MECHANISM OF ESTROGEN NEUROPROTECTION IN ALZHEIMERS DISE

描述（来自申请人摘要）女性是一种风险 阿尔茨海默氏病（AD）的发展因素。积累 有证据表明，雌激素水平的大幅下降， 发生在绝经后的女性似乎是主要变量 这一风险因素。 重要的是，雌激素的临床应用 绝经后妇女的替代疗法已被证明， 两者都延迟AD的发作并减缓其进展。由于雌激素 有许多 可能与抗AD的保护作用相关的细胞效应， 目前还不清楚什么样的雌激素作用是突出的， 其抑制AD病理。在这项拨款申请中， 申请人提出了一种新的雌激素神经保护机制， 预测它的功能是增加神经元的弹性， 与AD神经变性有关的变性刺激。基于 内分泌学和肿瘤学领域的最新进展， 从理论上说，在雌激素反应的大脑区域（例如，海马体， 内嗅皮层，杏仁核），雌激素激活其受体， 启动了一个基因组途径，改变了细胞凋亡的表达， 相关蛋白质特别是，他们的初步数据表明， 雌激素显著增加抗凋亡基因的表达， Bcl-XL蛋白。由于其对糖尿病相关疾病的监管， 蛋白质，他们的理论是雌激素动摇了神经细胞的平衡， 细胞凋亡途径，从而增加细胞的存活率， 雌激素反应神经元对凋亡变性的抵抗力。 因此，预计绝经后雌激素的损失将减少 神经元活力的重要内源性调节剂的水平， 使雌激素敏感的大脑区域易受细胞凋亡的影响， 挑战.申请人提出了三个目的来研究这部小说 理论：（1）使用细胞培养和体内范例，他们将评估 雌激素调节糖尿病相关神经元表达的能力 proteins.他们将鉴定雌激素靶蛋白，确定 受体活化和不同受体亚型反应的作用， 并检查与其他凋亡调节剂的可能协同作用;（2） 他们将调查预测， 雌激素的调节作用包括减少特定的 凋亡途径（例如，半胱天冬酶介导的蛋白水解）和增加 神经元活力;（3）他们将使用定量图像分析 相关技术 实验系统中的发现（目的 1和2）对正常老年人和AD脑的影响。 申请人预计 他们的新假设将产生新的洞察力， 雌激素调节神经元的生存能力，从神经 通过年龄相关的神经退行性疾病的发展。

DESCRIPTION (from applicant's abstract) Female gender is a risk factor for the development of Alzheimer's disease (AD). Accumulating evidence suggests that the massive reduction in estrogen levels that occurs in women following menopause appears to be the primary variable underlying this risk factor. Importantly, the clinical use of estrogen replacement therapy in postmenopausal women has been demonstrated to both delay the onset of AD and slow its progression. Because estrogen has many cellular effects potentially relevant to a protective role against AD, currently it is unclear what specific estrogen action(s) are salient to its inhibition of AD pathology. In this grant application, the applicants 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, they theorize that in estrogen responsive brain regions (e.g., hippocampus, entorhinal cortex, amygdala), estrogen activates its receptors, which initiates a genomic pathway that alters the expression of apoptosis- related proteins. In particular, their 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, they theorize that estrogen sways the balance of neuronal apoptotic pathways toward enhanced viability, thereby increasing the resistance of estrogen-responsive neurons to apoptotic 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. The applicants propose three aims to investigate this novel theory: (1) Using cell culture and in vivo paradigms, they will evaluate estrogen's ability to regulate neuronal expresssion of apoptosis-related proteins. They will identify estrogen target proteins, determine the role of receptor activation and differential receptor subtype response, and examine possible synergism with other apoptosis modulators; (2) They will investigate predictions that functional consequences of estrogen's regulatory actions include decreased activation of specific apoptotic pathways (e.g., caspase-mediated proteolysis) and increased neuronal viability; (3) They will use quantitative image analysis techniques to correlate findings made in experimental systems (Aims 1 and 2) to the normal aged and AD brain. The applicants anticipate that their novel hypotheses will generate new insight into the ability of estrogen to modulate neuronal viability throughout life, from neural development through age-related neurodegenerative disorders.