Role of Dickkopf-1, an antagonist of the Wnt/β-catenin signaling pathway, in estrogen-induced neuroprotection and attenuation of tau phosphorylation

Quan Guang Zhang, Ruimin Wang, Mohammad Khan, Virendra Mahesh, Darrell W. Brann

Research output: Contribution to journalArticlepeer-review

138 Scopus citations

Abstract

17β-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/β-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-β-catenin and elevation of nuclear β-catenin levels, as well as enhancement of Wnt-3, suggesting E2 activation of the Wnt/β-catenin signaling pathway. In agreement, the β-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 β-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.

Original languageEnglish (US)
Pages (from-to)8430-8441
Number of pages12
JournalJournal of Neuroscience
Volume28
Issue number34
DOIs
StatePublished - Aug 20 2008

Keywords

  • 17β-estradiol
  • Alzheimer's disease
  • Cerebral ischemia
  • Hippocampus
  • Neuronal cell death
  • Survivin

ASJC Scopus subject areas

  • Neuroscience(all)

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