AGING, AMYLOID B PEPTIDE AND MIGRATION OF MONOCYTES ACROSS THE VASCULAR WALL

衰老、淀粉样蛋白 B 肽和单核细胞跨血管壁的迁移

• 批准号: 6098832
• 负责人: VIJAY K. KALRA
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098832
• 关键词: Alzheimer's disease; Macaca mulatta; Saimiri; aging; amyloid proteins; amyloidosis; biological signal transduction; blood brain barrier; cell adhesion; cell migration; genetically modified animals; glycation; immunoprecipitation; laboratory mouse; laboratory rat; mitogen activated protein kinase; monocyte; nuclear factor kappa beta; phosphorylation; platelet activating factor; protein kinase C; receptor expression; vascular endothelium; vascular endothelium permeability; western blottings

Vascular deposition of amyloid-beta-peptide (Abeta) occurs during normal aging and is accelerated in Alzheimer's Disease (AD) and related disorders such as hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), a form of cerebral amyloid angiopathy (CAA). In CAA, HCHWA-D and AD increased vascular deposition of Abeta is associated with invasion of monocyte/macrophages in the vessel wall and activated microglial cells in the parenchyma. Relatively little is known about the cellular and molecular mechanisms in cerebral vasculature that may play a role in Abeta-mediated accumulation of peripheral inflammatory cells. Recent studies indicated that peripheral hematopoietic cells (i.e., monocytes) can cross the blood-brain barrier (BBB). Our studies shown that Abeta increases diapedesis of leukocytes across the vascular endothelium, and induces migration of monocytes across the human BBB in vitro, blocked by antibodies to PECAM-1 ( a cell junction molecule ) and RAGE (putative receptor for A beta). The central hypothesis is that interaction of Abeta with its putative receptor(s) in the brain vascular endothelium brings about cellular signaling which results in the modulation of PECAM-1 to allow migration of monocytes across the BBB. It is further hypothesized, that migration of monocytes is exaggerated across cerebral vasculature in AD and aged non-human primates, presumably due to increased expression and/or redistribution of Abeta receptors at the BBB. To test this hypothesis we will determine (1) the effect of Abeta on adhesion and migration of monocytes across monolayer of human brain microvascular endothelial cells (HBMVEC); (2) whether Abeta causes increased migration of monocytes in HBMVEC from geriatric and AD cases; (3) the role of p21/ras, MAP kinase, NF-kappaB,, RAGE and PAF in Abeta induced cellular signaling, using pharmacological inhibitors and over-expressing or knocking out genes by transfection of HBMVEC, and (4) the mechanisms of Abeta-induced adhesion and diapedesis of leukocytes across the vessel wall in transgenic (Tg) CC HCHWA-D mice and Tg vascular RAGE mice. Proposed studies will provide a novel insight into the mechanisms of Abeta-induced migration of hematopoietic cells across the vessel wall and the BB and will provide a molecular basis for the therapeutic rationale to modify Abeta- induced inflammatory reactions in the aging brain to ameliorate the neuronal injury.

淀粉样蛋白β-肽（ABETA）的血管沉积发生在正常衰老期间，并且在阿尔茨海默氏病（AD）中加速及相关疾病，例如荷兰淀粉样蛋白型（HCHWA）（HCHWA-D），遗传性脑出血（HCHWA-D），一种脑淀粉样蛋白Angiopate angiopate angiopathy（CAA）的形式。在CAA中，HCHWA-D和AD增加了Abeta的血管沉积与血管壁中的单核细胞/巨噬细胞的侵袭有关，并激活了实质中的小胶质细胞。关于可能在Abeta介导的外周炎性细胞积累中起作用的脑脉管系统中细胞和分子机制的知之甚少。最近的研究表明，周围造血细胞（即单核细胞）可以越过血脑屏障（BBB）。我们的研究表明，ABETA增加了整个血管内皮细胞的白细胞二子，并在体外诱导单核细胞迁移到人类BBB的体外，并被PECAM-1（细胞连接分子）的抗体阻塞，并rage（假定的受体）。中心假设是Abeta与其在脑血管内皮中的假定受体的相互作用会引起细胞信号传导，从而导致PECAM-1的调节以允许单核细胞跨BBB迁移。进一步假设，单核细胞的迁移被夸大了AD和年龄非人类灵长类动物的大脑脉管系统的迁移，这可能是由于BBB上ABETA受体的表达增加和/或重新分布。为了检验该假设，我们将确定（1）Abeta对人脑微血管内皮细胞单层单层的粘附和迁移的影响（HBMVEC）； （2）Abeta是否导致HBMVEC中单核细胞的迁移增加，从老年病例和AD病例中； （3）P21/RAS，MAP激酶，NF-KAPPAB，RAGE和PAF在ABETA中诱导的细胞信号传导，使用药理学抑制剂以及通过HBMVEC转染过表达或过表达或淘汰基因，以及（4）ABETA诱导的粘合剂和二聚体的机制，涉及二氧化物的机制，涉及勒克斯的机制，涉及勒克氏菌的传递。 HCHWA-D小鼠和TG血管愤怒小鼠。拟议的研究将提供一个新的洞察力，了解Abeta诱导的造血细胞在整个容器壁和BB中的迁移的机制，并将为治疗性基本原理提供分子基础，以修饰a诱导的a诱导的脑炎性脑中衰老的炎症反应，从而amile脑损伤。