Abstract WMP120: Long-Term Estrogen Deprivation Enhances Hippocampal Amyloidogenic Processing and Cognitive Decline after Global Cerebral Ischemia

Abstract

Women who enter menopause prematurely have a doubled lifetime risk of cognitive decline and dementia. The mechanism underlying this phenomenon is unclear, but it is postulated to be associated with dramatic and prolonged deprivation of the neuroprotective ovarian hormone 17beta-estradiol (E2). To shed light on this issue, 3-month-old female Sprague Dawley rats were bilaterally ovariectomized and had subcutaneous, osmotic mini-pumps containing a low, Diestrus I dose of E2 implanted either immediately (short-term E2 deprivation - STED) or 10 weeks later (long-term E2 deprivation - LTED). One week following continuous E2 replacement, all animals were subjected to 10 minutes of global cerebral ischemia (GCI) and sacrificed for tissue harvest. Intriguingly, we observed a profound induction of Alzheimer’s disease-related proteins (beta-amyloid and hyperphosphorylated-tau) throughout the hippocampus of LTED females who experienced GCI. In the same animals, we also noted a switch to amyloidogenic processing of amyloid precursor protein (APP), such that hippocampal expression of beta-amyloid cleaving enzyme 1 (BACE1) was enhanced and hippocampal expression of A D isintegrin A nd M etalloprotease 17 (ADAM17) was diminished. Hippocampal expression of an alternate alpha secretase, ADAM10, remained unchanged. Furthermore, LTED females demonstrated enhanced post-ischemic cognitive decline, as they performed worse than STED females on the Morris Water Maze after GCI. Importantly, while immediate replacement of ovarian E2 was capable of preventing these events in STED females, delayed treatment with low-dose E2 was ineffective. Finally, c-Jun N-terminal Kinase (JNK) was identified as a critical mediator of post-ischemic amyloidogenesis, cognitive decline, and apoptosis in LTED females, as delayed treatment with a JNK inhibitor was able to prevent these events. These data could help explain why surgically menopausal women have an increased risk of cognitive decline and dementia and why postmenopausal women fare worse than age-matched men following a stroke. Furthermore, they lend support to the critical period hypothesis, suggesting that only perimenopausal replacement of ovarian E2 will provide neurological benefit for post-menopausal women.