CEREBROVASCULAR AMYLOID PROTEIN IN ALZHEIMER'S DISEASE

本研究的主要目标之一是分离出 唐氏症阿尔茨海默病可能的β蛋白前体(S) 综合征和正常血清、脑脊液、尿液或组织 以确定是否存在化学差异，即“淀粉样变性” 阿尔茨海默病和唐氏综合症的同型。这个 这种同种类型的鉴定可能导致特定的 阿尔茨海默病的诊断血清或脑脊液测试 放射免疫分析的使用。另一个主要目标是 确定蛋白水解酶的特性 与β-肌动蛋白裂解有关的脑血管 脑血管壁形成淀粉样纤维的蛋白质前体 以及负责其蛋白质分解形成淀粉样蛋白的那些 “老年”斑块的纤维，以确定蛋白水解酶 脑实质细胞，如小胶质细胞和 内皮细胞，这可能解释了血管和血管的不同 斑块中淀粉样原纤维的化学成分。这项研究将 广泛使用生化程序进行分离和鉴定 溶酶体等的血管补体的特性 蛋白水解酶。器官型内皮细胞培养将 也将受雇于此次调查。在缺少 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酶切衍生物 将被用作酶底物。这样做的最终目的是 研究目的是开发选择性抑制细菌生长的试剂。 β蛋白对脑淀粉样原纤维形成的抑制作用 前体的水解，从而导致了一种治疗方法 阿尔茨海默氏症。此外，体外放射自显影 将采用受体结合的方法来确定 β蛋白前体的免疫组织化学定义为 可以验证受体结合蛋白。最终目标是 通过化学、免疫化学和免疫组织化学方法定义 成对的螺旋丝的性质和起源 阿尔茨海默病中的神经原纤维缠绕。

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.