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

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

Research output: Contribution to journalArticle

14 Citations (Scopus)

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

Fingerprint

Catenins
Brain Ischemia
Neurons
Rats
Estrogens
Estradiol
Hippocampal CA1 Region
JNK Mitogen-Activated Protein Kinases
In Situ Nick-End Labeling
Ovariectomy
Dementia
Hippocampus
Phosphotransferases
Aging of materials
Survival
Mortality
Neuroprotection

Keywords

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

ASJC Scopus subject areas

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

Cite this

Long-term estrogen deprivation leads to elevation of Dickkopf-1 and dysregulation of Wnt/β-Catenin signaling in hippocampal CA1 neurons. / Scott, Erin L.; Zhang, Quanguang; Han, Dong; Desai, Bhavna N.; Brann, Darrell W.

In: Steroids, Vol. 78, No. 6, 01.06.2013, p. 624-632.

Research output: Contribution to journalArticle

@article{f11f3ad4d3014445ac887b8a540ed70c,
title = "Long-term estrogen deprivation leads to elevation of Dickkopf-1 and dysregulation of Wnt/β-Catenin signaling in hippocampal CA1 neurons",
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.",
keywords = "Dkk1, Estrogen, Hippocampus, Long-term estrogen deprivation, Menopause, Neuroprotection",
author = "Scott, {Erin L.} and Quanguang Zhang and Dong Han and Desai, {Bhavna N.} and Brann, {Darrell W}",
year = "2013",
month = "6",
day = "1",
doi = "10.1016/j.steroids.2012.11.004",
language = "English (US)",
volume = "78",
pages = "624--632",
journal = "Steroids",
issn = "0039-128X",
publisher = "Elsevier Inc.",
number = "6",

}

TY - JOUR

T1 - Long-term estrogen deprivation leads to elevation of Dickkopf-1 and dysregulation of Wnt/β-Catenin signaling in hippocampal CA1 neurons

AU - Scott, Erin L.

AU - Zhang, Quanguang

AU - Han, Dong

AU - Desai, Bhavna N.

AU - Brann, Darrell W

PY - 2013/6/1

Y1 - 2013/6/1

N2 - 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.

AB - 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.

KW - Dkk1

KW - Estrogen

KW - Hippocampus

KW - Long-term estrogen deprivation

KW - Menopause

KW - Neuroprotection

UR - http://www.scopus.com/inward/record.url?scp=84876668606&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876668606&partnerID=8YFLogxK

U2 - 10.1016/j.steroids.2012.11.004

DO - 10.1016/j.steroids.2012.11.004

M3 - Article

VL - 78

SP - 624

EP - 632

JO - Steroids

JF - Steroids

SN - 0039-128X

IS - 6

ER -