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.

多项研究报告称，去甲肾上腺素能 (NA) 和 阿尔茨海默病 (AD) 会影响血清素能 (5-HT) 系统。 由于这些系统似乎在许多不同的功能中发挥着作用，例如 就像记忆、学习和注意力一样，学习很重要 这些系统的退行性变化可能与 AD 相关。 迄今为止，对于突触前的作用的研究还很少。 去甲肾上腺素（NE）和血清素（5-HT）的摄取系统 神经退行性疾病。 密度变化的测量 NE 和 5-HT 的吸收位点可以提供有关以下方面的具体信息 AD 中这些神经元系统的完整性。 我们的假设是 细胞内NE和5-HT的摄取位点密度将会减少 身体区域，考虑到之前有关该部位细胞计数减少的报告 蓝核（LC）和中缝背核（DR）。 我们还期望找到一个 末端区域 NE 和 5-HT 突触前位点丢失 给出了 AD 突触病理学的报告。 在本提案中，我们将 研究 LC 中 NE 和 5-HT 的摄取位点是否发生改变， 通过选择性放射性标记研究 AD 中的 DR、皮质 (CTX) 和海马 (HIP) NE（与 3H-nisoxetine）和 5-HT（与 3H- 氰基丙咪嗪）在来自不同大脑区域的组织切片中使用 定量放射自显影技术。 该技术提供了 与以前使用的方法相比，它有几个优点： 摄取位点密度的定量测量以及详细的 这些部位位置的解剖图。 AD 的神经病理学特征涉及形成 神经原纤维缠结（NFT）和淀粉样斑块（AP）被认为 导致 AD 和 HIP 中 CTX 和 HIP 的神经元变性 有关显着突触损失的报告表明，突触前 终末系统可能在病理事件中发挥重要作用 发生在公元后。 在这个提案中，我们将调查NFT、AP是否 和突触素（SYP）（一种突触前末端蛋白）具有相同的 解剖定位为 NE 和 5-HT 突触前摄取位点 细胞体和终场区域正在发生退化。 在这些研究中，与用于研究的大脑切片相邻的大脑切片 NE 和 5-HT 摄取位点的定量放射自显影分析将 被使用。 这些切片将使用免疫组织化学标记 tau 蛋白特异性单克隆抗体可确定相对 丰富的 NFT、β-淀粉样蛋白抗体或 A4 肽以研究 AP 形成和SY38来研究SYP免疫反应性。 这项研究的结果应该提供一个定量的测量 AD 中 NE 和 5-HT 系统的区域分布和完整性，如 以及确定缠结是否病理性形成 AD 中的斑块和突触衰退可能与 NA 和/或 5-HT 突触前系统位于同一大脑区域内。