Soluble aggregates of the amyloid-β protein activate endothelial monolayers for adhesion and subsequent transmigration of monocyte cells
Soluble aggregates of the amyloid-β protein activate endothelial monolayers for adhesion and subsequent transmigration of monocyte cells
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DOI：
10.1111/j.1471-4159.2007.04988.x
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发表时间：
2008-01-01
影响因子：
4.7
通讯作者：
Moss, Melissa A.
中科院分区：
文献类型：
--
作者：
Gonzalez-Velasquez, Francisco J.;Moss, Melissa A.
越来越多的证据表明，淀粉样蛋白斑块的沉积，主要由淀粉样蛋白β蛋白（A β），血管内是一个频繁发生在阿尔茨海默病，并可能在疾病的进展中发挥重要作用。因此，A β改变血管功能的致病机制可能具有治疗意义。尽管观察到A β在内皮细胞中引发了许多生理反应，从蛋白质表达的改变到细胞死亡，但导致这些反应的A β种类仍未被探索。在目前的研究中，我们发现，孤立的可溶性A β聚集中间体激活人脑微血管内皮细胞的粘附和随后的迁移的单核细胞在没有内皮细胞死亡和单层破坏。相反，未聚集的A β单体和成熟的A β原纤维不能诱导内皮粘附或迁移的任何变化。平均A β聚集体大小和观察到的粘附增加之间的相关性说明较小的可溶性聚集体是更有效的内皮激活剂。这些结果支持了先前的研究，证明了可溶性A β聚集体（包括A β衍生的可扩散配体、寡聚体和原纤维）的神经元活性增强，并进一步表明可溶性聚集体也选择性地在血管细胞模型中表现出活性。
Increasing evidence suggests that the deposition of amyloid plaques, composed primarily of the amyloid-beta protein (A beta), within the cerebrovasculature is a frequent occurrence in Alzheimer's disease and may play a significant role in disease progression. Accordingly, the pathogenic mechanisms by which A beta can alter vascular function may have therapeutic implications. Despite observations that A beta elicits a number of physiological responses in endothelial cells, ranging from alteration of protein expression to cell death, the A beta species accountable for these responses remains unexplored. In the current study, we show that isolated soluble A beta aggregation intermediates activate human brain microvascular endothelial cells for both adhesion and subsequent transmigration of monocyte cells in the absence of endothelial cell death and monolayer disruption. In contrast, unaggregated A beta monomer and mature A beta fibril fail to induce any change in endothelial adhesion or transmigration. Correlations between average A beta aggregate size and observed increases in adhesion illustrate that smaller soluble aggregates are more potent activators of endothelium. These results support previous studies demonstrating heightened neuronal activity of soluble A beta aggregates, including A beta-derived diffusible ligands, oligomers, and protofibrils, and further show that soluble aggregates also selectively exhibit activity in a vascular cell model.