MECHANISM OF ESTROGEN NEUROPROTECTION IN ALZHEIMERS DISE

女性是阿尔茨海默病（AD）发展的危险因素。 越来越多的证据表明，绝经后妇女雌激素水平的大幅下降是这种风险因素的主要变量。 重要的是，雌激素替代疗法的临床应用已被证明既能延迟AD的发作，又能减缓其进展。 目前，还不清楚雌激素的许多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，以增加神经元的弹性对退行性刺激牵连在AD神经变性。 基于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性脑区（例如，海马、内嗅皮层、杏仁核）雌激素调节癫痫相关蛋白的表达，这可能是通过经典的雌激素受体依赖性基因组途径。 特别是，我们的初步数据表明，雌激素显着增加抗凋亡蛋白Bcl-xL的表达。 由于其调节凋亡相关蛋白的结果，我们推测雌激素会使神经元凋亡途径的平衡向增强活力的方向摆动，从而增加雌激素反应神经元对变性的抵抗力。 因此，预计绝经后雌激素的损失会降低神经元活力的重要内源性调节剂的水平，使雌激素反应性脑区容易受到凋亡的挑战。 我们提出三个目的来研究这一理论：（1）使用细胞培养和体内范例，我们将评估雌激素的调节神经元表达的骨化相关蛋白的能力。 我们将鉴定雌激素靶蛋白，表征雌激素对靶蛋白的作用，并确定受体活化和差异受体亚型在这些雌激素作用中的作用;（2）我们将研究我们的预测，即雌激素调节作用的功能后果包括特定凋亡途径的活化减少（例如，半胱天冬酶介导的蛋白水解）和使用体外和体内模型增加的神经元活力;（3）我们将通过评估来自不同性别、AD病理学和激素状态的病例的脑组织中的雌激素/凋亡关系，将实验系统（目的1，2）中的发现扩展到人类状况。 我们预计，我们提出的研究将产生新的见解，雌激素调节神经元的活力在整个生命，从神经发育到年龄相关的神经退行性疾病的能力。

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.