MECHANISM OF ESTROGEN NEUROPROTECTION IN ALZHEIMERS DISE

雌激素对阿尔茨海默病的神经保护机制

• 批准号: 6349731
• 负责人: CHRISTIAN J PIKE
• 金额: $ 23.05万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6349731
• 关键词: Alzheimer's disease; Rodentias; aging; apoptosis; estrogen receptors; estrogens; hormone regulation /control mechanism; human tissue; neuroprotectants; tissue /cell culture

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.

描述（来自申请人的摘要）女性是一种风险 阿尔茨海默氏病（AD）发展的因素。累积 有证据表明，雌激素水平的大量降低 在更年期之后的女性中发生似乎是主要变量 这一危险因素的基础。 重要的是，雌激素的临床使用 绝经后妇女的替代疗法已被证明 两者都会延迟AD的发作，并减缓其进展。因为雌激素 有很多 细胞效应可能与针对AD的保护作用有关， 目前尚不清楚哪种特定的雌激素作用是显着的 它抑制AD病理学。在此赠款申请中 申请人提出了一种新型的雌激素神经保护机制 预测它可以提高针对神经元的弹性 退化性刺激与AD神经变性有关。基于 内分泌学和肿瘤学领域的最新进展， 理论上认为，在雌激素反应性大脑区域（例如，海马， 内嗅皮质，杏仁核），雌激素激活其受体，该受体，该受体 启动一种基因组途径，以改变凋亡的表达 相关蛋白质。特别是，他们的初步数据表明 雌激素可显着增加抗凋亡的表达 蛋白BCl-XL。由于其调节凋亡相关的调节 蛋白质，它们认为雌激素会挥舞神经元的平衡 凋亡途径可以增强生存能力，从而增加 雌激素反应性神经元对凋亡变性的抗性。 因此，预计更年期后雌激素的损失将减少 重要的内源性内源性调节剂的水平，神经元生存力， 使雌激素响应性大脑区域容易受到凋亡的影响 挑战。申请人提出了三个目标，以调查这部小说 理论：（1）使用细胞培养和体内范式，他们将评估 雌激素调节与凋亡相关的神经元表达的能力 蛋白质。他们将鉴定雌激素靶蛋白，确定 受体激活和差异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） 他们将调查预测的功能后果 雌激素的调节作用包括降低特异性的激活 凋亡途径（例如caspase介导的蛋白水解）并增加 神经元的生存能力； （3）他们将使用定量图像分析 将实验系统中提出的发现相关联的技术（目的 1和2）到正常的年龄和广告大脑。 申请人预料到 他们的新颖假设将对能力产生新的见解 雌激素从神经中调节神经元的生存力 通过与年龄相关的神经退行性疾病发展。