The role of estrogen receptors in Alzheimer?s disease

多年来，研究表明，大脑中的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然主要不清楚。它一般都是 认为女性绝经后雌激素的减少有助于 阿尔茨海默病等神经退行性疾病的发展 (Ad)。有一个密集的搜索与雌激素有关的疗法，可能 提供显著的好处，同时避免与 雌激素疗法。在许多这样的方法中，转录调控 大脑雌激素受体的功能是最普遍的调节形式 细胞功能，尽管我们对雌激素受体在 广告是非常有限的。最近，研究表明，这两种雌激素受体， α和β(ER和ER)在衰老过程中可能具有不同的功能 阿尔茨海默病的生理学和预防(Yamaguchi-Shima 2007，Porrello等人)。2006年， Corbo等人。2006年，Pirskanen等人。2005，Yaffe K 2007，Combarros 2007，Carroll 和派克，2008)。我们最近的研究表明大脑中雌激素的减少。 女性阿尔茨海默病患者的雌激素受体水平和ER？蛋白表达(Yue等人)2005)。 然而，对大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的神经变性。 雌激素受体预防预防作用的分子机制研究 AD，我们将使用基因打靶的方法来删除其中一个受体， 在阿尔茨海默病转基因小鼠模型APP23中定义ER？或ER？ 每种雌激素受体在AD神经元保护和APP处理中的作用。 在这个方案中，我们将检验大脑ER？和ER？是 参与不同的抗淀粉样蛋白信号转导通路 阿尔茨海默病大脑的病理和认知功能。

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.