ALZHEIMER AMYLOID B AND THE AGED CEREBRAL VESSEL WALL

阿尔茨海默病淀粉样蛋白 B 与老年脑血管壁

• 批准号: 6330601
• 负责人: JORGE A GHISO
• 金额: $ 25.73万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-25 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6330601
• 关键词: Alzheimer's disease; amyloid proteins; apolipoprotein E; apolipoproteins; brain circulation; clusterin; human tissue; laboratory mouse; molecular pathology; oxidized lipid; protein metabolism; protein transport; vascular endothelium; vascular endothelium permeability

Amyloid beta (Abeta), the major constituent of the amyloid fibrils deposited in cerebral blood vessels and parenchymal plaques Alzheimer s brains, is also normally found as a soluble component (sAbeta) in biological fluids, where it appears to be transported (greater than 90 percent) in association with lipoprotein particles. Although peptides homologous to sAbeta spontaneously polymerize in vitro, the potential contribution of the circulating soluble forms to the deposited Abeta remains unknown. It has been demonstrated that the blood brain barrier has the capability to modulate the uptake of Abeta species and that the interaction of Abeta with carrier apolipoproteins E and J results in either prevention or enhancing of the brain uptake respectively. In addition, an increased amount of sAbeta was found in soluble fractions of Alzheimer s disease and Down s syndrome brain homogenates, and this elevation appears to precede the appearance of Abeta deposits. The overall goal of this proposal is to investigate the contribution of circulating Abeta peptides to the vascular pathology observed in aging, Alzheimer s disease and related disorders. The knowledge of physiologic aspects of sAbeta turn-over, among them the peptide s half-life in circulation, its interaction(s) with circulating transport molecules, the organs involved in its catabolism and/or excretion and the putative cerebrovascular cell receptors responsible for its uptake by the cerebral vessel wall as well as how these physiologic parametes are modulated under pathologic situations will certainly contribute to better understanding of the mechanism(s) leading to the formation of vascular and perhaps parenchymal amyloid deposits. The four specific aims outlined in the project are focused a) to identify cell receptors for free and complexed Abeta species in cerebral endothelial cells (aim 1), b) to investigate the half- life of free and complexed Abeta species in circulation as well as to determine their systemic sites of catabolism and/or excretion (aim 2), c) to ascertain whether oxidation of the carrier lipoparticle may favor complexdisequilibrium resulting either in the release of free sAbeta or in the formation of oxidized Abeta (aim 3), and d) to clarify whether the physiologic variables evaluated in aims 1 and 2 are compromised in aging and Alzheimer s disease (aim 4).

淀粉样蛋白β（Abeta），淀粉样蛋白纤维的主要成分沉积在脑血管和实质斑块阿尔茨海默氏症的大脑，也通常被发现作为可溶性成分（sAbeta）在生物液体中，它似乎是运输（大于90%）与脂蛋白颗粒。 尽管与sAbeta同源的肽在体外自发地降解，但循环可溶形式对沉积的Abeta的潜在贡献仍然未知。 已经证明血脑屏障具有调节Abeta种类的摄取的能力，并且Abeta与载体载脂蛋白E和J的相互作用分别导致脑摄取的预防或增强。 此外，在阿尔茨海默病和唐氏综合征脑匀浆的可溶性组分中发现sAbeta的量增加，并且这种升高似乎先于Abeta沉积物的出现。 本提案的总体目标是研究循环Abeta肽对衰老、阿尔茨海默病和相关疾病中观察到的血管病理学的贡献。 sAbeta转换的生理学方面的知识，其中包括肽在循环中的半衰期，其与循环转运分子的相互作用，参与其catelation的器官和/或排泄和负责脑血管壁摄取的假定脑血管细胞受体以及这些生理参数在病理情况下如何调节肯定有助于更好地理解导致血管和可能的实质淀粉样沉积物形成的机制。该项目中概述的四个具体目标集中在a）鉴定脑内皮细胞中游离和复合的A β种类的细胞受体（目标1），B）研究循环中游离和复合的A β种类的半衰期以及确定它们的全身性代谢和/或排泄部位（目标2），c）确定载体脂质颗粒的氧化是否可能有利于复合物不平衡，导致游离sAbeta的释放或氧化Abeta的形成（目的3），以及d）澄清在目标1和2中评估的生理变量是否在衰老和阿尔茨海默病中受损（目标4）。