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: 2516898
• 负责人: HENRY C. POWELL
• 金额: $ 31.18万
• 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 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2516898
• 关键词: Alzheimer's disease; Downs syndrome; X ray crystallography; amyloid proteins; brain disorder diagnosis; cerebrospinal fluid; cerebrovascular system; chemical structure function; enzyme mechanism; gel electrophoresis; histochemistry /cytochemistry; human tissue; immunochemistry; laboratory mouse; laboratory rabbit; monoclonal antibody; neuritic plaques; neurofibrillary tangles; peptidases; protein sequence; radioimmunoassay; serology /serodiagnosis; tissue /cell culture; urinalysis

One of the major objectives of the present study is to isolate the putative beta protein precursor(s) from Alzheimer's disease, Down's syndrome and normal sera, cerebrospinal fluid, urine or tissue and to define if chemical differences exist, i.e. an "amyloidogenic" isotype in Alzheimer's disease and Down's syndrome. The identification of such an isotype may lead to a specific diagnostic serum or CSF test for Alzheimer's disease by the use of a radioimmunoassay. Another major objective is to define the proteolytic enzyme characteristics of cerebral vessels that are implicated in the cleavage of beta protein precursor to form amyloid fibrils in cerebral vessel walls and those responsible for its proteolysis to form the amyloid fibrils of "senile" plaques, in order to define proteolytic enzyme differences between cerebral parenchymal cells, e.g. microglia, and endothelial cells, that may explain the differences in vessel and plaque amyloid fibril chemical composition. This study will utilize biochemical procedures extensively for the isolation and characterization of the vascular complement of lysosomal and other proteolytic enzymes. Organotypic endothelial cell cultures will also be employed in this investigation. In the absence of a chemically characterized native amyloid beta protein precursor, the beta protein gene product and its hydrolytic cleavage derivatives will be used as enzyme substrates. The ultimate purpose of this study is to develop reagents selective for the inhibition of cerebral amyloid fibril formation by the prevention of beta protein precursor hydrolysis and, thus, lead to an approach to the therapy of Alzheimer's disease. In addition in vitro radioautographic receptor binding methods will be employed to determine whether the immunohistochemical definition of the beta protein precursor as a receptor-binding protein can be verified. A final objective is to define by chemical, immunochemical and immunohistochemical methods the nature and origin of the paired helical filaments of the neurofibrillary tangles in Alzheimer's disease.

本研究的主要目标之一是分离出 来自阿尔茨海默病、唐氏病的推定β蛋白前体 综合症与正常血清、脑脊液、尿液或组织以及 以确定是否存在化学差异，即“淀粉样蛋白生成” 阿尔茨海默病和唐氏综合征中的同种型。 的 这种同种型的鉴定可导致特异性的 阿尔茨海默病的诊断血清或CSF测试 使用放射免疫测定法。 另一个主要目标 是 到 定义蛋白水解酶的特性 参与β分裂的脑血管 脑血管壁中形成淀粉样纤维的蛋白质前体 以及负责其蛋白水解形成淀粉样蛋白的酶 “老年”斑的纤维，以确定蛋白水解酶 脑实质细胞（例如小胶质细胞）之间的差异，以及 内皮细胞，这可能解释了血管和 斑块淀粉样纤维的化学组成。 本研究将 广泛利用生物化学方法进行分离， 溶酶体和其他血管补体的表征 蛋白水解酶 器官型内皮细胞培养将 也会参与到这次调查中 在没有 化学表征的天然淀粉样β蛋白前体， β蛋白基因产物及其水解裂解衍生物 将用作酶底物。这样做的最终目的 研究的目的是开发选择性抑制 通过β蛋白阻止脑淀粉样纤维形成 前体水解，从而导致治疗方法 老年痴呆症的症状。 此外，体外放射自显影 受体结合方法将被用来确定是否 免疫组织化学将β蛋白前体定义为 可以验证受体结合蛋白。 最后一个目标是 通过化学、免疫化学和免疫组织化学方法确定 的性质和起源的成对螺旋丝的 阿尔茨海默病的神经系统缠结