ALZHEIMER AMYLOID B AND THE AGED CEREBRAL VESSEL WALL

淀粉样β蛋白(Abeta)是沉积在脑血管和阿尔茨海默病S脑实质斑块中的淀粉样纤维的主要成分，通常也以可溶性成分(SAbeta)的形式存在于生物体液中，在生物体液中似乎与脂蛋白颗粒一起运输(超过90%)。虽然与sAβ同源的多肽在体外自发聚合，但循环中的可溶性形式对沉积的Aβ的潜在贡献尚不清楚。已证实血脑屏障具有调节Abeta物种摄取的能力，Abeta与载体载脂蛋白E和J的相互作用分别导致脑摄取的抑制或增强。此外，在阿尔茨海默病、S病和S综合征患者的脑组织匀浆中，发现sAbeta的含量增加，而且这种升高似乎先于Abeta沉积的出现。这项建议的总体目标是调查循环中的Aβ多肽在衰老、阿尔茨海默病、S病和相关疾病中观察到的血管病理的贡献。了解sAβ翻转的生理方面，其中包括肽S在循环中的半衰期，它与循环中转运分子的相互作用(S)，参与其分解代谢和/或排泄的器官，负责它被脑血管壁摄取的可能的脑血管细胞受体，以及这些生理参数在病理情况下如何调节，必将有助于更好地理解导致血管，甚至实质淀粉样蛋白沉积的机制(S)。项目中概述的四个具体目标集中于a)确定脑内皮细胞中游离和复杂Abeta物种的细胞受体(目标1)，b)研究循环中游离和复杂Abeta物种的半衰期以及确定其全身分解代谢和/或排泄的部位(目标2)，c)确定载体脂质体的氧化是否可能导致复杂的失衡，从而导致游离sAbeta的释放或氧化Abeta的形成(目标3)，以及d)澄清目标1和2中评估的生理学变量在衰老和阿尔茨海默病中是否受到损害(目标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).