| 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 17beta-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 Dkkl in CA1 hippocampal neurons of long-term E2-deprived (LTED) female rats, with concurrent dysregulation of pro-survival Wnt/beta-Catenin signaling. We also noted a post-ischemic switch to amyloidogenic processing of amyloid precursor protein (APP) and robust induction of beta-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 PELP 1 in vivo with icy anti-sense oligonucleotides in E2-treated rats prior to GCI. Intriguingly, we saw loss of E2 regulation of pro-apoptotic JNK/c-Jun/Dkkl 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.;INDEX WORDS: Estrogen, Menopause, Hippocampus, Neurodegeneration, Alzheimer's disease, Cerebral Ischemia. |
