EFFECT OF ALZHEIMER'S DISEASE ON MONOAMINE UPTAKE SITES

阿尔茨海默病对单胺摄取位点的影响

• 批准号: 3418648
• 负责人: SHANAZ MOHAMMEDALI TEJANI-BUTT
• 金额: $ 9.48万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3418648
• 关键词: Alzheimer's disease; amyloid proteins; autoradiography; chemical binding; dorsal raphe nucleus; hippocampus; human tissue; immunocytochemistry; locus coeruleus; molecular site; monoclonal antibody; neural degeneration; neuritic plaques; neurofibrillary tangles; neurotransmitter receptor; neurotransmitter transport; norepinephrine; radiotracer; serotonin; serotonin receptor; synapses; tau proteins

Several studies have reported that the noradrenergic (NA) and the serotoninergic (5-HT) systems are affected in Alzheimer's Disease (AD). Since these systems appear to play a role in many diverse functions such as memory, learning and attention, it would be important to study degenerative changes in these systems that may be associated with AD. To date, little work has been done to study the role of the presynaptic uptake system for norepinephrine (NE) and serotonin (5-HT) in neurodegenerative diseases. A measure of the changes in the density of uptake sites for NE and 5-HT could provide specific information regarding the integrity of these neuronal systems in AD. Our hypotheses are that the density of uptake sites for NE and 5-HT will be decreased in the cell body areas, given previous reports of decreased cell counts in the locus coeruleus (LC) and dorsal raphe nucleus (DR). We also expect to find a loss of presynaptic sites for NE and 5-HT in the terminal field areas given reports of synaptic pathology in AD. In this proposal, we will investigate whether uptake sites for NE and 5-HT are altered in the LC, DR, cortex (CTX) and hippocampus (HIP) in AD by selective radiolabelling of uptake sites for NE (with 3H-nisoxetine) and 5-HT (with 3H- cyanoimipramine) in tissue sections from different brain regions using the technique of quantitative autoradiography. This technique offers several advantages over previously used methods in that it provides a quantitative measure of the density of uptake sites as well as a detailed anatomical map of the location of these sites. Neuropathological characterization of AD involves the formation of neurofibrillary tangles (NFT) and amyloid plaques (AP) which are thought to contribute to neuronal degeneration in the CTX and HIP in AD and reports of significant synaptic loss suggest that the presynaptic terminal system may play an important role in the pathological events that occur in AD. In this proposal, we will investigate whether NFT, AP and synaptophysin (SYP) (a presynaptic terminal protein) share the same anatomical localization as the NE and 5-HT presynaptic uptake sites that are undergoing degeneration in the cell body and terminal field areas. For these studies, brain sections adjacent to those used for the quantitative autoradiographic analysis of NE and 5-HT uptake sites will be used. These sections will be labelled immunohistochemically using monoclonal antibodies specific for tau proteins to determine the relative abundance of NFT, antibodies for beta-amyloid or A4 peptide to study AP formation and SY38 to study SYP immunoreactivity. The results of this study should provide a quantitative measure of the regional distribution and integrity of the NE and 5-HT systems in AD, as well as determine whether the pathological formation of tangles and plaques and synaptic decline in AD can be associated with losses in the NA and/or 5-HT presynaptic systems within the same brain regions.

几项研究报告说，去甲肾上腺素能（NA）和 血清素能（5-HT）系统受到阿尔茨海默氏病（AD）的影响。 由于这些系统似乎在许多不同的功能中起作用 作为记忆，学习和关注，学习将很重要 这些系统可能与AD相关的退化性变化。 迄今为止，研究突触前的作用很少 用于去甲肾上腺素（NE）和5-羟色胺（5-HT）的吸收系统 神经退行性疾病。 衡量密度变化的度量 NE和5-HT的吸收站点可以提供有关的特定信息 这些神经元系统在AD中的完整性。 我们的假设是 NE和5-HT的摄取位点的密度将在细胞中降低 鉴于以前关于基因座细胞计数减少的报道 COERULEUS（LC）和背部Raphe核（DR）。 我们还希望找到一个 终端场区域内NE和5-HT的突触前部位损失 给定AD中突触病理的报告。 在此提案中，我们将 研究LC中的NE和5-HT的吸收位点是否改变了 通过选择性放射性标记的DR，Cortex（CTX）和海马（HIP）（髋关节） NE的摄取位点（带有3H-二氧汀）和5-HT（3H- 使用不同大脑区域的组织切片的氰基氨基胺）使用 定量放射自显影技术。 该技术提供 比以前使用的方法有几个优点，因为它提供了 摄取位点密度的定量度量以及详细的 这些站点位置的解剖图。 AD的神经病理学表征涉及形成 被认为的神经原纤维缠结（NFT）和淀粉样斑块（AP） 为CTX中的神经元变性做出贡献，并在AD中髋关节变性 显着突触损失的报告表明突触前 终端系统可能在病理事件中起重要作用 在广告中发生。 在此提案中，我们将调查NFT，AP是否 和突触素（SYP）（突触前末端蛋白）共享相同 解剖学定位为NE和5-HT突触前摄取位点 正在细胞体和末端场区域进行变性。 对于这些研究，脑部与用于 NE和5-HT吸收位点的定量放射自显影分析将 被使用。 这些部分将使用 特异于tau蛋白的单克隆抗体确定相对 NFT的丰度，β-淀粉样蛋白或A4肽的抗体研究AP 形成和SY38研究SYP免疫反应性。 这项研究的结果应提供对 AD中NE和5-HT系统的区域分布和完整性 以及确定缠结和缠结的病理形成 AD的斑块和突触下降可能与损失有关 Na和/或5-HT在同一大脑区域内的突触前系统。