The role of estrogen receptors in Alzheimer?s disease

雌激素受体在阿尔茨海默病中的作用

• 批准号: 7915404
• 负责人: Rena Li
• 金额: $ 16.08万
• 依托单位: BANNER SUN HEALTH RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915404
• 关键词: Age; Age-Months; Aging; Aging-Related Process; Alzheimer disease prevention; Alzheimer' s Disease; Animal Model; Appearance; Brain; Brain Pathology; Breeding; Cell Line; Cell physiology; Cells; DNA; Data; Detergents; Development; Enzymes; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogen Therapy; Estrogens; Exhibits; Female; Figs - dietary; Gene Expression Regulation; Gene Targeting; Genetic; Genetic Transcription; Goals; Human; In Vitro; Insulinase; Knockout Mice; Knowledge; Lead; Learning; Memory; Memory Loss; Menopause; Molecular; Mus; Neprilysin; Nerve Degeneration; Neuroblastoma; Neurodegenerative Disorders; Neurons; Pathology; Pathway interactions; Patients; Physiology; Pike fish; Process; Production; Protein Isoforms; Publications; Regulation; Research; Response Elements; Role; Screening procedure; Senile Plaques; Signal Pathway; Signal Transduction Pathway; Testing; Therapeutic Intervention; Transcription Factor AP-1; Transgenic Animals; Transgenic Mice; Transgenic Organisms; amyloid pathology; amyloid precursor protein processing; beta secretase; beta-site APP cleaving enzyme 1; cognitive function; in vivo; male; mouse model; neuropathology; normal aging; prevent; promoter; protein expression; public health relevance; receptor; receptor function; secretase; transgenic model of alzheimer disease

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.

描述(申请人提供)：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，但控制雌激素功能的信号通路和调控机制仍不清楚。人们普遍认为，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展。人们正在积极寻找与雌激素相关的治疗方法，这些方法可能会提供显著的好处，同时避免与雌激素治疗相关的负面影响。在许多这样的途径中，大脑雌激素受体的转录调节功能是最普遍的调节细胞功能的形式，尽管我们对雌激素受体在AD中的作用的了解非常有限。最近的研究表明，雌激素的两种受体--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等人)。2006年，Corbo等人。2006年，Pirskanen等人。2005、Yaffe K 2007、Combarros 2007、Carroll和Pike，2008)。我们最近的研究表明，女性AD患者的大脑雌激素水平以及ER蛋白表达减少(Yue等人。2005)。然而，对脑内ER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变性。为了确定雌激素受体在预防阿尔茨海默病中作用的分子机制，我们将使用基因靶向的方法来缺失ER？或ER？在阿尔茨海默病转基因小鼠模型APP23中，以确定每个雌激素受体在阿尔茨海默病神经元保护和APP处理中的作用。在这个提议中，我们将检验大脑ER？和ER？参与了不同的信号转导通路，以对抗AD大脑中的淀粉样蛋白病理和认知功能。与公共健康相关：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，但控制雌激素功能的信号通路和调控机制仍不清楚。人们普遍认为，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展。人们正在积极寻找与雌激素相关的治疗方法，这些方法可能会提供显著的好处，同时避免与雌激素治疗相关的负面影响。在许多这样的途径中，大脑雌激素受体的转录调节功能是最普遍的调节细胞功能的形式，尽管我们对雌激素受体在AD中的作用的了解非常有限。最近的研究表明，雌激素的两种受体--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等人)。2006年，Corbo等人。2006年，Pirskanen等人。2005、Yaffe K 2007、Combarros 2007、Carroll和Pike，2008)。我们最近的研究表明，女性AD患者的大脑雌激素水平以及ER蛋白表达减少(Yue等人。2005)。然而，对脑内ER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变性。为了确定雌激素受体在预防阿尔茨海默病中作用的分子机制，我们将使用基因靶向的方法来缺失ER？或ER？在阿尔茨海默病转基因小鼠模型APP23中，以确定每个雌激素受体在阿尔茨海默病神经元保护和APP处理中的作用。在这个提议中，我们将检验大脑ER？和ER？参与了不同的信号转导通路，以对抗AD大脑中的淀粉样蛋白病理和认知功能。