Tangle Formation in P301L Transgenic Mice

描述（由申请人提供）：Tau病理学是许多癌症中的关键特征。 神经退行性疾病，包括进行性阿尔茨海默病 核上性麻痹、皮质基底节变性和额颞叶痴呆， 与17号染色体有关的帕金森症发展之前的事件 神经病理学和其他类型的tau病理学 神经变性在很大程度上是未知的。因为组织通常 对于早期tau蛋白病患者不可用，我们打算利用 一种新的小鼠模型，我们已经产生了研究的进展， 神经病理学这些转基因小鼠表达人tau蛋白， FTDP-17突变，P301 L，并发展tau神经元缠结，神经元 丧失、肌萎缩以及行为和运动缺陷。神经原纤维 这些小鼠中的缠结基本上概括了这些细胞的所有特征， 在人类tau蛋白病，包括阿尔茨海默病的病变， 也与神经元缺失有关。此外， tau小鼠的病理学和精神缺陷在某些方面类似于 进行性核上性肌萎缩侧性麻痹 硬化性帕金森病-痴呆（ALS-PD）和FTDP-17的变体。在这 我们将进行一系列的研究，以确定分子 在tau（P301 L）转基因小鼠中的发病机制。cDNA 从P301 L tau小鼠的中脑、脑桥和脊髓区域产生 将进行微阵列分析，以识别和分析基因， 在缠结的发生和发展过程中， 病理为了研究tau蛋白磷酸化对缠结形成的影响， 这被认为是一个主要的发病机制中的起始事件， 在tau蛋白病中，P301 L动物将与过表达以下任一者的小鼠杂交： GSK 3 β或p25，cdk 5的组成型激活剂。cdk 5和GSK 3beta 已被认为是正常脑和脑内的主要tau激酶。 疾病的发病机制。最后，为了确定氧化应激是否 与P301 L小鼠中观察到的病理学相关，我们将研究标记物 DNA、脂质和蛋白质的氧化损伤。从这个信息 研究将使人们更好地了解 Tau蛋白病的神经病理学和相关的神经变性， 以及可以改变病理的发生和进展的因素。

DESCRIPTION (provided by applicant): Tau pathology is a key feature in numerous neurodegenerative disease including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal dementia and parkinsonism linked to chromosome 17. The events preceding the development of neurofibrillary and other types of tau pathology including associated neurodegeneration are largely unknown. Because tissues are generally unavailable from early stage patients with tauopathies, we intend to utilize a novel mouse model that we have generated to study the progression of neurofibrillary pathology. These transgenic mice express human tau containing an FTDP-17 mutation, P301L, and develop tau neurofibrillary tangles, neuronal loss, amyotrophy, and behavioral and motor deficits. The neurofibrillary tangles in these mice recapitulate essentially all of the features of these lesions in Human tauopathies, including Alzheimer's disease, and critically are also associated with neuronal loss. In addition, the distribution of the pathology and the psychomotor deficits in the tau mice resemble some aspects of progressive supranuclear palsy, amyotrophic lateral sclerosisparkinsonism-dementia (ALS-PD) and variants of FTDP-17. In this project we will perform a series of studies to determine the molecular mechanisms that underlie pathogenesis in the tau (P301L) transgenic mice. cDNA generated from midbrain, pons and spinal cord regions from the P301 L tau mice will be subjected to microarray analysis to identify and profile genes that have altered expression levels during the onset and progression of tangle pathology. To study the effect of tau phosphorylation on tangle formation, which has been suggested as a major initiating event in the pathogenesis of tauopathies, P301L animals will be crossed with mice over expressing either GSK3beta or p25, the constitutive activator of cdk5. Both cdk5 and GSK3beta have been proposed as major tau kinases in both normal brain and in the pathogenesis of disease. Finally, to determine if oxidative stress is associated with the pathology seen in the P301L mice, we will look at markers for oxidative damage of DNA, lipid, and protein. The information from this study will provide a greater understanding of the development of neurofibrillary pathology and associated neurodegeneration in tauopathies as well as the factors that can modify the onset and progression of the pathology.