Tangle Formation in P301L Transgenic Mice

描述(由申请者提供)：tau病理是许多 神经退行性疾病，包括阿尔茨海默病，进行性 核上性瘫痪、皮质基底膜变性和额颞叶痴呆 与17号染色体相关的帕金森病。发生在帕金森病发生之前的事件 神经纤维性和其他类型的tau病理包括相关的 神经退行性变在很大程度上是未知的。因为组织通常是 不适用于早期患者，我们打算利用一种 我们建立了一种新的小鼠模型来研究 神经纤维性病理学。这些转基因小鼠表达的人tau含有 FTDP-17突变，P301L，并发展tau神经原纤维缠结，神经元 丧失，肌萎缩，行为和运动障碍。神经原纤维 这些老鼠身上的缠结基本上概括了所有这些特征 人类肌萎缩侧索硬化症的损害，包括阿尔茨海默病，严重的是 也与神经元丢失有关。此外，分布的 Tau小鼠的病理和精神运动缺陷在某些方面类似于 进行性核上性麻痹，肌萎缩侧索性 硬化性痴呆症(ALS-PD)和FTDP-17的变种。在这 我们将进行一系列研究来确定分子 Tau(P301L)转基因小鼠的致病机制。Cdna 来源于P301 L Tau小鼠的中脑、桥脑和脊髓区域 将接受微阵列分析，以识别和分析 在缠结的发生和发展过程中表达水平发生了变化 病理学。为了研究tau磷酸化对缠结形成的影响， 它被认为是慢性粒细胞白血病发病机制中的一个重要始动事件。 Tauopathy，P301L动物将与小鼠杂交，过度表达 GSK3β或p25，CDK5的结构性激活剂。CDK5和GSK3测试版 已被认为是正常大脑和脑内的主要tau激酶。 疾病的发病机制。最后，要确定氧化应激是否 与在P301L小鼠中看到的病理相关，我们将查看标记 用于DNA、脂肪和蛋白质的氧化损伤。从这里得到的信息 研究将提供对……发展的更多了解 肌萎缩侧索硬化症的神经原纤维病理和相关的神经变性 以及可以改变病理发生和发展的因素。

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.