AMYLOID PROTEINS OF CEREBRAL MICROVESSELS IN AGING

描述(研究人员摘要)：脑淀粉样血管病 阿尔茨海默病患者常累及脑部大小血管 阿尔茨海默病(AD)、唐氏综合征及相关疾病。目前尚不清楚 血管中淀粉样蛋白是如何沉积的。这项提议的长远目标是 是为了阐明淀粉样蛋白沉积发生的机制。 阿尔茨海默病及相关疾病患者脑微血管和小动脉的研究 紊乱，并确定这种沉积是否与 血管系统的异常，可能与病因或 参与阿尔茨海默病的发病。为了解决这些问题， 然而，首先要知道淀粉样蛋白的程度和比率。 在衰老和疾病期间，脑血管中会发生沉积 淀粉样蛋白是血管内皮或血管的主要结构 蛋白质定位。许多疾病常见的淀粉样β/A4蛋白是 来源于膜相关前体蛋白(APP)。是这个吗 蛋白质是血管的正常成分，如果是这样，与哪个亚细胞一起 血管间隔(S)有关联吗？有没有证据表明 阿尔茨海默病患者与衰老患者组织特异性加工的差异 控制系统？此外，血管淀粉样蛋白沉积是否与变化有关？ 在基底膜成分中，如IV型胶原或 脑血管内皮细胞的糖胺多聚糖？ 为了调查这些问题，调查人员建议聘请 使用生化和免疫化学进行相对简单的体外研究 离体脑毛细血管和小动脉的获取方法 阿尔茨海默病受试者和非阿尔茨海默病患者的老年人和年轻人的大脑皮质的尸检 神经系统疾病的证据。单抗和多克隆抗体 到β蛋白和APP的各种多肽片段将被用于 血管部分和分离的血管制剂的探针免疫印迹。 分离的血管及其亚细胞部分的分析将允许 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 阿尔茨海默病的发病机制及相关疾病的治疗 接近了。

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.