ALTERED PROTEIN KINASES IN ALZHEIMERS DISEASE

阿尔茨海默病中蛋白质激酶的改变

• 批准号: 2050105
• 负责人: TSUNAO SAITOH
• 金额: $ 19.43万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2050105
• 关键词: Alzheimer's disease; SDS polyacrylamide gel electrophoresis; amyloid proteins; annexins; casein kinase; caseins; cell death; confocal scanning microscopy; histones; human tissue; immunocytochemistry; neural growth associated protein; neurofibrillary tangles; neurons; paired helical filament; phosphoproteins; phosphorylation; protein kinase; protein purification; spectrin; tau proteins; western blottings

DESCRIPTION (Investigator's Abstract): We hypothesize that altered protein phosphorylation reactions are deleterious to neurons and might be involved in neurodegeneration in Alzheimer's disease (AD). It is now well recognized that protein phosphorylation is a key biochemical reaction required for the regulation of cell growth and cell survival. Thus, it is possible that aberrant phosphorylation reactions play an important role in the neuronal degeneration. There are age-associated declines of some protein kinases. Therefore, it is possible that the neurodegeneration observed in AD which is an age-associated disease, might be at least partly explained by the altered protein phosphorylation reactions. In affected neurons, there are neurofibrially tangles composed of cytoskeletal proteins, ubiquitin, and still unknown molecules. Immunohistochemical studies have revealed that the constituents of tangles as well as proteins in neurons at risk are excessively phosphorylated. Our in vitro phosphorylation study has supported the notion that the phosphorylation cascade reactions are aberrant in AD. We have identified protein kinase C (PKC), casein kinase II (CK-ll), and protein tyrosine kinase (PTK) as altered in AD. Interestingly, PKC alteration might be associated with neuritic plaque pathology in AD and CK-ll alteration with neurofibrillary tangle pathology. In the current proposal, we extend this study to their substrate proteins employing biochemical and immunohistochemical techniques. Furthermore, we attempt to identify an unknown protein kinase, the activity of which, measured with exogenous histone lll-S, is increased in AD, and a phosphoprotein, P60, which was found by in vitro phosphorylation of AD cytosol. In addition, possible phosphorylation of t, a tangle constituent, by CK-ll and other kinases will be studied. The purpose of the project is to pull all the altered molecules of protein phosphorylation into a cohesive cascade of AD pathology. To this end, we will study the localization of various components of protein phosphorylation.

描述（研究者摘要）：我们假设改变了蛋白质 磷酸化反应对神经元有害，可能涉及 阿尔茨海默病 (AD) 中的神经退行性疾病。 现在人们普遍认识到蛋白质磷酸化是一个关键的生化过程。 调节细胞生长和细胞存活所需的反应。 因此，异常的磷酸化反应可能会发挥作用 在神经元变性中起重要作用。 有与年龄有关的 一些蛋白激酶的下降。 因此，有可能 AD 中观察到的神经变性是一种与年龄相关的疾病，可能 至少部分可以通过蛋白质磷酸化的改变来解释 反应。 在受影响的神经元中，存在由神经原纤维缠结组成的 细胞骨架蛋白、泛素和仍然未知的分子。 免疫组织化学研究表明，缠结的成分 以及处于危险中的神经元中的蛋白质过度磷酸化。 我们的 体外磷酸化研究支持了这样的观点： AD 中的磷酸化级联反应是异常的。 我们已经确定 蛋白激酶 C (PKC)、酪蛋白激酶 II (CK-ll) 和蛋白酪氨酸 激酶 (PTK) 在 AD 中发生改变。 有趣的是，PKC 改变可能是 与 AD 中的神经炎斑块病理学和 CK-ll 改变相关 神经原纤维缠结病理学。 在当前的提案中，我们扩展了这一点 利用生物化学和方法研究其底物蛋白 免疫组织化学技术。 此外，我们试图确定一个 未知的蛋白激酶，其活性通过外源性测定 组蛋白 III-S 在 AD 中增加，磷蛋白 P60 在 AD 中增加 通过 AD 细胞质的体外磷酸化发现。 此外，还可以 t（一种缠结成分）被 CK-ll 和其他激酶磷酸化 被研究。 该项目的目的是拉动所有改变的 蛋白质磷酸化分子形成 AD 的内聚级联 病理。 为此，我们将研究各种本土化 蛋白质磷酸化的组成部分。