Tau Nitration and Oxidation in Alzheimer's Disease

描述（由申请人提供）：Tau蛋白通常稳定脑中神经元过程中的微管。在阿尔茨海默氏病和某些其它神经变性疾病的过程中，这些蛋白质从微管解离，并且开始在脑的特定疾病相关区域中的神经元和神经胶质细胞的细胞体内聚集。这一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和相关额颞叶痴呆中，tau蛋白主要在特定的酪氨酸残基处被硝化;此外，tau蛋白也可以通过双酪氨酸键交联。我们建议使用生物化学建模研究来确定硝化在tau蛋白丝形成中的作用，并产生仅识别tau蛋白上特定硝化残基和双酪氨酸交联区域的抗体，用于在死于AD或其他tau蛋白病的患者的大脑中进行这一过程。具体来说，我们将：1。研究硝化对每个tau亚型组装的影响; 2.研究特定位点硝化的tau蛋白对正常tau蛋白组装的抑制作用; 3.使用免疫组织化学和激光扫描共聚焦显微镜与我们的特异性抗体对不同的硝化位点的tau蛋白，以评估在AD和其他tau蛋白病变的过程中硝化事件的时间和作用。我们还将生产针对tau蛋白上其他硝化位点的单克隆抗体，并在患病的大脑中对其进行评估;生产双酪氨酸交联tau的单克隆抗体，以确定AD和其他tau蛋白病过程中何时发生该事件。我们假设位点特异性tau硝化和二酪氨酸交联事件代表AD和其他tau蛋白病中纤维状病理形成和稳定的关键因素。这些研究的成功完成将大大有助于我们理解炎症在AD和其他tau蛋白病中的作用。公共卫生相关性：在阿尔茨海默病和相关痴呆症等疾病中，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内。这种聚集伴随着炎症过程，导致这些蛋白质在称为酪氨酸的氨基酸上发生改变。我们建议确定这些改变在疾病中的功能，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.