Long-term estrogen deprivation leads to elevation of Dickkopf-1 and dysregulation of Wnt/β-Catenin signaling in hippocampal CA1 neurons

Erin L. Scott, Quan Guang Zhang, Dong Han, Bhavna N. Desai, Darrell W. Brann

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Surgically menopausal women incur a 2- to 5-fold increased risk for dementia and mortality from neurological diseases, but the mechanisms underlying these increased risks remain unclear. Previously, we demonstrated that after global cerebral ischemia (GCI), 17β-estradiol (E2 or estrogen) suppresses hippocampal elevation of the Wnt antagonist Dickkopf-1 (Dkk1), a neurodegenerative factor. We, thus, hypothesized that prolonged loss of E2 may lead to dysregulation of neural Dkk1 and Wnt/β-Catenin signaling, which could contribute to an increased risk of neurodegeneration. To test this hypothesis, we examined the effect of short-term (1 week-STED) and long-term E2 deprivation (10 weeks-LTED) via ovariectomy upon basal and E2-regulated Dkk1 levels and Wnt/β-Catenin signaling in the hippocampal CA1 region following GCI. In STED rats, E2 exerted robust neuroprotection against GCI, suppressed post-ischemic elevation of Dkk1, and enhanced pro-survival Wnt/β-Catenin signaling, effects that were lost in LTED rats. Intriguingly, LTED rats displayed modest basal changes in Dkk1 and survivin expression. Further work showed that c-Jun N-terminal Kinase (JNK) mediated GCI-induced changes in Dkk1 and survivin, and JNK inhibition afforded neuroprotection in LTED rats. Finally, we extended our findings to natural aging, as 24-month-old, reproductively senescent female rats also displayed a modest increase in basal Dkk1 in the CA1, which consistently co-localized with the apoptotic marker TUNEL after GCI and coincided with a loss of E2 neuroprotection. As a whole, this study supports the "critical period hypothesis" and further suggests that perimenopausal estradiol replacement may prevent neurodegenerative changes in the hippocampus by maintaining favorable Wnt/β-Catenin signaling.

Original languageEnglish (US)
Pages (from-to)624-632
Number of pages9
JournalSteroids
Volume78
Issue number6
DOIs
StatePublished - Jun 1 2013

Keywords

  • Dkk1
  • Estrogen
  • Hippocampus
  • Long-term estrogen deprivation
  • Menopause
  • Neuroprotection

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry

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