The role of estrogen receptors in Alzheimer?s disease

多年来，研究表明，大脑雌激素和雌激素受体 对神经细胞功能至关重要，但信号通路和调节 控制雌激素功能的机制仍不清楚。一般 认为女性绝经后雌激素的减少有助于 神经退行性疾病如阿尔茨海默病的发展 （AD）。有一个激烈的研究有关的治疗雌激素， 提供显著的益处，同时避免与 雌激素疗法在许多这样的方法中，转录调节 脑雌激素受体的功能是最普遍的调节形式， 细胞功能，虽然我们的知识，雌激素受体的作用， AD非常有限。最近，研究表明，这两种雌激素受体， α和β（ER <$和ER <$）在衰老方面可能具有不同的功能 AD的生理学和预防（Yamaguchi-Shima 2007，Porrello等2006， Corbo等人，2006年; Pirskanen等人，2005年; Yaffe K，2007年; Combarros，2007年;卡罗尔 和Pike，2008年）。我们最近的研究表明大脑雌激素减少 在女性AD患者中，ER水平以及ER？蛋白表达（Yue et al. 2005）。 然而，人们对脑的细胞和分子功能知之甚少， ER <$和ER <$以及它们的功能丧失如何导致AD中的神经变性。 为了明确雌激素受体在预防乳腺癌中的分子机制， AD，我们将使用基因靶向方法删除其中一种受体， 在阿尔茨海默氏症转基因小鼠模型APP 23中， 每种雌激素受体在AD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 <$和ER <$是 参与对抗淀粉样蛋白的不同信号转导途径 病理学和认知功能。

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.