Tyrosine phosphorylation in Alzheimer's disease

阿尔茨海默病中的酪氨酸磷酸化

• 批准号: 8811394
• 负责人: Gloria Lee
• 金额: $ 30.03万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811394
• 关键词: Affect; Age; Alzheimer' s Disease; Animal Model; Behavior; Binding; Biological Markers; Brain; Caring; Cause of Death; Cell Count; Cell Death; Cell Line; Cells; Cessation of life; Chemosensitization; Data; Dementia; Disease; Disease Progression; Early Diagnosis; Exhibits; Family; Frontotemporal Dementia; Genes; Goals; Grant; Human; Investigation; Knowledge; Laboratories; Lead; Link; MAP Kinase Gene; Methods; Microtubule-Associated Proteins; Microtubules; Modeling; Mus; Mutate; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neuropathogenesis; PTPN11 gene; PXXP Motif; Pathology; Pathway interactions; Patient Care; Patients; Phosphorylation; Phosphotransferases; Process; Proline-Rich Domain; Property; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Proteins; Regulation; Research; Research Personnel; Role; SH3 Domains; Signal Transduction; Staging; Tauopathies; Therapeutic; Transcription Factor AP-1; Tyrosine; Tyrosine Phosphorylation; United States; abnormally phosphorylated tau; age related; cost; mouse model; neurofibrillary tangle formation; neuron loss; neuropathology; novel therapeutics; src-Family Kinases; targeted treatment; tau Proteins; tau function; tau mutation; tau phosphorylation; tau-1

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) affects 20% of those over the age of 75 and 50% over the age of 85. It is difficult to identify early stages of AD and there are no methods to quantitatively follow disease progression. Therapies to slow AD or to cure AD are also absent. One of the neuropathological features of AD is the neurofibrillary tangles made of abnormally phosphorylated tau protein. The discovery of mutations in the tau gene that cause age-related neurodegenerative diseases, such as frontotemporal dementia, has led to research showing that (1) abnormally phosphorylated tau is sufficient to cause disease and (2) neuronal death is caused by abnormal tau. Moreover, AD is now considered a "tauopathy". To discover new biomarkers and therapeutics for AD and other tauopathies, it is critical to determine how tau causes disease. While many investigators have focused in the well-known property of tau as a microtubule-associated protein, we have focused on identifying new properties for tau, as there are many microtubule-associated proteins that have no connection to AD. We have found that tau associates with Src-family non-receptor tyrosine kinases and is tyrosine phosphorylated. We have also found that tau can up-regulate kinase activity and that both abnormally phosphorylated and mutated forms of tau can associate more strongly with Fyn, a Src-family kinase. In fact, other investigators have shown that deleting Fyn is neuroprotective for AD in mouse models. Because tau is tyrosine phosphorylated, we investigated the possibility that tau might function as a signal transduction protein. We found that tau potentiated NGF-induced MAPK and AP1 activation in neuronal cells and that phosphorylation of tau at thr231 and tyr18/tyr29 were critical for this new property. Microtubule binding was not involved. In addition, we found that tau associated with the protein tyrosine phosphatase SHP2 in an NGF-dependent manner. In this application, we propose to investigate the tyrosine phosphorylation of tau using two approaches. In Specific Aim I, we will determine if deletion of Fyn from a tauopathy mouse model alters the tau pathology and neuronal viability in the model. We will also determine if the behavior of the mouse is altered. In Specific Aim II, we will investigate the function of abnormally phosphorylated tau. Specifically, we will investigate the role of phosphorylation in the interaction between tau and SHP2 as well as the functional significance of the interaction. In Specific Aim III, we will determine if SHP2 is activated in AD. SHP2 and MAPK activation will also be investigated in a mouse tauopathy model. These aims will (1) advance our knowledge of the mechanisms undertaken by abnormally phosphorylated tau and (2) determine if these mechanisms are taking place during neurodegeneration. Abnormally phosphorylated tau is the earliest sign of neurodegenerative disease and our investigation aims to identify the earliest steps taken towards the neuropathogenic process. Our data will aid in the identification of new targets for disease therapeutics and new biomarkers for tracking disease progress.

描述(申请人提供)：阿尔茨海默病(AD)影响20%的75岁以上的人和50%的85岁以上的人。阿尔茨海默病的早期阶段很难识别，也没有定量跟踪疾病进展的方法。延缓阿尔茨海默病或治愈阿尔茨海默病的疗法也不存在。阿尔茨海默病的神经病理特征之一是由异常磷酸化的tau蛋白组成的神经原纤维缠结。Tau基因突变的发现导致了与年龄相关的神经退行性疾病，如额颞叶痴呆，研究表明：(1)异常磷酸化的tau足以致病，(2)神经元死亡是由tau异常引起的。此外，阿尔茨海默病现在被认为是一种“紧张症”。为了发现AD和其他tau病的新生物标记物和治疗方法，确定tau如何导致疾病是至关重要的。虽然许多研究人员都专注于tau作为微管相关蛋白的众所周知的性质，但我们专注于鉴定tau的新特性，因为有许多微管相关蛋白与AD无关。我们发现tau与Src家族的非受体酪氨酸激酶相关，并且是酪氨酸磷酸化的。我们还发现，tau可以上调激酶活性，并且异常磷酸化和突变形式的tau都可以更强地与Src家族的激酶Fyn结合。事实上，其他研究人员已经表明，删除FYN对 在鼠标模型中的广告。因为tau是酪氨酸磷酸化的，所以我们研究了tau可能作为信号转导蛋白发挥作用的可能性。我们发现，tau增强了NGF诱导的神经细胞中MAPK和AP1的激活，并且tau在TH231和tyr18/tyr29处的磷酸化对这一新特性至关重要。未见微管结合。此外，我们还发现tau与蛋白酪氨酸磷酸酶SHP2以一种NGF依赖的方式相关。在这个应用中，我们建议使用两种方法来研究tau的酪氨酸磷酸化。在特定的目标I中，我们将确定Fyn的缺失是否会改变tau病理和该模型中神经元的存活。我们还将确定鼠标的行为是否发生了变化。在特定的目标II中，我们将调查 异常磷酸化tau的功能。具体地说，我们将研究磷酸化在tau和SHP2相互作用中的作用以及相互作用的功能意义。在特定的目标III中，我们将确定SHP2是否在AD中被激活。Shp2和MAPK的激活也将在小鼠肌萎缩症模型中进行研究。这些目的将(1)促进我们对异常磷酸化tau所采取的机制的了解，以及(2)确定这些机制是否发生在神经退化过程中。异常磷酸化的tau是神经退行性疾病的最早迹象，我们的研究旨在确定神经致病过程中最早采取的步骤。我们的数据将有助于确定疾病治疗的新靶点和跟踪疾病进展的新生物标记物。