GABAA RECEPTORS IN AGING & ALZHEIMER'S DISEASE

GABAA 受体在衰老过程中的作用

• 批准号: 2863991
• 负责人: David M. Armstrong
• 金额: $ 28.93万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2863991
• 关键词: Alzheimer's disease; GABA receptor; aging; autoradiography; hippocampus; human tissue; immunocytochemistry; in situ hybridization; messenger RNA; protein binding; protein structure function; receptor expression

DESCRIPTION: (Applicant's abstract) Gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the mammalian CNS, hyperpolarizes neuronal membranes by opening a C1 channel intrinsic to the GABA A receptor. The proposed studies investigate the anatomical features and expression of selected GABA A receptor subunits (i.e., alpha1, alpha2, alpha3, alpha4, alpha5, beta1-3, gama2) in human hippocampus of non-pathologic mature and aged individuals (30-90 years of age) and those with Alzheimer's disease (AD) pathology. Underlying these studies are investigations of the P.I. and co-investigators demonstrating (I) subunit specific alteration (i.e., alpha1) in the CA1 field and dentate gyrus of aged rats; (ii) GABA A receptor subunit protein and mRNA alterations (i.e., alpha1, beta2, beta3) in the hippocampal formation of aged brains with AD pathology; (iii) time-dependent alterations of GABA A beta2/3 immunoreactivity in the dentate gyrus following perforant pathway lesions. In addition, pharmacological studies have demonstrated altered drug sensitivities, for example, to benzodiazepines, in the elderly. To date, it is not known the extent to which altered drug responses in the elderly may be attributed to emotional or physical disease, over- or undernutrition, use or abuse of other medications, or alterations in the molecular composition of the GABA A receptor. Throughout these studies we will employ immunohistochemical, in situ hybridization, in situ autoradiogaphic, and biochemical techniques in order to study the regional and laminar pattern of GABA A receptor subunit protein and mRNA expression in the hippocampal formation of aging individuals (SPECIFIC AIM 1) and those with varying extent of AD pathology (SPECIFIC AIM 2). It is our hypothesis that selected GABA A receptor subunits will display differential levels of expression and binding within the various regions of the hippocampus. Moreover, brain tissue obtained from elderly patients will not only show altered levels of expression of specific GABA A subunits, but will have a different subunit composition of the GABA A receptor complex compared to controls. In AD, we hypothesize that these receptor subunits will also display altered levels of expression and binding within selected subregions of the hippocampus. In addition, many of these changes will occur during the early phases of the disease (i.e., plastic/compensatory phase) and be unique from those observed during the end stages of the disease (i.e., neurodegenerative phase). A unique aspect of this study is the study of both aging and AD subjects. Notably, a comparison of these two populations of subjects will provide us with the opportunity of differentiating whether alterations in the anatomy of specific GABA A receptor subunits are associated with normal aging or represent a neuropathologic process.

描述：（申请人的摘要）γ-氨基丁酸（GABA），主要 哺乳动物中枢神经系统中的抑制性神经递质，使神经元超极化 通过打开GABA A受体固有的C1通道来膜。这 拟议的研究研究了选定的解剖特征和表达 GABA A受体亚基（即alpha1，alpha2，alpha3，alpha3，alpha4，alpha5，alpha5， beta1-3，gama2）在非病理成熟和老化的人海马中 个体（30-90岁）和患有阿尔茨海默氏病的人（AD） 病理。这些研究的基础是对P.I.的研究和 共同投资者证明了（i）亚基特异性变化（即alpha1） 在老年大鼠的CA1场和牙齿回旋中； （ii）GABA A受体亚基 海马蛋白和mRNA改变（即α1，beta2，beta3） 具有AD病理学的老化大脑的形成； （iii）与时间相关的变化 GABA A齿状回穿孔后齿状回的β2/3免疫反应性 途径病变。此外，药理学研究表明 例如，老年人对苯二氮卓类药物的敏感性。迄今为止， 尚不清楚老年人的药物反应在多大程度上可能 归因于情绪或身体疾病，过度或不足，使用或 滥用其他药物，或改变的分子组成 GABA A受体。在这些研究中，我们将采用免疫组织化学， 原位杂交，原位自载和生化技术 为了研究GABA A受体亚基的区域和层流模式 衰老个体的海马形成中的蛋白质和mRNA表达 （特定目的1）和具有不同范围的AD病理学的目标（特定目的 2）。我们的假设是选定的GABA A受体亚基将显示 表达的差异水平和结合在各个区域内 海马。此外，从老年患者获得的脑组织将不会 仅显示特定GABA A亚基的表达水平改变，但 与GABA A受体复合物具有不同的亚基组成 控件。在AD中，我们假设这些受体亚基也将显示 在选定子区域内的表达和结合水平改变了 海马。此外，其中许多更改将在早期发生 该疾病的阶段（即塑料/补偿阶段），并且是独一无二的 在疾病末期观察到的那些（即神经退行性 阶段）。这项研究的一个独特方面是对衰老和AD的研究 主题。值得注意的是，对这两个受试者人群的比较将 为我们提供区分改变是否改变的机会 特定GABA A受体亚基的解剖学与正常衰老有关 或代表神经病理过程。