ALTERED PROTEIN KINASES IN ALZHEIMERS DISEASE

描述（研究者摘要）：我们假设改变的蛋白质 磷酸化反应对神经元有害， 阿尔茨海默病（AD）的神经退行性变。 现在已经很好地认识到，蛋白质磷酸化是一个关键的生化反应， 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是导致细胞凋亡的原因之一。 在神经元变性中起重要作用。 与年龄相关的 一些蛋白激酶的下降。 因此，有可能 AD是一种与年龄相关的疾病， 至少部分可以用蛋白质磷酸化的改变来解释 反应. 在受影响的神经元中，有神经纤维缠结， 包括细胞骨架蛋白、泛素和未知分子。 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被过度磷酸化。 我们 体外磷酸化研究支持了这样的观点， 磷酸化级联反应在AD中异常。 我们已经确定 蛋白激酶C（PKC）、酪蛋白激酶II（CK-II）和蛋白酪氨酸 在AD中改变的PTK。 有趣的是，PKC的改变可能是 与AD中神经炎斑块病理学和CK-II改变相关， 神经缠结病理学 在目前的提案中，我们将此 利用生物化学和生物信息学方法对其底物蛋白进行研究， 免疫组织化学技术。 此外，我们试图找出一个 未知蛋白激酶，其活性用外源性 组蛋白III-S在AD中增加，而磷蛋白P60在AD中增加。 通过AD胞质溶胶的体外磷酸化发现。 此外，可能 由CK-11和其它激酶引起的t（缠结成分）的磷酸化将 被研究。 这个项目的目的是把所有改变了的 蛋白质磷酸化分子转化为AD的内聚级联反应 病理 为此，我们将研究各种 蛋白质磷酸化的组成部分。

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.