Gonadotropin involvement in cognition and Alzheimer's disease: Therapeutic Implic

促性腺激素参与认知和阿尔茨海默病：治疗意义

基本信息

批准号：
7673705
负责人：
Gemma Casadesus
金额：
$ 28.97万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-15 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7673705
关键词：
21 year old Acetates Acute Address Affect Age Age-associated memory impairment Aging Agonist Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Anabolism Andropause Animal Model Animals Aromatase Behavior Brain Cessation of life Cholesterol Classification Clinical Data Cognition Cognitive Cognitive deficits Cytochrome P450 Data Dementia Deposition Development Disease Progression Disease susceptibility Down Syndrome Effectiveness Elderly Elements Epidemiology Estrogen Replacement Therapy Estrogen Replacements Estrogens Etiology Event Feedback Female Gender Gene Expression General Population Goals Gonadal Steroid Hormones Gonadal structure Gonadotropin Hormone Releasing Hormone Gonadotropin-Releasing Hormone Receptor Gonadotropins High Prevalence Hippocampus (Brain)Hormonal Hormone replacement therapy Hormones Impaired cognition Impairment In Vitro Incidence Indium Individual LH Receptors Laboratories Lead Learning Leuprolide Acetate Life Light Link Literature Luteinizing Hormone Measures Mediator of activation protein Memory Menopause Modeling Molecular Mus Neuronal Dysfunction Neuronal Plasticity Neurons Onset of illness Outcome Output Ovariectomy Pathogenesis Pathology Pathway interactions Patients Pattern Performance Play Population Postmenopause Predisposition Process Protein Precursors Publishing Reporting Rodent Role Saline Serum Signal Transduction Steroid biosynthesis Steroids Stroke Structure Synapses Synaptic plasticity Testing Tg2576 Therapeutic Therapeutic Intervention Time Transgenic Mice Treatment Protocols Woman Women&apos s Health Work age related aged base cognitive change cognitive enhancement cognitive function critical period density genetic regulatory protein high risk hypothalamic pituitary gonadal axis improved men mitochondrial membrane morris water maze mortality mouse model novel therapeutics prevent protective effect protein expression public health relevance receptor receptor expression reproductive hormone research study steroid hormone synaptic function

项目摘要

DESCRIPTION (provided by applicant): Estrogen is thought to play an important role in age-related cognitive decline, neuronal plasticity, as well as the pathogenesis of Alzheimer disease (AD). Epidemiological evidence linked decreased incidence of AD and cognitive decline in women previously exposed to hormone (estrogen) replacement therapy (HRT). Further, clinical data correlates estrogen deficiency to the etiology of AD, yet initiating HRT in elderly (age 65 and over) post-menopausal women failed to improve cognitive performance. These findings have led many in the field, including us, to re-examine the role of estrogen in cognition and AD and to look beyond the direct effects of estrogen to more indirect, though perhaps no less important, effects. To this end, declining levels of sex steroids in women and men, albeit to a lesser degree, result in increases in gonadotropins such as luteinizing hormone (LH) through loss of feedback inhibition. LH, like estrogen, is modulated by HRT and serum levels of LH are higher in AD patients compared to aged-matched controls. Moreover, recent published and preliminary data, including our own studies, show that LH is capable of modulating cognitive behavior and associated neuronal plasticity markers, is present in the brain, has the highest levels of receptors in the hippocampus, is increased in the AD brain, and is capable of altering amyloid-b protein precursor processing. In this proposal, our goal is to dissect the hormonal contributions and interactions of estrogen and LH on cognition, synaptic plasticity, and AD pathogenesis using animal models of menopause and AD. Specifically, we propose to measure cognitive behavior [Morris Water Maze (MWM) task], neuronal plasticity as measured by structural and functional changes in synaptic remodeling, and cognitive decline (MWM) and amyloid-b synthesis and deposition in female C57/BLJ6 and AD transgenic mice (Tg2576) after ovariectomy and thereafter assess the effect of a "critical window" of efficacy of pharmacological manipulation of estrogen and LH levels, either singly or in combination. This systematic analysis will not only address the importance of hormonal action in cognition but will also begin to dissect the individual contributions of estrogen and LH and how these aspects are affected by the post-menopausal timing of HRT. PUBLIC HEALTH RELEVANCE: Postmenopausal changes in HPG-axis hormones, in particular estrogen, is tightly linked to cognitive impairment in older individuals and development of AD. This proposal trascends beyond the study of estrogen to determine the influence of other HPG-axis hormones. Specifically, the objective of this body of work is to investigate whether luteinizing hormone is a central mediator of such impairment, independently or in conjunction with estrogen. Outcomes of the proposal are not only important from a scientific perspective but could lead to immediate novel therapeutic regimens.