EFFECT OF ALZHEIMER'S DISEASE ON MONOAMINE UPTAKE SITES

几项研究报道，去甲肾上腺素能（NA）和 阿尔茨海默病（AD）中的多巴胺能（5-HT）系统受到影响。 由于这些系统似乎在许多不同的功能中发挥作用， 就像记忆、学习和注意力一样， 这些系统的退行性变化可能与AD相关。 到目前为止，很少有人研究突触前神经元的作用， 去甲肾上腺素（NE）和5-羟色胺（5-HT）摄取系统 神经退行性疾病 一种测量密度变化的方法， NE和5-HT的摄取位点可以提供关于 这些神经系统的完整性。 我们的假设是 细胞内NE和5-HT摄取部位密度降低 身体区域，考虑到先前报告的该部位细胞计数减少 蓝斑核（LC）和中缝背核（DR）。 我们还希望找到一个 NE和5-HT在终末区突触前位点的丢失 给出了AD中突触病理学的报告。 在本提案中，我们将 研究LC中NE和5-HT的摄取位点是否改变， 选择性放射性标记AD的DR、皮质（CTX）和海马（HIP） NE（用3H-尼索西汀）和5-HT（用3H- 氰基丙咪嗪）在来自不同脑区域的组织切片中， 定量放射自显影技术。 这项技术提供 与先前使用的方法相比的几个优点在于， 定量测量吸收点的密度以及详细的 这些位置的解剖图。 AD的神经病理学特征涉及以下的形成： 神经纤维缠结（NFT）和淀粉样斑块（AP）， 导致AD中CTX和HIP的神经元变性， 关于突触丢失的报道表明， 终末系统可能在病理过程中起重要作用 发生在AD。 在本提案中，我们将调查NFT、AP 和突触素（SYP）（突触前末端蛋白）有相同的 作为NE和5-HT突触前摄取部位的解剖定位， 在细胞体和终末区域发生变性。 在这些研究中，大脑切片邻近用于 NE和5-HT摄取位点的定量放射自显影分析将 被利用 这些部分将使用以下化学标记 特异于tau蛋白的单克隆抗体，以确定 NFT、β-淀粉样蛋白抗体或A4肽的丰度，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量化的措施， AD中NE和5-HT系统的区域分布和完整性， 以及确定缠结的病理形成和 AD中的斑块和突触衰退可能与 NA和/或5-HT突触前系统在相同的大脑区域。

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.