Acute estrogen (17B-estradiol) treatments ameliorate molecular and behavioral biomarkers of brain aging

Estrogen replacement therapy has been shown in several clinical studies to have significant effects on memory of post-menopausal women. However, other studies have failed to observe these improvements. There is also disagreement in the efficacy of estrogen replacement on cognition in animal models. Factors studied include dose, duration of treatment, and duration of estrogen deprivation prior to treatment. Interestingly, declined memory function with advancing age is related to Ca2+-homeostasis in the brain. Furthermore, estrogen has been shown in several studies to affect Ca2+-homeostatic mechanisms in a way diametrically opposite that of advancing age. Therefore, Ca2+-dependent pathways provide potential targets by which estrogen can affect cognition.; The first specific aim focuses on the effect of acute estrogen treatments on calcineurin (CaN) and protein phosphatase 1 (PP1), two protein phosphatases that are involved in memory consolidation and synaptic function in the hippocampus. These studies showed that acute estrogen treatments rapidly reduced hippocampal phosphatase activity and increased relative phosphorylation of CaN and PP1 substrates that modulate memory formation and neural survival in female rats over the course of aging. However, the estrogen effect was significantly reduced in aged animals relative to young and adult animals.; The second specific aim utilizes estrogen receptor (ER) knockout mice to investigate to role of ERα and ERβ in the estrogen mediated reduction of hippocampal CaN and PP1 activity. The results of these studies suggested that neither ERα nor ERβ was necessary for estrogen effects upon hippocampal phosphatase activity. However, the results suggest that ERα is involved in regulation of baseline phosphatase activity.; The third specific aim studied the effects of acute post-training estrogen treatments on retention of hippocampal-dependent spatial and nonspatial memories in female rats over the course of aging. These studies demonstrated that the acute post training estrogen treatments can significantly improve retention of these memories in rats over the course of aging. Furthermore, biochemical studies showed that improved retention was related to increase phosphorylation of CaN and PP1 substrates.