MECHANISM OF ESTROGEN NEUROPROTECTION IN ALZHEIMERS DISE

女性性别是阿尔茨海默病(AD)发病的危险因素。越来越多的证据表明，绝经后女性雌激素水平的大幅下降是这一风险因素背后的一个主要变量。重要的是，雌激素替代疗法的临床应用已被证明既可以延缓AD的发病，又可以减缓其进展。目前，尚不清楚雌激素的多种细胞作用中的哪一种有助于其抑制AD病理。在这项拨款申请中，我们提出了一种新的雌激素神经保护机制，并预测它的功能是增加神经元对AD神经变性所涉及的变性刺激的弹性。根据内分泌学和肿瘤学领域的最新进展，我们推测，在雌激素反应的大脑区域(如海马体、内嗅皮层、杏仁核)，雌激素可能通过经典的雌激素受体依赖的基因组途径来调节凋亡相关蛋白的表达。特别是，我们的初步数据表明，雌激素显著增加了抗凋亡蛋白Bclxl的表达。由于其对凋亡相关蛋白的调节，我们推测雌激素动摇了神经元凋亡途径的平衡，从而增强了存活能力，从而增加了雌激素反应神经元对退化的抵抗力。因此，绝经后雌激素的丢失预计会降低神经元活力的一个重要内源性调节剂的水平，使雌激素反应的大脑区域容易受到细胞凋亡的挑战。我们提出了三个目标来研究这一理论：(1)利用细胞培养和体内范例，我们将评估雌激素调节神经元凋亡相关蛋白表达的能力。我们将识别雌激素靶蛋白，鉴定雌激素对靶蛋白的影响，并确定受体激活和差异受体亚型在这些雌激素作用中的作用；(2)我们将使用体外和体内模型研究我们的预测，即雌激素调节作用的功能后果包括特定凋亡通路的激活减少(例如，caspase介导的蛋白降解)并提高神经元存活率；(3)我们将通过评估不同性别、AD病理和激素状态的病例，将实验系统(AIMS 1、2)中的发现扩展到人类条件下。我们预计，我们提出的研究将对雌激素调节神经元活性的能力产生新的见解，从神经发育到与年龄相关的神经退行性疾病。

Female gender is a risk factor for the development of Alzheimer's disease (AD). Accumulating evidence suggests that the large reduction in estrogen levels that occurs in postmenopausal women is a primary variable underlying this risk factor. Importantly, the clinical use of estrogen replacement therapy has been demonstrated to both delay the onset of AD and slow its progression. Currently, it is unclear which of estrogen's many cellular effects contribute to its inhibition of AD pathology. In this grant application, we propose a novel neuroprotective mechanism of estrogen and predict that it functions to increase neuronal resilience against degenerative stimuli implicated in AD neurodegeneration. Based upon recent advances in the fields of endocrinology and oncology, we theorize that in estrogen- responsive brain regions (e.g., hippocampus, entorhinal cortex, amygdala) estrogen modulates the expression of apoptosis-related proteins, perhaps via a classic estrogen receptor-dependent genomic pathway. In particular, our preliminary data suggest that estrogen significantly increases expression of the anti-apoptotic protein Bcl-xL. As a consequence of its regulation of apoptosis-related proteins, we theorize that estrogen sways the balance of neuronal apoptotic pathways towards enhanced viability, thereby increasing the resistance of estrogen-responsive neurons to degeneration. Thus, the loss of estrogen following menopause is predicted to decrease levels of an important endogenous modulator of neuronal viability, rendering estrogen-responsive brain regions vulnerable to apoptotic challenge. We propose three aims to investigate this theory: (1) Using cell culture and in vivo paradigms, we will evaluate estrogen's ability to regulate neuronal expression of apoptosis-related proteins. We will identify estrogen target proteins, characterize estrogen effects on target proteins, and determine the role of receptor activation and differential receptor subtype in these estrogen actions; (2) We will investigate our prediction that functional consequences of estrogen's regulatory actions include decreased activation of specific apoptotic pathways (e.g., caspase-mediated proteolysis) and increased neuronal viability using both in vitro and in vivo models; (3) We will extend findings made in experimental systems (Aims 1, 2) to the human condition by evaluating the estrogen/apoptosis relationship in brain tissue from cases that vary by gender, AD pathology, and hormonal status. We anticipate that our proposed studies will generate new insight into the ability of estrogen to modulate neuronal viability throughout life, from neural development through age-related neurodegenerative disorders.