Aging and Dementia: Cholinergic neuron biochemistry

衰老与痴呆：胆碱能神经元生物化学

• 批准号: 7183517
• 负责人: PETER P DAVIES
• 金额: $ 33.85万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7183517
• 关键词: Aging; Alzheimer' s Disease; Amyloid beta-Protein; Binding; Biochemistry; Brain; Cell Culture System; Cell Death; Cells; Cultured Cells; Data; Dementia; Development; Event; Family; Genetic; Lead; Maps; Mediating; Molecular Conformation; Mus; Mutation; Pathology; Phosphorylation; Phosphotransferases; Process; Production; Protein Conformation; Protein Isoforms; Proteins; Reading; Receptor Protein-Tyrosine Kinases; Serine; Site; System; Testing; Threonine; Tissues; Tumor Necrosis Factor-alpha; Tyrosine Phosphorylation; Work; abeta deposition; amyloid precursor protein processing; cholinergic neuron; design; human TNF protein; immunocytochemistry; neurofibrillary tangle formation; novel strategies; novel therapeutics; presenilin; tau Proteins; tau conformation; tau interaction; tau phosphorylation; tau-1

DESCRIPTION (provided by applicant): This work is designed to build on our growing understanding of the mechanism by which tau becomes abnormal in Alzheimer's disease, and the critical factors that lead to tangle formation and cell death. We now seek to test new specific hypotheses regarding the mechanisms responsible for these events. Tyrosine phosphorylation of tau seems to be a very early event in AD, and the kinases responsible for these phosphorylations will be a major focus of this application. Mechanisms that can activate these kinases will also be examined to determine if associations with pathology can be demonstrated. New data on an apparent AD-specific phosphorylation of APP and the binding of Pin1 have suggested approaches to examination of the relationship between changes in APP processing and tau pathology. The specific aims are: 1. We will test the hypothesis that phosphorylation of tau on Y18 and/or 394 are candidates for production of conformational changes in tau in AD. Fyn and abl are the kinases that may be responsible for these phosphorylations, and the association of these proteins with tau pathology will be examined in detail. 2. The hypothesis that Abeta deposition triggers activation of src family kinases (and tyrosine phosphorylation of tau) has been proposed by others, and this will be tested in a rigorous fashion in the AD brain. The accumulation of pY18, fyn and abl with Abeta will be examined by immunocytochemistry using the same tissues employed in Aim 1. The possibility that Abeta effects on tyrosine phosphorylation of tau might be indirectly mediated through microglial production of TNF alpha will also be examined. 3. The interaction of tau with fyn and abl will be further examined in cultured cells. Cells will be transfected with specific tau isoforms along with fyn or abl. The hypothesis that tyrosine phosphorylation of tau causes conformational changes that may be sensitive to tau isoform composition will be tested. 4. We will test the hypothesis that changes in APP processing can induce changes in tau conformation and phosphorylation in cell culture systems selected to have a variety of tau isoform compositions. 5. Pin1 binds to both phosphorylated tau and phosphorylated APP, and both sites are phosphorylated in the AD brain. The hypothesis that Pin1 is involved in conformation changes of tau and perhaps in modifying APP processing will be tested. This work will help understand the process of AD, and help lead to new therapeutic strategies.

描述（由申请人提供）：这项工作旨在建立在我们对阿尔茨海默病中tau异常的机制以及导致缠结形成和细胞死亡的关键因素的日益了解的基础上。我们现在试图测试有关导致这些事件的机制的新的具体假设。tau蛋白的酪氨酸磷酸化似乎是AD的一个非常早期的事件，而负责这些磷酸化的激酶将是该应用的主要焦点。激活这些激酶的机制也将被研究，以确定是否与病理相关。关于ad特异性APP磷酸化和Pin1结合的新数据为研究APP加工变化与tau病理之间的关系提供了新的方法。具体目标是：1。我们将验证Y18和/或394上的tau磷酸化是AD中tau构象变化的候选假设。Fyn和abl是可能负责这些磷酸化的激酶，这些蛋白与tau病理的关联将被详细研究。2. 其他人已经提出了Abeta沉积触发src家族激酶激活（以及tau蛋白酪氨酸磷酸化）的假设，这将在AD大脑中以严格的方式进行测试。pY18、fyn和abl与Abeta的积累将通过免疫细胞化学检测，使用与Aim 1相同的组织。β对tau蛋白酪氨酸磷酸化的影响可能通过小胶质细胞产生TNF α间接介导的可能性也将被研究。3. tau与fyn和abl的相互作用将在培养细胞中进一步研究。细胞将与fyn或abl一起转染特定的tau亚型。酪氨酸磷酸化导致构象变化的假设可能对tau亚型组成敏感，这一假设将被检验。4. 我们将验证APP加工的变化可以诱导具有多种tau亚型组成的细胞培养系统中tau构象和磷酸化的变化的假设。5. Pin1结合磷酸化的tau蛋白和磷酸化的APP，这两个位点在AD大脑中都被磷酸化。Pin1参与tau构象改变并可能参与修改APP加工的假设将被验证。这项工作将有助于了解阿尔茨海默病的发病过程，并有助于开发新的治疗策略。