Aging and Dementia: Cholinergic neuron biochemistry

衰老与痴呆：胆碱能神经元生物化学

• 批准号: 7772363
• 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 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7772363
• 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）：这项工作旨在建立我们对Tau在阿尔茨海默氏病异常异常的机制的不断理解的基础上，以及导致纠缠形成和细胞死亡的关键因素。现在，我们试图测试有关这些事件的机制的新特定假设。 Tau的酪氨酸磷酸化似乎是AD的早期事件，负责这些磷酸化的激酶将是该应用的主要重点。还将检查可以激活这些激酶的机制，以确定是否可以证明与病理的关联。有关APP明显的AD特异性磷酸化和PIN1结合的新数据，提出了检查应用程序处理变化与TAU病理学之间关系的方法。具体目的是：1。我们将检验以下假设：y18和/或394在y18和/或394上的磷酸化是用于产生AD中Tau构象变化的候选者。 Fyn和ABL是可能导致这些磷酸化的激酶，这些蛋白质与TAU病理学的关联将进行详细检查。 2。假设Abeta沉积会触发SRC家族激酶的激活（和TAU的酪氨酸磷酸化），这是其他人提出的，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AIM 1中使用的相同组织进行免疫细胞化学研究。可能还会检查ABETA对TAU酪氨酸磷酸化的影响可能通过TNF Alpha的小胶质细胞产生而间接介导的Abeta对Tau的磷酸化的可能性。 3。将在培养的细胞中进一步研究TAU与FYN和ABL的相互作用。细胞将用特定的TAU同工型与FYN或ABL一起转染。 TAU的酪氨酸磷酸化引起可能对Tau同工型组成敏感的构象变化的假设将被测试。 4。我们将检验以下假设：应用程序处理的变化可以诱导被选为具有多种TAU同工型组成的细胞培养系统中Tau构象和磷酸化的变化。 5。PIN1与磷酸化的TAU和磷酸化的应用结合，并且两个位点在AD脑中均磷酸化。将测试PIN1参与TAU构象变化以及修改应用程序处理的假设。这项工作将有助于了解广告的过程，并帮助导致新的治疗策略。