OR06-4 Long-Term Estrogen Deprivation Enhances JNK-Mediated AD Protein Induction after Global Cerebral Ischemia: Potential Role for PELP1

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR06-Molecular Mechanisms of Estrogen Action and Androgen Synthesis
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 12:15 PM
Room 256 (Moscone Center)
Erin Scott*1, Quanguang Zhang1, Ruimin Wang2, Gangadhara Reddy Sareddy3, Ratna Vadlamudi3 and Darrell Wayne Brann1
1Georgia Regents University, Augusta, GA, 2Hebei United University, Tangshan, China, 3UTHSCSA, San Antonio, TX
Women who enter menopause prematurely have a doubled lifetime risk of cognitive decline and dementia. The mechanism underlying this phenomenon is unclear, but dramatic and prolonged deprivation of the neuroprotective ovarian hormone 17beta-estradiol (E2) is thought to play a key role. To further investigate this issue, we utilized short-term and long-term E2 deprivation models in which 3-month-old female Sprague Dawley rats were bilaterally ovariectomized and treated with vehicle or a low, physiological dose of E2 either immediately (short-term E2 deprivation - STED) or 10 weeks later (long-term E2 deprivation - LTED). One week after initiation of vehicle or E2 treatment, animals were subjected to 10 minutes of global cerebral ischemia (GCI) and sacrificed following reperfusion. The results revealed that LTED females had dramatically increased hippocampal expression of the Alzheimer’s disease (AD)-related proteins beta-amyloid, beta-amyloid cleaving enzyme 1 (BACE1), and hyperphosphorylated tau following GCI. We hypothesized that the increase in AD-related proteins may be mediated by activation of c-Jun N-terminal kinase (JNK), since JNK activation can lead to enhanced BACE1 expression and hyperphosphorylation of tau and since we previously showed that E2 can markedly attenuate JNK activation in STED, but not LTED, rats. In support of a role for JNK in post-ischemic AD-protein induction and cell death, our studies demonstrated that administration of a JNK inhibitor 15 minutes prior to GCI ameliorated hippocampal AD protein induction and exerted strong neuroprotection in LTED animals. Intriguingly, further work using mass spectrometry analysis and co-immunoprecipitation identified JNK and its upstream regulator, Mitogen-Activated Protein Kinase Kinase 7 (MKK7), as potential interacting proteins of the novel estrogen receptor co-regulator, Proline-, Glutamic Acid-, and Leucine- Rich Protein 1 (PELP1), which has been implicated as a key mediator of E2’s genomic and nongenomic signaling. Along these lines, PELP1 interaction with JNK and MKK7 appears functionally important, as in vivo knockdown of hippocampal PELP1 reversed E2’s attenuation of post-ischemic JNK activation and reversed E2 neuroprotection. Taken as a whole, these studies shed new light on the mechanisms of E2 signaling and neuroprotection and provide important insight into the detrimental effects of LTED on the brain.

Nothing to Disclose: ES, QZ, RW, GRS, RV, DWB

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NINDS, NIH: NS050730 AHA: 12PRE11530009 AHA: 10SDG2560092