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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG032441-05
Application #
8335497
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Miller, Marilyn
Project Start
2009-08-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$303,343
Indirect Cost
$108,267
Name
Roskamp Institute, Inc.
Department
Type
DUNS #
119173933
City
Sarasota
State
FL
Country
United States
Zip Code
34243
Li, Rena; Cui, Jie; Shen, Yong (2014) Brain sex matters: estrogen in cognition and Alzheimer's disease. Mol Cell Endocrinol 389:13-21
Li, Rena; Singh, Meharvan (2014) Sex differences in cognitive impairment and Alzheimer's disease. Front Neuroendocrinol 35:385-403
Jiang, Hong; He, Ping; Xie, Junxia et al. (2014) Genetic deletion of TNFRII gene enhances the Alzheimer-like pathology in an APP transgenic mouse model via reduction of phosphorylated I?B?. Hum Mol Genet 23:4906-18
Cheng, Xin; He, Ping; Lee, Taehee et al. (2014) High activities of BACE1 in brains with mild cognitive impairment. Am J Pathol 184:141-7
Cheng, Xin; He, Ping; Yao, Hailan et al. (2014) Occludin deficiency with BACE1 elevation in cerebral amyloid angiopathy. Neurology 82:1707-15
Li, Rena (2014) Why women see differently from the way men see? A review of sex differences in cognition and sports. J Sport Health Sci 3:155-162
Sun, Qiying; Hampel, Harald; Blennow, Kaj et al. (2014) Increased plasma TACE activity in subjects with mild cognitive impairment and patients with Alzheimer's disease. J Alzheimers Dis 41:877-86
Cui, Jie; Jothishankar, Balaji; He, Ping et al. (2014) Amyloid precursor protein mutation disrupts reproductive experience-enhanced normal cognitive development in a mouse model of Alzheimer's disease. Mol Neurobiol 49:103-12
Li, Rena; He, Ping; Cui, Jie et al. (2013) Brain endogenous estrogen levels determine responses to estrogen replacement therapy via regulation of BACE1 and NEP in female Alzheimer's transgenic mice. Mol Neurobiol 47:857-67
Cui, Jie; Shen, Yong; Li, Rena (2013) Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med 19:197-209

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