AMYLOID PROTEINS OF CEREBRAL MICROVESSELS IN AGING AND A

衰老过程中脑微血管的淀粉样蛋白

• 批准号: 3121994
• 负责人: RAJ N KALARIA
• 金额: $ 12.41万
• 依托单位: CASE WESTERN RESERVE 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 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3121994
• 关键词: Alzheimer's disease; SDS polyacrylamide gel electrophoresis; aging; amyloid proteins; basement membrane; brain circulation; cerebrovascular disorders; collagen; enzyme linked immunosorbent assay; human tissue; microcirculation; mucopolysaccharides; vascular endothelium; western blottings

DESCRIPTION (Investigator's Abstract): Cerebral amyloid angiopathy involving large and small vessels of the brain is common in Alzheimer's disease (AD), Down's syndrome and some related disorders. It is not known how amyloid deposits in the vessels. The long-range goal of this proposal is to elucidate the mechanisms by which amyloid deposition occurs in cerebral microvessels and arterioles in subjects with AD and related disorders, and to determine if such deposition is associated with abnormalities in the vasculature that may relate to the cause or contribute to the pathogenesis of AD. To address these questions, however, it is first vital to know the extent and rate at which amyloid deposition occurs in cerebral vessels during aging and disease and with what principal structures of the endothelium or vessel is the amyloid protein localized. The amyloid beta/A4 protein common to many diseases is derived from a membrane associated precursor protein (APP). Is this protein a normal constituent of the vessel, if so with which subcellular vascular compartment(s) is it associated and is there any evidence of differences in tissue-specific processing between AD subjects and aging controls? Furthermore, is vascular amyloid deposition related to changes in basement membrane components such as collagen IV or the glycosoaminoglycans of the cerebral endothelium? To investigate these issues, the investigators propose to employ relatively simple in vitro studies using biochemical and immunochemical methods on isolated cerebral capillaries and arterioles obtained postmortem from cortex of AD subjects and aged and young controls without evidence for neurological disease. Monoclonal and polyclonal antibodies to beta-protein and to various peptide fragments of APP will be used to probe immunoblots of vessel fractions and isolated vessel preparations. Assay of isolated vessels and their subcellular fractions will permit considerably better resolution of detection and metabolism of amyloid proteins than gained from this project will help in better understanding the pathogenesis of AD and related disorders and provide therapeutic approaches.

描述（研究者摘要）：脑淀粉样血管病 在阿尔茨海默氏症中， 疾病（AD）、唐氏综合征和一些相关疾病。 目前还不知道 淀粉样蛋白是如何在血管中沉积的 这项提案的长远目标是 是为了阐明淀粉样蛋白沉积发生的机制， AD及相关疾病受试者的脑微血管和小动脉 疾病，并确定这种沉积是否与 可能与病因有关的血管系统异常，或 有助于AD的发病机制。 为了解决这些问题， 然而，首先必须了解淀粉样蛋白的程度和速率， 沉积发生在脑血管老化和疾病， 淀粉样蛋白是内皮或血管的主要结构 蛋白定位 淀粉样β/A4蛋白在许多疾病中是常见的， 来源于膜相关前体蛋白（APP）。 这是 蛋白质是血管的正常成分，如果是这样，亚细胞 是否与血管腔室相关，是否有任何证据表明 AD受试者和衰老之间组织特异性加工的差异 控制？此外，血管淀粉样蛋白沉积是否与 在基底膜成分中，如胶原IV或 大脑内皮的糖胺聚糖 为了调查这些问题，调查人员建议雇用 使用生物化学和免疫化学的相对简单的体外研究 方法对分离的脑毛细血管和小动脉获得 AD受试者以及老年和年轻对照者的皮质尸检， 神经系统疾病的证据 单克隆和多克隆抗体 β-蛋白和APP的各种肽片段将用于 血管组分和分离的血管制备物的探针免疫印迹。 分离的血管及其亚细胞组分的测定将允许 淀粉样蛋白的检测和代谢的分辨率大大提高 从这个项目中获得的蛋白质将有助于更好地理解 AD和相关疾病发病机制，并提供治疗 接近。