BLOOD BRAIN BRARRIER AB TRANSPORT IN VARIOUS MODELS

各种型号的血脑屏障 AB 运输

• 批准号: 6355546
• 负责人: ZLOKOVIC V BERISLAV
• 金额: $ 20.93万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6355546
• 关键词: Alzheimer's disease; Macaca mulatta; Saimiri; age difference; aging; amyloid proteins; amyloidosis; autoradiography; blood brain barrier; brain metabolism; cerebrospinal fluid; cerebrovascular disorders; disease /disorder model; genetically modified animals; glycation; glycoproteins; high performance liquid chromatography; human tissue; laboratory mouse; molecular chaperones; neurophysiology; postmortem; protein binding; protein localization; protein metabolism; protein transport; radiotracer; receptor expression

Vascular deposition of amyloid beta peptide (Abeta) occurs during normal aging and is accelerated in Alzheimer's disease (AD). Abeta is considered to be implicated in the cerebrovascular pathology in AD and related disorders such as hereditary cerebral hemorrhage with amyloidosis of Dutch type, a form of cerebral amyloid angiopathy (CAA). Recent studies suggest a major role for the blood-brain barrier (BBB) and cerebrospinal fluid (CSF) clearance in regulating the concentrations of soluble Abeta in cerebral vasculature and brain. Our preliminary data indicate that glycoprotein 330 the 'receptor for advanced glycation and products' (RAGE), scavenger receptor, and yet molecularly non-identified receptor(s)/transporter(s) participate in endothelial binding and/or BBB transcytosis of free and/or bound form of Abeta. Preliminary finding suggest enhanced Abeta endothelial binding and BB transport in the brain of senescent non-human primates and in AD. We propose to use senescent non-human primates, in vitro BB model, and transgenic (Tg) CAA (Dutch type, wild) AND Tg vascular RAGE mice to test the hypothesis that aging predisposes to cerebrovascular and parenchymal accumulation and deposition of Abeta by upsetting the balance between transport of Abeta across the BB, its metabolism and clearance from brain and CSF, and this is further enhanced by the presence of CC and over-expression of vascular RAGE. We will determine in vivo pharmacokinetics, BBB permeability and microvascular-accumulation (aim 1) and clearance from brain and CSF (aim 2) of Abeta in aged versus adult non-human primates. Aim 3 is molecular characterization and isolation of Abeta brain endothelial receptors/transporters in an in vitro BB model in non-human primates and humans (controls, AD). In aim 4 we will determine blood-to-brain transport and vascular sequestration, and in aim 5 brain and CSF clearance of Abeta in Tg CAA, Tg vascular RAGE and crossed Tg CAA/RAGE mice. Proposed studies will define the roles of circulating and brain-derived Abeta in the development of cerebrovascular amyloidosis, and provide the molecular basis for new therapeutic strategies to prevent cerebrovascular Abeta accumulation, amyloid formation and their pathogenic effects on the vascular system and brain.

淀粉样β肽（ABETA）的血管沉积发生在正常衰老期间，并在阿尔茨海默氏病（AD）中加速。 ABETA被认为与AD的脑血管病理学有关，以及与遗传性脑出血诸如荷兰类型的淀粉样蛋白病（一种脑淀粉样血管病（CAA）的一种形式）。最近的研究表明，血脑屏障（BBB）和脑脊液（CSF）清除率在调节脑血管和大脑中可溶性Abe​​ta的浓度中起主要作用。我们的初步数据表明，糖蛋白330“晚期糖基化和产物的受体”（愤怒），清道夫受体，但尚未分子未识别的受体/转运蛋白参与内皮结合和/或Abeta的自由和/或绑定的Abeta的内皮结合和/或BBB。初步发现表明，在衰老的非人类灵长类动物和AD中，ABETA内皮结合和BB转运增强。 We propose to use senescent non-human primates, in vitro BB model, and transgenic (Tg) CAA (Dutch type, wild) AND Tg vascular RAGE mice to test the hypothesis that aging predisposes to cerebrovascular and parenchymal accumulation and deposition of Abeta by upsetting the balance between transport of Abeta across the BB, its metabolism and clearance from brain and CSF, and this is further CC的存在和血管愤怒的过表达增强。我们将确定体内药代动力学，BBB的渗透性和微血管 - 蓄能率（AIM 1）和Abeta的大脑和CSF（AIM 2）的清除率与成人非人类灵长类动物相比。 AIM 3是在非人类灵长类动物和人类中体外BB模型中Abeta脑内皮受体/转运蛋白的分子表征和分离（对照，AD）。在AIM 4中，我们将确定血液到脑运输和血管隔离，以及在TG CAA，TG血管愤怒和交叉TG CAA/RAGE小鼠中ABETA的AIM 5大脑和CSF清除率。拟议的研究将定义循环和脑衍生的ABETA在脑血管淀粉样变性发展中的作用，并为防止脑血管abeta积累，淀粉样蛋白形成及其对血管系统和大脑的致病作用提供新的治疗策略的分子基础。