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.
authors.affiliation: Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Scott
authors.forename: Quan-Guang
authors.initials: QG
authors.lastname: Zhang
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.forename: Bhavna N
authors.initials: BN
authors.lastname: Desai
authors.forename: Darrell W
authors.initials: DW
authors.lastname: Brann
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology*; D004958:Estradiol / Q000172:deficiency* / Q000494:pharmacology; D005260:Female; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051176:beta Catenin; D004958:Estradiol