Molecular Mechanisms Underlying Enhanced Risk of Neurological Disease Following Premature Menopause

Hdl Handle:
http://hdl.handle.net/10675.2/325665
Title:
Molecular Mechanisms Underlying Enhanced Risk of Neurological Disease Following Premature Menopause
Authors:
Scott, Erin L.
Abstract:
Prematurely menopausal women have a doubled lifetime risk of dementia and a 5-fold increased risk of mortality from neurological disorders. However, the molecular mechanisms underlying these enhanced risks remain unknown. Prolonged loss of ovarian-derived 17β-estradiol (E2) is thought to contribute, as low-dose E2 therapy (ET) initiated at the time of premature menopause and continued until the age of 51 normalizes these risks. The central hypothesis of the current study is that following chronic loss of ovarian function, three key changes occur in CA1 hippocampal neurons: 1) elevation of neurodegenerative factors, 2) enhanced stress-induced amyloidogenesis, and 3) a neural E2 signaling deficit, which, collectively, act to sensitize the hippocampus to stressors, such as global cerebral ischemia (GCI), thereby enhancing cell death and worsening cognitive outcome. To test this hypothesis, we used a rat model of surgical menopause (10-week ovariectomy in young, adult females) with ET delayed to the end of the ovariectomy period. One week after continuous, subcutaneous ET, we subjected animals to 10-min GCI to assess cellular damage and E2 neuroprotection status. In support of our hypothesis, the present study revealed basal upregulation of the neurodegenerative Wnt antagonist Dkk1 in CA1 hippocampal neurons of long-term E2-deprived (LTED) female rats, with concurrent dysregulation of pro-survival Wnt/β-Catenin signaling. We also noted a post-ischemic switch to amyloidogenic processing of amyloid precursor protein (APP) and robust induction of β-amyloid in LTED females subjected to GCI. Finally, we saw evidence of a neural E2 signaling deficit, as we observed a 40% decrease in basal hippocampal expression of the estrogen receptor co-regulator Proline-, Glutamate-, and Leucine-Rich Protein 1 (PELP1) levels after LTED. To further investigate the consequences of decreased hippocampal PELP1 expression, we knocked down PELP1 in vivo with icv anti-sense oligonucleotides in E2-treated rats prior to GCI. Intriguingly, we saw loss of E2 regulation of pro-apoptotic JNK/c-Jun/Dkk1 signaling, loss of E2 regulation of APP processing, and loss of E2 neuroprotection status, similar to events observed in LTED females. These studies partially explain the enhanced risk of dementia and mortality from neurological disorders seen in prematurely menopausal women and support timely initiation of ET to yield maximum neurological benefit.
Issue Date:
Apr-2014
URI:
http://hdl.handle.net/10675.2/325665
Additional Links:
http://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/1524048545?accountid=12365
Type:
Dissertation
Language:
en
Appears in Collections:
Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorScott, Erin L.en
dc.date.accessioned2014-09-03T03:15:22Z-
dc.date.available2014-09-03T03:15:22Z-
dc.date.issued2014-04-
dc.identifier.urihttp://hdl.handle.net/10675.2/325665-
dc.description.abstractPrematurely menopausal women have a doubled lifetime risk of dementia and a 5-fold increased risk of mortality from neurological disorders. However, the molecular mechanisms underlying these enhanced risks remain unknown. Prolonged loss of ovarian-derived 17β-estradiol (E2) is thought to contribute, as low-dose E2 therapy (ET) initiated at the time of premature menopause and continued until the age of 51 normalizes these risks. The central hypothesis of the current study is that following chronic loss of ovarian function, three key changes occur in CA1 hippocampal neurons: 1) elevation of neurodegenerative factors, 2) enhanced stress-induced amyloidogenesis, and 3) a neural E2 signaling deficit, which, collectively, act to sensitize the hippocampus to stressors, such as global cerebral ischemia (GCI), thereby enhancing cell death and worsening cognitive outcome. To test this hypothesis, we used a rat model of surgical menopause (10-week ovariectomy in young, adult females) with ET delayed to the end of the ovariectomy period. One week after continuous, subcutaneous ET, we subjected animals to 10-min GCI to assess cellular damage and E2 neuroprotection status. In support of our hypothesis, the present study revealed basal upregulation of the neurodegenerative Wnt antagonist Dkk1 in CA1 hippocampal neurons of long-term E2-deprived (LTED) female rats, with concurrent dysregulation of pro-survival Wnt/β-Catenin signaling. We also noted a post-ischemic switch to amyloidogenic processing of amyloid precursor protein (APP) and robust induction of β-amyloid in LTED females subjected to GCI. Finally, we saw evidence of a neural E2 signaling deficit, as we observed a 40% decrease in basal hippocampal expression of the estrogen receptor co-regulator Proline-, Glutamate-, and Leucine-Rich Protein 1 (PELP1) levels after LTED. To further investigate the consequences of decreased hippocampal PELP1 expression, we knocked down PELP1 in vivo with icv anti-sense oligonucleotides in E2-treated rats prior to GCI. Intriguingly, we saw loss of E2 regulation of pro-apoptotic JNK/c-Jun/Dkk1 signaling, loss of E2 regulation of APP processing, and loss of E2 neuroprotection status, similar to events observed in LTED females. These studies partially explain the enhanced risk of dementia and mortality from neurological disorders seen in prematurely menopausal women and support timely initiation of ET to yield maximum neurological benefit.en
dc.language.isoenen
dc.relation.urlhttp://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/1524048545?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.-
dc.subjectEstrogenen
dc.subjectMenopauseen
dc.subjectHippocampusen
dc.subjectNeurodegenerationen
dc.subjectAlzheimer's Diseaseen
dc.subjectCerebral Ischemiaen
dc.titleMolecular Mechanisms Underlying Enhanced Risk of Neurological Disease Following Premature Menopauseen
dc.typeDissertationen
dc.description.advisorBrann, Darrell W.-
dc.description.committeeDhandapani, Kris; Ergul, Adviye; McCluskey, Lynette; Terry, Alvin Jr.-
dc.description.degreeDoctor of Philosophy (Ph.D.)-
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