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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

基本信息

批准号：
8197400
负责人：
Rena Li
金额：
$ 30.33万
依托单位：
ROSKAMP INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197400
关键词：
Age-Months Aging Aging-Related Process Alzheimer disease prevention Alzheimer&apos s Disease Animal Model Appearance Brain Brain Pathology Breeding Cell Line Cell physiology Cells DNA Data Detergents Development Disease Enzymes Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogen Therapy Estrogens Exhibits Female Gene Expression Regulation Gene Targeting Genetic Genetic Transcription Goals Health Human In Vitro Insulinase Knockout Mice Knowledge Lead Learning Memory Memory Loss Menopause Molecular Mus Neprilysin Nerve Degeneration 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 neuroblastoma cell neuropathology normal aging prevent promoter protein expression receptor receptor function secretase transgenic model of alzheimer disease

项目摘要

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.