AMYLOID PRECURSOR IN ALZHEIMER DISEASE

描述：(改编自申请人的摘要) 1986年末淀粉样前体蛋白(APP)基因的克隆 APP的测序和鉴定已经成为可能，重要性 APP在阿尔茨海默病(AD)发病机制中的作用 未知。在上一个供资期间，几种免疫化学和 本实验室生产并使用生化探针得出结论 神经元是老年斑APP的主要来源，老年斑是 淀粉样蛋白沉积。他们认为这些发现是直接相关的 对他们最初的假设：神经元内细胞骨架的变化 AD的神经纤维性病理(NFP)是 APP与细胞质的相互作用。NFP包含的发现 丰富的硫酸肝素蛋白多糖(HSPG)为它们提供了化学基础 对于这种结合，因为APP是一种ASPG结合蛋白。装订中 研究发现，许多NFP成分特别与 应用程序累积。因此，支持这一假设的是 NFP组件通过相互绑定结合在一起。在 目前的建议，他们将通过以下方式扩展这些研究 目标：(1)将NFP的生物化学定义为 以及传统的生化特性；(2)确定HSPG是否 与其他疾病的NFP相关；(3)确定 阿尔茨海默病患者和对照组神经元性改变与淀粉样蛋白沉积的关系 大脑；(4)通过大脑研究APP在大脑中的梯度效应 APP和B蛋白的植入；(5)NFP表位的物理映射。

DESCRIPTION: (Adapted from the applicant's abstract) Although with the cloning of the cDNA for the amyloid precursor protein (APP) in late 1986 the sequences and identification of APP have been possible, the importance of APP in the pathogenesis of Alzheimer Disease (AD) is essentially unknown. During the previous funding period, several immunochemical and biochemical probes were produced and used by this laboratory to conclude that neurons are the major source of APP in the senile plaque, the site of the amyloid deposition. They suggest these findings are directly relevant to their original hypothesis: that the intraneuronal cytoskeletal changes of AD, neurofibrillary pathology (NFP), is a direct result of the interaction of APP with the cytoskelton. The finding that NFP contains abundant heparin sulfate proteoglycans (HSPG) gave them a chemical basis for this binding, since APP is an ASPG binding protein. In binding studies, they found that many NFP components specifically associate with APP accumulations. Support was therefore found for the hypothesis that NFP components are incorporated through reciprocal binding. In the present proposal, they will extend these studies through the following aims: (1) Binding studies that will define NFP's biochemistry in situ as well as traditional biochemical properties; (2) determine whether HSPG's are associated with the NFP's of other diseases; (3) determine the relationship of neuritic change to amyloid deposition in AD and control brains; (4) study the effect of APP gradients in the brain through brain implants of APP and B-protein; (5) physical mapping of NFP epitopes.