AMYLOID PRECURSOR PROTEIN (APP) AND ALZHEIMER'S DISEASE

淀粉样前体蛋白 (APP) 与阿尔茨海默病

• 批准号: 3122518
• 负责人: MERRILL D BENSON
• 金额: $ 28.12万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-01 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3122518
• 关键词: Alzheimer's disease; amyloid proteins; disease /disorder proneness /risk; gene expression; gene mutation; genetic disorder; human subject; messenger RNA; molecular cloning; nucleic acid hybridization; nucleic acid sequence; phenylalanine; polymerase chain reaction; protein sequence; protein structure function; radiotracer; valine

The overall objective of this proposal is to understand the role of the amyloid precursor protein (APP) in the pathogenesis of amyloid deposition in Alzheimer's disease (AD). AD which is characterized by deposition of amyloid fibrils in neuritic plaques, cerebral vascular amyloidosis, and neurofibrillary tangles within neurons is one of the most common causes of dementia. While most cases of AD are sporadic, a significant number of individuals are members of kindreds in which AD is inherited as an autosomal dominant trait. The availability of these families allows for study of AD in a controlled manner which may provide insight into pathogenesis. In preliminary studies we have identified a mutation in the APP gene in individuals with early onset hereditary AD. This mutation results in a substitution of phenylalanine for valine in the transmembrane domain of APP. We have been able to show inheritance of this mutation and segregation with Alzheimer's disease. We propose to study the pathogenesis of AD in this family using both molecular biology and protein chemistry techniques. Specific aims include: 1) complete characterization of the Val to Phe mutation by developing a DNA test to screen individuals at risk, determine prevalence of the mutation in the extended family, and complete the sequence of coding regions of the APP gene in the affected proband; 2) extend the studies to other individuals with Alzheimer's disease both familial and sporadic; 3) isolate amyloid subunit protein from an affected member of this kindred and verify the size of the subunit protein to determine whether the mutation is incorporated into the fibrils; 4) study expression of the APP mutant. These specific aims are formulated to test the hypothesis that this APP mutation is a direct cause of amyloid deposition and presenile dementia in this family. These studies may elucidate factors in pathogenesis that may have application to other forms of Alzheimer's disease.

本建议的总体目标是了解 淀粉样前体蛋白在淀粉样沉积发病机制中的作用 阿尔茨海默病（AD）。 AD的特征是沉积 神经炎斑块中的淀粉样纤维，脑血管淀粉样变性， 神经元内的神经纤维缠结是导致神经元损伤的最常见原因之一。 痴呆 虽然大多数AD病例是散发性的，但相当数量的 个体是运动神经元的成员，其中AD作为一种遗传因子被遗传。 常染色体显性性状 这些家庭的可用性允许 以受控方式研究AD，这可能会提供有关以下方面的见解 发病机制 在初步研究中，我们已经确定了APP基因的突变， 早发性遗传性AD患者。 该突变导致 苯丙氨酸取代缬氨酸的跨膜结构域 附录 我们已经能够证明这种突变的遗传性， 与老年痴呆症隔离。 我们建议研究AD的发病机制，在这个家庭使用这两个 分子生物学和蛋白质化学技术。 具体目标包括： 1)通过开发一种DNA，完整表征瓦尔至Phe突变 测试筛选个体的风险，确定突变的患病率， 该大家族，并完成APP的编码区序列 先证者的基因; 2）将研究扩展到其他个体 家族性和散发性阿尔茨海默病; 3）分离淀粉样蛋白 亚基蛋白质，并验证大小 以确定突变是否被掺入 4）研究APP突变体的表达。 这些具体 目的是制定测试的假设，这种APP突变是一个 淀粉样蛋白沉积和早老性痴呆的直接原因。 这些研究可能阐明发病机制中的因素， 应用于其他形式的阿尔茨海默病。