RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain
RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain
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DOI：
10.1038/nm890
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发表时间：
2003-07-01
期刊：
影响因子：
82.9
通讯作者：
Zlokovic, B
中科院分区：
文献类型：
--
作者：
Deane, R;Yan, SD;Zlokovic, B
淀粉样β肽（Abeta）与血管系统相互作用以影响脑和脑血流中的Abeta水平，从而提供放大Abeta诱导的细胞应激的手段，所述细胞应激是神经元功能障碍和痴呆的基础。全身性Abeta输注和遗传操作小鼠的研究表明，Abeta与血管壁中携带晚期糖基化终末产物（AGEs）的细胞的受体相互作用导致Abeta转运穿过血脑屏障（BBB），并表达促炎细胞因子和内皮素-1（ET-1），后者介导Abeta诱导的血管收缩。在小鼠转基因模型中，RAGE-配体相互作用的抑制抑制了A β在脑实质中的积累。这些发现表明，血管内皮细胞是抑制A β-血管相互作用的致病后果的靶点，包括脑淀粉样变性的发展。
Amyloid-beta peptide (Abeta) interacts with the vasculature to influence Abeta levels in the brain and cerebral blood flow, providing a means of amplifying the Abeta-induced cellular stress underlying neuronal dysfunction and dementia. Systemic Abeta infusion and studies in genetically manipulated mice show that Abeta interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Abeta across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Abeta-induced vasoconstriction. Inhibition of RAGE-ligand interaction suppresses accumulation of Abeta in brain parenchyma in a mouse transgenic model. These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of Abeta-vascular interactions, including development of cerebral amyloidosis.