Biochemical and in vivo determinants of tau neurotoxicity

tau 神经毒性的生化和体内决定因素

基本信息

批准号：
8885932
负责人：
MEL B FEANY
金额：
$ 45.99万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-28 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8885932
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Amino Acids Amyloid beta-Protein Precursor Animal Model Asses Binding Biochemical Biochemistry Biological Biological Models Brain Cell Culture Techniques Cells Cessation of life Chromosomes, Human, Pair 17 Data Deposition Diamond Disease Drosophila genus FTD with parkinsonism Frontotemporal Dementia Gene Transfer Techniques Generations Genes Genetic Health Human In Vitro Inclusion Bodies Influentials Laboratories Lesion Link Mediating Mediator of activation protein Memory impairment Methods Microtubule Stabilization Microtubules Missense Mutation Modeling Molecular Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Parkinsonian Disorders Pathogenesis Pathogenicity Pathologic Production Progressive Supranuclear Palsy Property Protein Isoforms Publishing RNA Splicing Reporting Resources Senile Plaques System Tauopathies Testing Time Toxic effect Transgenic Mice Transgenic Organisms Variant Work age related corticobasal degeneration density design experience extracellular human disease in vivo mouse model mutant neurotoxic neurotoxicity progressive neurodegeneration protein aggregate research study synuclein tau Proteins tau aggregation tau microtubule binding domain tau mutation tau phosphorylation tool

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease is the most common neurodegenerative disorder and is characterized pathologically by the intraneuronal deposition of abnormally phosphorylated and aggregated tau protein and by the formation of extracellular amyloid plaques. Abnormal deposition of tau into neurofibrillary tangles is also the primary pathologic feature of a group of less common disorders, collectively termed the "tauopathies." To define the molecular mechanisms controlling tau-induced neurodegeneration we (Dr. Gamblin) have performed extensive biochemical characterization of tau variants, including splicing isoforms and mutants linked to the familial tauopathy frontotemporal dementia and parkinsonism linked to chromosome 17. Importantly, these biochemical studies have defined tau variants with altered aggregation and microtubule binding properties. In parallel we (Dr. Feany) have created Drosophila models of tauopathy. Our models recapitulate key features of the human diseases, including age-dependent neurodegeneration, abnormal tau phosphorylation, aggregation of tau into fibrillary tangle-like inclusions, and early death. We will now combine our strengths in biochemistry and in vivo tauopathy modeling to define the species of tau that cause cellular and organismal toxicity in tauopathies.

描述（由申请人提供）：阿尔茨海默氏病是最常见的神经退行性疾病，在病理上以异常磷酸化和骨料的tau蛋白的神经内沉积和细胞外淀粉样蛋白的形成来表征。 Tau在神经原纤维缠结中的异常沉积也是一组较少常见疾病的主要病理特征，统称为“ tauopathies”。为了定义控制TAU诱导的神经退行性的分子机制，我们（Gamblin博士）对TAU变体进行了广泛的生物化学特征，包括剪接同工型和与家族性的Tauopathy thauopathy脑性肌肉痴呆症和帕金森氏症相关的剪接和突变体，这些变化与这些变化型的tine tini tatchemiction。微管结合特性。同时，我们（Feany博士）创建了Tauopathy的果蝇模型。我们的模型概括了人类疾病的关键特征，包括依赖年龄的神经变性，异常的tau磷酸化，tau聚集到纤维状缠结的夹杂物中以及早期死亡。我们现在将结合我们的生物化学和体内tauopathy建模的优势，以定义tau的物种，从而引起陶氏病细胞和生物毒性。