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于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。人们普遍认为，女性绝经后雌激素的减少会导致阿尔茨海默病（AD）等神经退行性疾病的发生。人们正在大力寻找与雌激素相关的疗法，这些疗法可能会提供显着的益处，同时避免与雌激素疗法相关的负面影响。在许多此类方法中，脑雌激素受体的转录调节功能是调节细胞功能的最普遍形式，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，两种雌激素受体α和β（ER？和ER¿）在衰老生理学和预防AD方面可能具有不同的功能（Yamaguchi-Shima 2007，Porrello等人2006，Corbo等人2006，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¿ 蛋白表达均有所下降（Yue 等，2005）。然而，人们对大脑 ER 的细胞和分子功能知之甚少？和 ER¿ 以及它们功能的丧失如何导致 AD 中的神经变性。为了确定雌激素受体在预防 AD 中发挥作用的分子机制，我们将使用基因靶向方法删除任一受体 ER？或 ER¿ 在阿尔茨海默病转基因小鼠模型 APP23 中，以确定每种雌激素受体在 AD 神经元保护和 APP 处理中的作用。在这个提案中，我们将测试大脑 ER？ ER¿ 和 ER¿ 参与针对 AD 大脑中淀粉样蛋白病理和认知功能的不同信号转导途径。公共健康相关性：多年来，研究表明大脑雌激素和雌激素受体对于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。人们普遍认为，女性绝经后雌激素的减少会导致阿尔茨海默病（AD）等神经退行性疾病的发生。人们正在大力寻找与雌激素相关的疗法，这些疗法可能会提供显着的益处，同时避免与雌激素疗法相关的负面影响。在许多此类方法中，脑雌激素受体的转录调节功能是调节细胞功能的最普遍形式，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，两种雌激素受体α和β（ER？和ER¿）在衰老生理学和预防AD方面可能具有不同的功能（Yamaguchi-Shima 2007，Porrello等人2006，Corbo等人2006，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¿ 蛋白表达均有所下降（Yue 等，2005）。然而，人们对大脑 ER 的细胞和分子功能知之甚少？和 ER¿ 以及它们功能的丧失如何导致 AD 中的神经变性。为了确定雌激素受体在预防 AD 中发挥作用的分子机制，我们将使用基因靶向方法删除任一受体 ER？或 ER¿ 在阿尔茨海默病转基因小鼠模型 APP23 中，以确定每种雌激素受体在 AD 神经元保护和 APP 处理中的作用。在这个提案中，我们将测试大脑 ER？ ER¿ 和 ER¿ 参与针对 AD 大脑中淀粉样蛋白病理和认知功能的不同信号转导途径。