CEREBROVASCULAR AMYLOID PROTEIN IN ALZHEIMER'S DISEASE

阿尔茨海默病中的脑血管淀粉样蛋白

• 批准号: 3116390
• 负责人: GEORGE G GLENNER
• 金额: $ 15.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-30 至 1988-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3116390
• 关键词: Alzheimer's disease; Downs syndrome; X ray crystallography; amyloidosis; biomedical resource; blood brain barrier; body fluids; cerebrovascular disorder diagnosis; cerebrovascular system; computer data analysis; electron microscopy; gel electrophoresis; high performance liquid chromatography; histochemistry /cytochemistry; human tissue; mental disorder diagnosis; monoclonal antibody; neurofibrillary tangles; postmortem; radioimmunoassay

Alzheimer's disease (SDAT) is the fourth most common cause of death in the U.S. affecting over 2 million people. It represents 60% of all cases of senile dementia, but no specific diagnostic test for it, short of brain biopsy, is available to avoid misdiagnosis of treatable dementias. Of SDAT patients 92% have been found at autopsy to have cerebrovascular amyloidosis (Congophilic angiopathy). These fibrillar vascular deposits are presumed to have a deleterious effect by making incompetent the blood-brain barrier. It is suggested that they may, therfore, be causal in the pathogenesis of the neurofibrillary tangles and neuritic plaques characteristic of SDAT. The proposed research is directed at determining the chemical nature of the cerebrovascular amyloid fibrils in this condition by isolation, solubilization, fractionation and analytical methods, e.g. amino acid sequence analysis, previously utilized by the applicant to define the protein composition of the fibrils in acquired systemic "primary" amyloidoses. Utilization of these methods should define the fibril protein chemically, but may not elucidate its origin. Monoclonal antibodies raised to the fibril protein will be employed in double immunodiffusion, radioimmunoassay and immunohistochemical techniques to determine the fibril proteinis/ origin and to quantitate the level of the protein precursor in tissue and body fluids for potential diagnostic purposes. These antibodies will also be employed for immunoabsorbant chromatography to isolate the fibril precursor protein (presumed to be of serum origin) and to characterize it chemically. These studies will determine the mechanism of fibril formation, e.g. if a lysosomal defect in the endothelial processing of the fibril protein precursor causes the amyloid deposits. Evidence of either a cerebrovascular enzymic defect in processing of the fibril precursor or the existence of a protein synthetic abnormality may lead to therapeutic approaches to arrest the course of SDAT. The recent finding of cerebrovascular amyloidosis, in addition to plaques and tangles, in 100% of Down's syndrome adults may indicate that they may be a predictable model for SDAT. Therefore, the above studies will also be performed on tissues and body fluids from such Down's cases. The uniqueness of this investigation is that it focuses on the amyloid angiopathy of SDAT in order to determine the nature of the amyloid fibril protein and its pathogenesis, but more importantly it has the potential to define a specific diagnostic serum test for SDAT and to lead directly to an understanding of its etiology and pathogenesis.

阿尔茨海默病（SDAT）是第四大常见的死亡原因， 美国影响了两百多万人 它代表了所有病例的60%， 老年痴呆症，但没有具体的诊断测试，缺乏大脑 活检，可避免误诊可治疗的痴呆症。 系统动态性思维 尸检发现92%的患者患有脑血管淀粉样变性 （Congophilic angiopathy）。 推测这些纤维状血管沉积物 通过使血脑功能不全而产生有害影响 屏障 有人建议，他们可能，因此，在因果关系， 神经纤维缠结和神经炎性斑块的发病机制 SDAT的特点。 该研究旨在确定 脑血管淀粉样纤维的化学性质 通过分离、溶解、分级和分析条件 方法，如氨基酸序列分析，以前使用的 申请人定义了获得性纤维中的蛋白质组成， 全身性“原发性”淀粉样变性。 这些方法的使用应定义 原纤维蛋白的化学，但可能无法阐明其来源。 针对原纤维蛋白产生的单克隆抗体将用于 免疫双扩散、放射免疫分析和免疫组织化学技术 以确定原纤维蛋白质/来源并定量 组织和体液中用于潜在诊断的蛋白质前体 目的 这些抗体也将用于免疫吸附剂。 通过色谱法分离原纤维前体蛋白（推测为 血清来源）并对其进行化学表征。 这些研究将 确定原纤维形成的机制，例如， 原纤维蛋白前体的内皮加工导致 淀粉样沉积物 脑血管酶缺陷的证据 原纤维前体的加工或蛋白质合成物的存在 异常可能导致治疗方法，以阻止过程中， SDAT。 脑血管淀粉样变性的最新发现，除了 在100%的唐氏综合征成人中出现斑块和缠结可能表明， 它们可能是SDAT的可预测模型。 因此，上述研究 也将在唐氏病例的组织和体液上进行。 这项研究的独特之处在于它关注淀粉样蛋白 SDAT的血管病，以确定淀粉样纤维的性质 蛋白质及其发病机制，但更重要的是，它有可能 定义SDAT的特定诊断血清测试，并直接导致 了解其病因和发病机制。