Soluble aggregates of the amyloid-β protein activate endothelial monolayers for adhesion and subsequent transmigration of monocyte cells

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.