ALTERED PROTEIN KINASES IN ALZHEIMERS DISEASE

描述(研究人员摘要)：我们假设改变的蛋白质 磷酸化反应对神经元有害，并可能参与 在阿尔茨海默病(AD)的神经退行性变中。 现已公认，蛋白质的磷酸化是一种关键的生化反应。 调节细胞生长和细胞存活所需的反应。 因此，异常的磷酸化反应有可能起到 在神经元退行性变中起重要作用。有与年龄相关的 一些蛋白激酶的含量下降。因此，有可能 AD是一种与年龄相关的疾病，在AD中观察到的神经变性可能 至少部分可以通过改变蛋白质的磷酸化来解释 反应。在受影响的神经元中，有神经纤维缠结组成 细胞骨架蛋白，泛素，以及未知分子。 免疫组织化学研究表明，纠缠蛋白的成分 以及处于危险中的神经元中的蛋白质被过度磷酸化。我们的 体外磷酸化研究支持这样一种观点，即 在AD中，磷酸化级联反应异常。我们已经确定了 蛋白激酶C(PKC)、酪蛋白激酶II(CK-11)和蛋白酪氨酸 蛋白酪氨酸激酶(PTK)在AD中的变化。有趣的是，PKC的改变可能是 阿尔茨海默病与神经炎性斑块病理及CK-11变化的关系 神经原纤维缠绕病理。在目前的提案中，我们延长了这一点 用生物化学和生物化学方法研究它们的底物蛋白 免疫组织化学技术。此外，我们尝试确定一个 未知的蛋白激酶，其活性，用外源 组蛋白11-S在AD中升高，而磷蛋白P60在AD中表达增加。 通过AD胞浆的体外磷酸化发现。此外，有可能 CK-11和其他酶将使缠结成分t的磷酸化 被研究。这个项目的目的是把所有被改变的 蛋白质磷酸化分子参与AD的凝聚级联反应 病理学。为此，我们将研究各种不同的本地化 蛋白质磷酸化的成分。

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.