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: 2049272
• 负责人: HENRY C. POWELL
• 金额: $ 28.74万
• 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 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2049272
• 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.

本研究的主要目的之一是分离