Tau conditional knockout mice to elucidate the function of tau in the adult brain

Tau 条件敲除小鼠阐明 tau 在成年大脑中的功能

• 批准号: 9310415
• 负责人: Salvatore Oddo
• 金额: $ 23.18万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310415
• 关键词: Acute; Adult; Alzheimer' s Disease; Animal Model; Axonal Transport; Behavioral; Binding Proteins; Brain; Chronic; Cognitive; Development; Disease; Embryonic Development; Enterobacteria phage P1 Cre recombinase; Excision; Exons; Frontotemporal Dementia; Genes; Goals; Impaired cognition; Knock-out; Knockout Mice; Lead; Learning; LoxP-flanked allele; MAPT gene; Mediating; Memory; Microtubule Stabilization; Microtubules; Motor; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Phenotype; Physiology; Pick Disease of the Brain; Positioning Attribute; Protein Isoforms; Proteins; Reporting; Role; Structure; Synapses; Tamoxifen; Tauopathies; Testing; Toxic effect; Up-Regulation; behavior test; corticobasal degeneration; experimental study; gain of function; homologous recombination; hyperphosphorylated tau; loss of function; mouse model; neuron loss; promoter; tau Proteins; tau function; therapeutic target; tool

Abstract Tau is a protein involved in several neurodegenerative disorders, including Alzheimer's disease (AD), frontotemporal dementia, Pick's disease, and corticobasal degeneration. Growing evidence points to tau as a valid therapeutic target for mitigating some of these disorders. However, the role of tau in the adult brain remains elusive. We used homologous recombination to flox exon 4 of the mouse tau gene. By combining these tau floxed mice with an inducible, neuronal-specific, CRE line, we are uniquely positioned to selectively knockout Mapt in adult neurons. In this application, we will test the hypothesis that tau is necessary for learning and memory in the adult brain. Specifically, we will leverage these newly developed tau conditional knockout mice by removing tau from the brains of 6-month-old mice. This will be accomplished by crossing the tau floxed mice with a tamoxifen-inducible Cre recombinase, whose expression is controlled by a neuronal specific promoter. We will assess the acute and chronic effect of knocking out tau by testing mice in a battery of cognitive and non-cognitive behavioral tests, one week and two months after the Cre-mediated removal of Mapt. We will also perform rescue experiments using the three major murine tau isoforms. These experiments will determine whether removing tau in the brain of adult mice has an effect on cognitive and motor function. This is a critical step towards the development of anti-tau therapies for AD and other tauopathies. In summary, we have generated the much needed tau conditional knockout mice, which will allow us to selectively and inducibly ablate Mapt in the adult brain. These mice may have a long-lasting impact on the field and may represent an invaluable tool to evaluate the role of tau and study potential anti-tau therapies in AD and other tauopathies.

摘要 Tau是一种参与多种神经退行性疾病的蛋白质，包括阿尔茨海默病（AD）， 额颞叶痴呆、皮克病和皮质基底节变性。越来越多的证据表明，tau蛋白是一种 有效的治疗目标，以减轻这些疾病中的一些。然而，tau蛋白在成人大脑中的作用 仍然难以捉摸我们使用同源重组到小鼠tau基因的flox外显子4。通过组合 这些tau蛋白融合的小鼠具有可诱导的神经元特异性CRE系，我们处于独特的位置，可以选择性地 在成年神经元中敲除Mapt。在本申请中，我们将测试tau对于以下假设是必要的： 成人大脑的学习和记忆具体来说，我们将利用这些新开发的tau条件 通过从6个月大的小鼠大脑中去除tau蛋白来敲除小鼠。这将通过跨越 用他莫昔芬诱导的Cre重组酶的tau floxed小鼠，其表达由神经元 特异性启动子我们将通过在一系列小鼠中进行测试来评估敲除tau蛋白的急性和慢性影响 认知和非认知行为测试，一个星期和两个月后，铬介导的删除， 地图我们还将使用三种主要的鼠tau同种型进行拯救实验。这些实验 将确定去除成年小鼠大脑中的tau蛋白是否会对认知和运动功能产生影响。 这是开发用于AD和其他tau蛋白病的抗tau疗法的关键一步。总的来说， 我们已经产生了急需的tau条件性敲除小鼠，这将使我们能够选择性地， 诱导性消融成人大脑中的MAP这些老鼠可能会对该领域产生持久的影响， 代表了评估tau的作用和研究AD和其他疾病中潜在的抗tau疗法的宝贵工具。 tau蛋白病