ALZHEIMERS DISEASE AND AMYLOID PROTEINS

阿尔茨海默病和淀粉样蛋白

• 批准号: 2052181
• 负责人: BLAS FRANGIONE
• 金额: $ 78.37万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2052181
• 关键词: Alzheimer's disease; amyloid proteins

The amyloid of neurodegenerative diseases like Alzheimer's Disease (AD) and related disorders in man is derived by proteolysis of a large membrane precursor protein (APP). Our central interest lies in the apparent link between neurodegeneration and amyloidogenic proteins, and the determination of the factors that initiate and perpetuate amyloid formation. Our working hypothesis is that genetic variant(s) and/or some aberrant posttranslational modification of Alzheimer's APP causes structural/conformational modifications. Proteins thus altered may strongly resist proteolytic attack, and/or they may undergo abnormal degradation. These protease-resistant cleavage peptides with strong tendency to aggregate may bind to other cellular or serum components, thus facilitating polymerization and fibril formation. The most likely pathological cascade for AD, then, is: amyloid deposition, neurofibrillary tangle formation and neuronal death. Better biochemical understanding of this pathological process in human and in animal models would facilitate therapeutic intervention. The Specific Aims of this LEAD award application are: i) The biochemical and immunohistochemical characterization of amyloid proteins and preamyloid lesions from familial and sporadic AD and Hereditary Cerebral Hemorrhage with Amyloidosis, Dutch type (HCHWA-D) (PROJECT 1). ii) The mechanisms of amyloid formation: to study the influence of the known mutations of the APP gene and amyloid associated proteins on fibril formation using synthetic peptides and the 16-19 kDa APP fragments produced by alternative degradation pathways. Therapeutic approaches to inhibit fibrillogenesis will be evaluated in transgenic mice (PROJECT 2). iii) The study of the alternative processing and biological properties of APP (PROJECT 3).. iv) The identification of mutations of the APP gene in families with early onset FAD and the construction of an animal model: transgenic mice harboring the human APP gene with the different mutations (PROJECT 4). v) The characterization of a novel type of familial cerebrovascular amyloidosis with dementia in British patients that is not related to other known types.

神经退行性疾病（如阿尔茨海默氏病（AD）和 大膜的蛋白水解得出了人类的相关疾病 前体蛋白（APP）。 我们的核心利益在于明显的链接 神经变性和淀粉样蛋白蛋白与测定之间 引发和永久形成的因素。 我们的工作 假设是遗传变异和/或某些异常 阿尔茨海默氏症应用程序的翻译后修改原因 结构/构象修饰。 蛋白质因此改变可能 强烈抵抗蛋白水解攻击和/或它们可能发生异常 降解。 这些抗蛋白酶的切割肽具有强 聚集的趋势可能与其他细胞或血清成分结合，因此 促进聚合和原纤维形成。 最有可能的 因此，AD的病理级联反应是：淀粉样蛋白沉积，神经纤维 缠结形成和神经元死亡。 对生化的更好理解 人类和动物模型中的病理过程将有助于 治疗干预。 该领先奖项申请的具体目的是：i）生化 淀粉样蛋白和前蛋白的免疫组织化学表征 家族和零星广告的病变以及遗传性脑出血 与淀粉样变性，荷兰人类型（HCHWA-D）（项目1）。 ii）机制 淀粉样蛋白形成：研究已知突变的影响 使用纤维形成的APP基因和淀粉样蛋白相关蛋白使用 合成肽和16-19 KDA应用片段由替代品产生 退化途径。 抑制原纤维发生的治疗方法 将在转基因小鼠中进行评估（项目2）。 iii）研究 应用程序的替代处理和生物学特性（项目3）.. IV） 早期家庭中应用基因突变的鉴定 FAD和动物模型的结构：转基因小鼠 带有不同突变的人类应用基因（项目4）。 v） 一种新型家族性脑血管的表征 英国患者的淀粉样变性与痴呆症无关 已知类型。