Tau Nitration and Oxidation in Alzheimer's Disease

描述(申请人提供)：tau蛋白通常稳定大脑神经元突起中的微管。在阿尔茨海默病和某些其他神经退行性疾病的过程中，这些蛋白质从微管中解离，并开始聚集在大脑特定疾病相关区域的神经元和神经胶质细胞的细胞体中。这个过程伴随着炎症反应，其结果之一是某些蛋白质的硝化和氧化交联。我们已经发现，在AD和相关的额颞部痴呆中，tau主要是在特定的酪氨酸残基上硝化；此外，tau也可以通过双酪氨酸键进行交联。我们建议使用生物化学模拟研究来确定硝化作用在tau细丝形成中的作用，并产生仅识别tau上特定硝化残基和双酪氨酸交联区的抗体，用于在死于AD或其他tau病的患者的大脑中跟踪这一过程。具体地说，我们将：1.研究硝化作用对每个tau亚型组装的影响；2.研究tau在特定位置硝化对正常tau组装的抑制作用；3.利用我们针对tau上不同硝化部位的特异性抗体，使用免疫组织化学和激光扫描共聚焦显微镜来评估在AD和其他tau病过程中硝化事件的时机和作用。我们还将生产针对tau上更多硝化位点的单抗，并在患病的大脑中进行评估；以及，4.制造针对双酪氨酸交联tau的单抗，以确定这一事件在AD和其他tau病过程中何时发生。我们假设，特定部位的tau硝化和双酪氨酸交联事件是AD和其他tau病纤维病变形成和稳定的关键因素。这些研究的成功完成将极大地帮助我们理解炎症在阿尔茨海默病和其他疾病中的作用。公共卫生相关性：在阿尔茨海默病和相关痴呆症等疾病中，被称为tau的蛋白质聚集在神经元和某些神经胶质细胞的细胞体中。这种聚集伴随着一个炎症过程，导致这些蛋白质在称为酪氨酸的氨基酸上发生变化。我们建议确定这些变化在疾病中的功能，并确定它们发生的时间和地点。

DESCRIPTION (provided by applicant): Tau proteins normally stabilize microtubules in neuronal processes in the brain. During the course of Alzheimer's disease and certain other neurodegenerative diseases, these proteins dissociate from the microtubule and begin to aggregate within cell bodies of neurons and glial cells in specific disease-related regions of the brain. This process is accompanied by an inflammatory response, one result of which is the nitration and oxidative crosslinking of certain proteins. We have discovered that tau gets nitrated predominantly at specific tyrosine residues in AD and related frontotemporal dementias; moreover, tau also can be crosslinked by dityrosine bonds. We propose to use biochemical modeling studies to determine the role of nitration in tau filament formation and to produce antibodies that only recognize specific nitrated residues and dityrosine crosslinked areas on tau for use in following this process in the brains of patients that died with AD or another tauopathy. Specifically, we will: 1. Study the affect of nitration on the assembly of each of the tau isoforms; 2. Study the inhibition of assembly of normal tau by tau nitrated at specific sites; 3. Use immunohistochemistry and laser scanning confocal microscopy with our specific antibodies to different nitrated sites on tau to assess the timing and role of nitrative events during the course of AD and other tauopathies. We will also produce monoclonal antibodies to additional nitrated sites on tau and assess them in diseased brains as well; and, 4. Manufacture monoclonal antibodies to dityrosine cross-linked tau in order to determine when this event occurs during the course of AD and other tauopathies. We hypothesize that site-specific tau nitration and dityrosine cross-linking events represent key elements in the formation and stabilization of the fibrillar pathologies in AD and other tauopathies. Successful completion of these studies will contribute greatly to our understanding of the role of inflammation in AD and other tauopathies. PUBLIC HEALTH RELEVANCE: In maladies such as Alzheimer's disease and related dementias, proteins known as tau aggregate within the cell bodies of neurons and certain glial cells. This aggregation is accompanied by an inflammatory process that causes these proteins to be altered on amino acids called tyrosines. We propose to determine the function of these alterations in disease and to determine when and where they occur.