EFFECT OF ALZHEIMER'S DISEASE ON MONOAMINE UPTAKE SITES

已有多项研究报道去甲肾上腺素(NA)和 5-羟色胺(5-HT)系统在阿尔茨海默病(AD)中受到影响。 由于这些系统似乎在许多不同功能中发挥作用 作为记忆、学习和注意力，学习是很重要的 这些系统中可能与AD有关的退行性变化。 到目前为止，很少有人研究突触前的作用。 去甲肾上腺素(NE)和5-羟色胺(5-HT)的摄取系统 神经退行性疾病。密度变化的一种量度 去甲肾上腺素和5-羟色胺的摄取部位可以提供关于 这些神经元系统在AD中的完整性。我们的假设是 去甲肾上腺素和5-羟色胺在细胞内的摄取部位密度降低 身体面积，给出了先前关于局部细胞计数减少的报告 蓝斑(LC)和中缝背核(DR)。我们还希望找到一个 去甲肾上腺素和5-羟色胺在终末野区的突触前部位丢失 给出了AD的突触病理报告。在这项提案中，我们将 研究去甲肾上腺素和5-羟色胺在LC中的摄取部位是否改变， 选择性放射性标记检测AD患者的DR、皮质(CTX)和海马区(HIP) 去甲肾上腺素(与~3H-尼索西汀)和5-羟色胺(与~3H-羟色胺)的摄取部位 氰基丙咪胺)在不同脑区的组织切片上使用 定量放射自显影技术。这项技术提供了 与以前使用的方法相比，它的几个优点在于它提供了 摄取部位密度的定量测量以及详细的 这些地点的位置的解剖地图。 阿尔茨海默病的神经病理特征包括 被认为是神经纤维缠结(NFT)和淀粉样斑块(AP) 促进AD患者CTX和HIP的神经元退行性变 有关突触显著丢失的报道表明，突触前 终末系统可能在病理事件中起重要作用 发生在公元后。在这份提案中，我们将调查NFT、AP 和突触素(SYP)(一种突触前终末蛋白)具有相同的特征 去甲肾上腺素和5-羟色胺突触前摄取部位的解剖定位 正在经历细胞体和终端场区域的退化。 在这些研究中，大脑切片与用于 去甲肾上腺素和5-羟色胺摄取部位的放射自显影分析 被利用。这些部分将用免疫组织化学方法进行标记 用抗tau蛋白的单抗测定其相对分子质量 丰富的NFT、β-淀粉样蛋白或A4多肽抗体用于AP研究 形成和SY38研究SYP免疫反应性。 这项研究的结果应该提供一个量化的衡量标准 去甲肾上腺素和5-羟色胺系统在AD、AS中的区域分布和完整性 以及确定缠结的病理形成和 阿尔茨海默病的斑块和突触减少可能与 NA和/或5-羟色胺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.