Surgical menopause enhances hippocampal amyloidogenesis following global cerebral ischemia

Erin L. Scott, Quanguang Zhang, Yan Dong, Dong Han, Rui Min Wang, Ratna K. Vadlamudi, Darrell W Brann

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Background: Prematurely menopausal women have a doubled lifetime risk of dementia and a 5-fold increased risk of mortality from neurological disorders, but the molecular mechanisms underlying these risks remain unclear. We hypothesized that ischemia-induced amyloidogenesis may be enhanced in the hippocampus following prolonged loss of ovarian 17β-estradiol (E2), which could contribute to these phenomena. Methods: The current study used a rat model of premature surgical menopause (10-week bilateral ovariectomy) with E2 therapy either initiated immediately (short-term E2 deprivation (STED)) or delayed to the end of the ovariectomy period (long-term E2 deprivation (LTED)). One week after continuous, subcutaneous E2 therapy, we subjected animals to 10-min global cerebral ischemia (GCI) to assess the effect of LTED on ischemia-induced amyloidogenesis in the hippocampal CA1. Results: The present study revealed that while hippocampal β-amyloid (Aβ) is not typically enhanced following GCI, there is a rapid, robust elevation of endogenous Aβ in LTED females after GCI. In STED females, we observed that GCI attenuates and E2 maintains ADAM 10 expression in the hippocampal CA1, and concurrently, GCI increases and E2 decreases BACE1 levels in the same region. Intriguingly, however, we observed a loss of E2 regulation of ADAM 10, ADAM 17, and BACE1 levels in the hippocampal CA1 of LTED females, which provides mechanistic evidence for the enhanced post-ischemic Aβ load following LTED. We also observed loss of E2 regulation of tau hyperphosphorylation in LTED females subjected to GCI. Conclusion: Collectively, these studies partially explain the enhanced risk of dementia and mortality from neurological disorders seen in prematurely menopausal women and support timely initiation of E2 therapy to yield maximum neurological benefit.

Original languageEnglish (US)
Pages (from-to)206-216
Number of pages11
JournalJournal of Sport and Health Science
Volume3
Issue number3
DOIs
StatePublished - Jan 1 2014

Keywords

  • Amyloid
  • Dementia
  • Estrogen
  • Ischemia
  • Surgical menopause

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Physical Therapy, Sports Therapy and Rehabilitation

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