and hippocampus of APP/PS1 mice with enhanced SUMOylation. Systemic estrogen administration led to reduced ubc9 expression in ovariectomized APP/PS1 mice and reduced SUMOylation. The inhibition of ubc9 expression by estrogen was found to be dose-dependent in cultured neurons. However, estrogen receptor (ER) antagonist ICI182780 did not block the inhibition of ubc9 expression by estrogen. Furthermore, the reduced expression of ubc9 was not mediated by ERα or ERβ agonists alone or in combination, but by the membrane-impermeable ER agonist E2-bovine serum albumin. The activation of the G protein-coupled ER mediated the inhibition of ubc9 expression of estrogen. A phosphoinositide 3-kinase (PI3K) inhibitor, rather than an extracellular signal-regulated kinase inhibitor, blocked the inhibition of ubc9 by estrogen. Estrogen treatment significantly increased the phosphorylation of PI3K, which suggests that activation of the PI3K pathway by estrogen is required for ubc9 regulation. Further, ubc9 interacted with the synaptic proteins post-synaptic density protein 95 (PSD95) and synaptophysin. Estrogen decreased the interaction of ubc9 with post-synaptic PSD95, but increased the interaction of ubc9 with pre-synaptic synaptophysin. These results suggest that a membrane-bound ER might mediate the estrogen inhibition of ubc9 in cortical neurons, where PI3K plays an important role. We also show that ubc9 can interact with synaptic proteins, which are subject to estrogen regulation.

Keywords

Estrogen ubc9 Neuroplasticity PSD95 Synaptophysin 

Notes

Acknowledgements

This work was supported by NSFC grants (numbers 81171197 and 81220108010) and a Bureau of Health of Chongqing Medical Research grant (number 2011-1-018) to G-J. C.

Compliance with Ethical Standards

All protocols were approved by the Commission of Chongqing Medical University for Ethics of Experiments on Animals and were conducted in accordance with international standards.

Competing Interests

The authors declare that they have no competing interests.

Supplementary material

12031_2017_884_Fig1_ESM.gif (110 kb)
ESM 1

Supplementary figure legend. Estrogen decreases ubc9 expression in cultured cortical neurons. Primary cultured cortical neurons were treated with vehicle (DMSO), 17β-estradiol, the non-selective estrogen antagonist ICI, or 17β-estradiol and ICI. (A) Estrogen dose-dependently decreased ubc9 expression in cortical neurons. Neurons were incubated with vehicle DMSO or various 17β-estradiol (E2) concentrations (1 nM, 10 nM, 100 nM or 1 μM) for 24 h, and ubc9 protein was then measured, which were performed in triplicate. (B) Estrogen time-dependently decreased ubc9 expression in cortical neurons. Time-course response showed that ubc9 protein levels were decreased within 24 h, and remained to be up to 72 h in the presence of E2 (10 nM, Fig. B),which were performed in triplicate. (C) ICI182780 failed to block the effects of estrogen on ubc9 expression. We pre-incubated the neurons with the non-selective ER antagonist ICI182780 at a range of concentrations (1 μM, 10 μM, and 100 μM), which were performed in triplicate. (GIF 109 kb)

12031_2017_884_MOESM1_ESM.tif (1.7 mb)
High Resolution Image (TIFF 1732 kb)

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Yu-Jie Lai
    • 1
  • Lu Liu
    • 1
  • Xiao-Tong Hu
    • 1
  • Ling He
    • 1
  • Guo-Jun Chen
    • 1
  1. 1.Department of Neurology, Chongqing Key Laboratory of NeurologyHospital of Chongqing Medical UniversityChongqingChina

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