Estrogen and cognition over the lifespan

雌激素与整个生命周期的认知

基本信息

批准号：
10370371
负责人：
THOMAS C FOSTER
金额：
$ 38.09万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10370371
关键词：
Address Aftercare Age-associated memory impairment Aging Alzheimer&apos s Disease Animals Attenuated Behavior Behavioral Body Regions Brain Cognition Cognition Disorders DNA DNA Methylation Data Dithiothreitol Effectiveness Elderly Episodic memory Equilibrium Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Exhibits Funding Gene Expression Gene Expression Profile Genes Genetic Transcription Genomics Goals Gonadal Steroid Hormones Hippocampus (Brain)Hormones Hour Hypermethylation Impaired cognition Injections Introns Link Long-Term Effects Longevity Measures Mediating Membrane Memory Methylation Mitochondria N-Methyl-D-Aspartate Receptors Neurodegenerative Disorders Oils Ontology Oxidation-Reduction Oxidative Stress Oxides Periodicity Phosphoric Monoester Hydrolases Phosphotransferases Physiology Proteins Reducing Agents Regulation Research Series Sex Differences Signal Transduction Site Stress Synapses Synaptic Receptors Synaptic Transmission Synaptic plasticity Testing Therapeutic Tissues Whole-Cell Recordings Work age related aged aging brain antioxidant enzyme behavior test calmodulin-dependent protein kinase II cognitive benefits deprivation differential expression enzyme activity epigenetic regulation improved juvenile animal male middle age neuroprotection novel object recognition patch clamp protein biomarkers receptor function response therapeutic effectiveness water maze

项目摘要

Abstract Sex differences are evident in vulnerability to age-related cognitive decline and diseases of aging. Estradiol (E2) is protective against neurodegenerative diseases, including Alzheimer’s disease, implicating sex hormone effects on sex differences in vulnerability. However, obstacles to sex steroid treatments include closing of the therapeutic window observed as decreased effectiveness of E2 treatment with advanced age. The goal of the proposed research is to provide an understanding of the mechanisms for E2 effects on memory and the closing of the therapeutic window. Closing of the therapeutic window is marked by a decrease in E2-responseive transcription and an inability of E2 treatment to enhance N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic transmission examined several days after treatment. Aim 1 will test the hypothesis that E2 treatment, several days prior to testing, specifically influences NMDAR-dependent episodic memory, such that it can rescue an age-related decline in episodic memory examined on the water maze and novel object recognition tasks. Aim 2 will test the hypothesis that E2 effects on memory and NMDAR function are mediated by reversal of NMDAR hypofunction, mediated by redox regulation of phosphatase/kinase activity, similar to that previously described in aging males. Thus, it is predicted that prior to closing of the therapeutic window (i.e. in animals in which E2 treatment improves cognition and increases NMDAR function), E2 treatment will promote antioxidant enzyme activity, reduce oxidative stress, and minimize redox-mediated decrease in CaMKII activity and NMDAR function. Further, following closing of the therapeutic window (i.e. for animals in which E2 does not rescue cognition and NMDAR function), E2 treatment will not promote antioxidant enzyme activity or reduce oxidative stress, and the NMDAR response and CaMKII activity will be decreased due to an oxidized redox state. Aim 3 will test the hypothesis that age- related changes in transcriptional responsiveness to E2 are due, at least in part, to epigenetic regulation through DNA methylation. It is predicted that decreased responsiveness of E2-sensitive genes will be associated with DNA hypermethylation, particularly in gene body regions (introns), and specific to CpG, relative to non-CpG methylation sites. The proposed studies will employ a powerful combination of behavioral tests that are sensitive to NMDAR function, patch-clamp recording of NMDAR synaptic responses, measures of oxidative stress and enzyme activity, transcription, and DNA methylation.

抽象的性别差异在与年龄相关的认知能力下降和衰老疾病的易感性方面存在明显差异。 (E2) 可以预防神经退行性疾病，包括与性有关的阿尔茨海默病激素对脆弱性的性别差异的影响然而，性类固醇治疗的障碍包括。随着年龄的增长，E2 治疗的有效性降低，观察到治疗窗的关闭。拟议研究的目标是了解 E2 影响的机制记忆和治疗窗口的关闭治疗窗口的关闭以减少为标志。 E2 反应性转录和 E2 处理无法增强 N-甲基-D-天冬氨酸受体 (NMDAR) 介导的突触传递在治疗几天后进行检查，目标 1 将测试假设测试前几天的 E2 治疗特别影响 NMDAR 依赖性情景记忆，这样它就可以挽救与年龄相关的情景记忆衰退，在水上检查目标 2 将检验 E2 对记忆和记忆的影响这一假设。 NMDAR 功能是通过逆转 NMDAR 功能减退来介导的，而 NMDAR 功能减退是由氧化还原调节介导的磷酸酶/激酶活性，与之前在老年男性中描述的相似，因此，预测之前。治疗窗口的关闭（即在动物中，E2 治疗可改善认知并增加 NMDAR功能），E2治疗会促进酶的抗氧化活性，减少氧化应激，并且最大限度地减少氧化还原介导的 CaMKII 活性和 NMDAR 功能的降低。治疗窗口（即对于 E2 不能挽救认知和 NMDAR 功能的动物），E2 治疗不会促进抗氧化酶活性或减少氧化应激，并且 NMDAR 反应 CaMKII 活性将由于氧化的氧化还原状态而降低目标 3 将检验年龄-的假设。 E2 转录反应性的相关变化至少部分归因于表观遗传调控预计 E2 敏感基因的反应性会降低。与 DNA 高甲基化相关，特别是在基因体区域（内含子），并且特定于 CpG，相对于非 CpG 甲基化位点，拟议的研究将采用行为的强大组合。对 NMDAR 功能敏感的测试、NMDAR 突触反应的膜片钳记录、测量氧化应激和酶活性、转录和 DNA 甲基化。