ESTROGEN IN ALZHEIMER DISEASE

描述(摘自申请者的摘要)女性性别是一种风险 阿尔茨海默病(AD)的发病因素。积累 有证据表明，雌激素水平的大幅下降 绝经后妇女的发病情况似乎是主要的变量 这一风险因素的潜在原因。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 两者均可延缓阿尔茨海默病的发病并延缓其进展。因为雌激素 有很多 细胞效应可能与AD的保护作用有关， 目前还不清楚(S)具体的雌激素作用是什么 其对AD病理的抑制作用。在这项拨款申请中， 申请人提出了一种新的雌激素和神经保护机制 预测它的功能是增加神经元对 退行性刺激与阿尔茨海默病神经退变有关。基于 内分泌学和肿瘤学领域的最新进展 理论上认为，在雌激素反应的大脑区域(例如，海马体， 内嗅皮质，杏仁核)，雌激素激活其受体，这 启动了一条改变细胞凋亡表达的基因组途径- 相关蛋白质。特别是，他们的初步数据表明， 雌激素显著增加抗细胞凋亡的表达 蛋白Bclxl。作为其对细胞凋亡相关调控的结果 蛋白质，他们的理论是雌激素动摇了神经元的平衡 通过凋亡途径提高生存能力，从而增加 雌激素反应神经元对凋亡变性的抵抗力。 因此，绝经后雌激素的损失预计会减少。 一个重要的神经元活性内源性调节剂的水平， 使雌激素反应的大脑区域易受细胞凋亡的影响 挑战。申请者提出了调查这部小说的三个目的 理论：(1)使用细胞培养和活体范例，他们将评估 雌激素对神经细胞凋亡相关基因表达的调控作用 蛋白质。他们将识别雌激素靶蛋白，确定 受体激活和不同受体亚型反应的作用 并研究与其他细胞凋亡调节剂的协同作用；(2) 他们将调查预测的功能性后果 雌激素的调节作用包括减少特定的 凋亡途径(例如，caspase介导的蛋白分解)和增加 神经元活性；(3)他们将使用定量图像分析 将实验系统中的发现关联起来的技术(AIMS 1和2)正常老年组和阿尔茨海默病组。申请者期待着 他们的新奇假设将产生对这种能力的新见解 雌激素在整个生命过程中调节神经元的活性，从神经 通过与年龄相关的神经退行性疾病发展。

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.