BABAA RECEPTORS IN AGING & ALZHEIMER'S DISEASE

老化过程中的巴巴受体

• 批准号: 6169158
• 负责人: David M. Armstrong
• 金额: $ 27.93万
• 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/6169158
• 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：（申请人摘要）γ-氨基丁酸（GABA），主要的 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 通道来进入细胞膜。这 拟议的研究调查了选定的解剖特征和表达 GABA A 受体亚基（即 alpha1、alpha2、alpha3、alpha4、alpha5、 非病理性成熟和衰老的人海马β1-3、gama2） 个人（30-90 岁）和阿尔茨海默病 (AD) 患者 病理。这些研究的基础是对 P.I. 的调查。和 共同研究人员证明 (I) 亚基特异性改变（即 alpha1） 老年大鼠的CA1区和齿状回； (ii) GABA A 受体亚基 海马中的蛋白质和 mRNA 改变（即 alpha1、beta2、beta3） 具有 AD 病理学特征的老年大脑的形成； (iii) 随时间变化的 穿孔后齿状回中的 GABA A beta2/3 免疫反应性 通路病变。此外，药理学研究表明， 药物敏感性，例如老年人对苯二氮卓类药物的敏感性。迄今为止， 目前尚不清楚老年人的药物反应改变会在多大程度上 归因于情绪或身体疾病、营养过剩或不足、使用或 滥用其他药物，或改变药物的分子组成 GABA A 受体。在整个这些研究中，我们将采用免疫组织化学， 原位杂交、原位放射自显影和生化技术 为了研究GABA A受体亚基的区域和层状模式 衰老个体海马结构中蛋白质和 mRNA 的表达 （具体目标 1）和具有不同程度 AD 病理的患者（具体目标 2）。我们假设选定的 GABA A 受体亚基会显示 不同区域内的表达和结合水平存在差异 海马体。此外，从老年患者身上获取的脑组织不会 只显示特定 GABA A 亚基表达水平的改变，但会 与 GABA A 受体复合物相比，具有不同的亚基组成 控制。在 AD 中，我们假设这些受体亚基也会表现出 改变了选定亚区域内的表达和结合水平 海马体。此外，其中许多变化将在早期发生 疾病的阶段（即塑性/代偿阶段）并且是独特的 在疾病末期（即神经退行性疾病）观察到的那些 阶段）。这项研究的一个独特之处是对衰老和 AD 的研究 科目。值得注意的是，这两个受试者群体的比较将 为我们提供了区分是否发生变化的机会 特定 GABA A 受体亚基的解剖结构与正常衰老相关 或代表神经病理过程。