ALZHEIMER AMYLOID B AND THE AGED CEREBRAL VESSEL WALL

淀粉样蛋白（Abeta）是沉积在阿尔茨海默氏症大脑血管和实质斑块中的淀粉样蛋白原纤维的主要成分，通常也作为可溶性成分（sAbeta）存在于生物体液中，与脂蛋白颗粒一起运输（90%以上）。虽然与β同源的多肽在体外自发聚合，但循环可溶性形式对沉积的β的潜在贡献仍然未知。已经证明血脑屏障有能力调节β的摄取，并且β与载体载脂蛋白E和J的相互作用分别导致阻止或增强脑摄取。此外，在阿尔茨海默病和唐氏综合征脑匀浆的可溶组分中发现了β β含量的增加，这种升高似乎先于β β沉积的出现。本提案的总体目标是研究循环β肽在衰老、阿尔茨海默病和相关疾病中观察到的血管病理中的作用。sAbeta翻转的生理方面的知识，其中包括肽在循环中的半衰期，它与循环转运分子的相互作用，参与其分解代谢和/或排泄的器官和脑血管壁摄取的脑血管细胞受体，以及这些生理参数在病理情况下如何被调节，必将有助于更好地理解导致血管和实质淀粉样蛋白沉积形成的机制。该项目概述的四个具体目标集中在a)识别脑内皮细胞中游离和络合Abeta物种的细胞受体（目标1），b)研究循环中游离和络合Abeta物种的半衰期，并确定其分解代谢和/或排泄的系统位置（目标2）。c)确定载体脂质的氧化是否有利于络合不平衡，从而释放游离的β或形成氧化的β（目的3），d)阐明目的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到损害（目的4）。

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).