Hypersensitivity of Hippocampal CA3 to Ischemic Damage and AD Protein Induction Following Long Term E2 Deprivation

Women have a greater risk of Alzheimer's disease (AD) and dementia as compared to men, although the mechanisms for this difference remain unclear. Preliminary findings by the PI may shed light on this issue as preliminary work has revealed that long term E2 (17-estradiol) deprivation (long term ovariectomy) leads to hypersensitivity of the hippocampal CA3 region to ischemic injury and elevated induction of AD-related proteins. The work raises the possibility that increased risk of women to AD and dementia may be due in part to increased sensitivity of the hippocampal CA3 region to injury by stressors (such as ischemia), with a concomitant increase in AD protein induction. The PI has found that there is significant down-regulation of a key estrogen receptor coregulator in the brain, PELP1, which has been implicated as an important mediator of nongenomic and genomic signaling by E2. PELP1 also has been implicated to potentially function as a corepressor for glucocorticoid receptor and activated protein-1 (AP-1) transactivation. Thus, dysregulation of PELP1 may lead to altered cell signaling and transcription, and potentially explain the hypersensitivity of the CA3 to ischemic damage following prolonged hypoestrogenicity. The goal of the current study is to elucidate the mechanisms underlying the enhanced hypersensitivity of the hippocampal CA3 region to ischemic damage and AD protein induction following prolonged hypoestrogenicity and to determine if E2 treatment prior to prolonged hypoestrogenicity protects the CA3 from induction of hypersensitivity. Aim 1 would thus determine the role of PELP1 in hippocampal CA3 hypersensitivity to ischemic damage and AD protein induction following long term E2 deprivation, and establish whether E2 replacement initiated prior to prolonged hypoestrogenicity protects the CA3. Aim 2 would determine whether long term E2 deprivation leads to an enhanced endoplasmic reticulum (ER) stress response in the CA3 following cerebral ischemia, and establish whether E2 and/or PELP1 have a role in attenuating or restraining the ER stress response. Aim 3 would determine whether PELP1 functions as a corepressor of the glucocorticoid receptor (GR) and/or AP1 transcriptional complex in the hippocampal CA3 region, and whether the down-regulation of PELP1 after long term E2 deprivation leads to enhanced GR and AP-1 transcriptional activation following global cerebral ischemia and thus enhanced stress and apoptotic signaling. (AHA Program: Scientist Development Grant)