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

基本信息

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
项目类别：
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&apos 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

Acute Adult Alzheimer&apos 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

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项目摘要

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.

抽象的 Tau是一种参与几种神经退行性疾病的蛋白质，包括阿尔茨海默氏病（AD），额颞痴呆，Pick的疾病和皮质型变性。越来越多的证据表明tau是缓解其中一些疾病的有效治疗靶点。但是，tau在成人大脑中的作用仍然难以捉摸。我们对小鼠tau基因的Flox外显子4使用了同源重组。通过组合这些tau floxed小鼠，具有诱导，神经元特异性的CRE系，我们是独特的定位于选择性的成人神经元中的敲除措施。在此应用程序中，我们将测试tau是必要的假设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有条件通过从6个月大的小鼠的大脑中去除tau来敲除小鼠。这将通过越过用他莫昔芬诱导的CRE重组酶Tau floxed小鼠，其表达受神经元的控制特定启动子。我们将评估通过在电池中测试小鼠击倒Tau的急性和慢性效应 CRE介导的去除后一个星期零两个月，认知和非认知行为测试 mapt。我们还将使用三个主要的鼠TAU同工型进行救援实验。这些实验将确定去除成年小鼠大脑中的tau是否对认知和运动功能有影响。这是朝着开发抗TAU疗法的AD和其他Tauopathies的关键一步。总之，我们已经生成了急需的tau条件敲除小鼠，这将使我们有选择地和在成人大脑中诱导的烧蚀剂。这些老鼠可能会对田野产生持久的影响，并且可能代表了评估tau和研究AD和其他抗TAU疗法的作用的宝贵工具 tauopathies。