The role of estrogen receptors in Alzheimer?s disease

描述（申请人提供）：多年来，研究表明脑雌激素和雌激素受体对神经元细胞功能至关重要，但控制雌激素功能的信号通路和调节机制仍不清楚。一般认为，女性绝经后雌激素的减少有助于阿尔茨海默病（AD）等神经退行性疾病的发生。人们正在积极寻找与雌激素相关的治疗方法，以期在避免雌激素治疗的负面影响的同时提供显著的益处。在许多这样的方法中，脑雌激素受体的转录调节功能是最普遍的调节细胞功能形式，尽管我们对雌激素受体在AD中的作用的了解非常有限。最近，研究表明，两种雌激素受体，α和β (ER？和ER¿)，可能在衰老生理和预防AD方面具有不同的功能（Yamaguchi-Shima 2007, Porrello et al. 2006, Corbo et al. 2006, Pirskanen et al. 2005, Yaffe K 2007, Combarros 2007, Carroll and Pike, 2008）。我们最近的研究表明，女性AD患者的脑雌激素水平和ER¿蛋白表达降低（Yue et al. 2005）。然而，我们对脑内质网的细胞和分子功能知之甚少。以及它们的功能丧失如何导致阿尔茨海默病的神经退行性变。为了确定雌激素受体在预防AD中的分子机制，我们将采用基因靶向的方法删除其中一个受体，ER？在阿尔茨海默氏症转基因小鼠模型APP23中，以确定每种雌激素受体在阿尔茨海默氏症神经元保护和APP加工中的作用。在这个提议中，我们将测试大脑ER？和ER¿参与不同的信号转导途径对抗淀粉样蛋白病理和AD大脑的认知功能。公共卫生相关性：多年来，研究表明脑雌激素和雌激素受体对神经元细胞功能至关重要，但控制雌激素功能的信号通路和调节机制仍不清楚。一般认为，女性绝经后雌激素的减少有助于阿尔茨海默病（AD）等神经退行性疾病的发生。人们正在积极寻找与雌激素相关的治疗方法，以期在避免雌激素治疗的负面影响的同时提供显著的益处。在许多这样的方法中，脑雌激素受体的转录调节功能是最普遍的调节细胞功能形式，尽管我们对雌激素受体在AD中的作用的了解非常有限。最近，研究表明，两种雌激素受体，α和β (ER？和ER¿)，可能在衰老生理和预防AD方面具有不同的功能（Yamaguchi-Shima 2007, Porrello et al. 2006, Corbo et al. 2006, Pirskanen et al. 2005, Yaffe K 2007, Combarros 2007, Carroll and Pike, 2008）。我们最近的研究表明，女性AD患者的脑雌激素水平和ER¿蛋白表达降低（Yue et al. 2005）。然而，我们对脑内质网的细胞和分子功能知之甚少。以及它们的功能丧失如何导致阿尔茨海默病的神经退行性变。为了确定雌激素受体在预防AD中的分子机制，我们将采用基因靶向的方法删除其中一个受体，ER？在阿尔茨海默氏症转基因小鼠模型APP23中，以确定每种雌激素受体在阿尔茨海默氏症神经元保护和APP加工中的作用。在这个提议中，我们将测试大脑ER？和ER¿参与不同的信号转导途径对抗淀粉样蛋白病理和AD大脑的认知功能。

DESCRIPTION (provided by applicant): For years, studies have shown that brain estrogen and estrogen receptors are critical for neuronal cell functions, yet the signal pathways and regulatory mechanisms that control estrogen function remain main unclear. It is generally believed that the reduction of estrogen after menopause in females contributes to the development of neurodegenerative diseases such as Alzheimer's disease (AD). There is an intense search for therapies related to estrogen that might provide significant benefits while avoiding the negative aspects associated with estrogen therapy. Among many such approaches, the transcriptional regulatory function of brain estrogen receptors is the most prevalent form of regulatory cellular function, although our knowledge about the role of estrogen receptors in AD is very limited. Recently, studies have shown that the two estrogen receptors, alpha and beta (ER? and ER¿), may have different functions in term of aging physiology and prevention of AD (Yamaguchi-Shima 2007, Porrello et al. 2006, Corbo et al. 2006, Pirskanen et al. 2005, Yaffe K 2007, Combarros 2007, Carroll and Pike, 2008). Our recent studies demonstrated a reduction in brain estrogen levels as well as ER¿ protein expression in female AD patients (Yue et al. 2005). However, very little are known about the cellular and molecular functions of brain ER? and ER¿ and how loss of their functions causes neurodegeneration in AD. To identify the molecular mechanisms of estrogen receptor function in preventing AD, we will use a gene-targeting approach to delete either one of the receptors, ER? or ER¿ in an Alzheimer's transgenic mouse model, APP23, to define the role of each estrogen receptor in neuronal protection and APP processing in AD. In this proposal, we will test the hypothesis that brain ER? and ER¿ are involved in distinct signal transduction pathways against amyloid pathology and cognitive functions in the AD brain. PUBLIC HEALTH RELEVANCE: For years, studies have shown that brain estrogen and estrogen receptors are critical for neuronal cell functions, yet the signal pathways and regulatory mechanisms that control estrogen function remain main unclear. It is generally believed that the reduction of estrogen after menopause in females contributes to the development of neurodegenerative diseases such as Alzheimer's disease (AD). There is an intense search for therapies related to estrogen that might provide significant benefits while avoiding the negative aspects associated with estrogen therapy. Among many such approaches, the transcriptional regulatory function of brain estrogen receptors is the most prevalent form of regulatory cellular function, although our knowledge about the role of estrogen receptors in AD is very limited. Recently, studies have shown that the two estrogen receptors, alpha and beta (ER? and ER¿), may have different functions in term of aging physiology and prevention of AD (Yamaguchi-Shima 2007, Porrello et al. 2006, Corbo et al. 2006, Pirskanen et al. 2005, Yaffe K 2007, Combarros 2007, Carroll and Pike, 2008). Our recent studies demonstrated a reduction in brain estrogen levels as well as ER¿ protein expression in female AD patients (Yue et al. 2005). However, very little are known about the cellular and molecular functions of brain ER? and ER¿ and how loss of their functions causes neurodegeneration in AD. To identify the molecular mechanisms of estrogen receptor function in preventing AD, we will use a gene-targeting approach to delete either one of the receptors, ER? or ER¿ in an Alzheimer's transgenic mouse model, APP23, to define the role of each estrogen receptor in neuronal protection and APP processing in AD. In this proposal, we will test the hypothesis that brain ER? and ER¿ are involved in distinct signal transduction pathways against amyloid pathology and cognitive functions in the AD brain.