title: Soluble aggregates of the amyloid-beta protein activate endothelial monolayers for adhesion and subsequent transmigration of monocyte cells.
abstract: Increasing evidence suggests that the deposition of amyloid plaques, composed primarily of the amyloid-beta protein (Abeta), 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 Abeta can alter vascular function may have therapeutic implications. Despite observations that Abeta elicits a number of physiological responses in endothelial cells, ranging from alteration of protein expression to cell death, the Abeta species accountable for these responses remains unexplored. In the current study, we show that isolated soluble Abeta 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 Abeta monomer and mature Abeta fibril fail to induce any change in endothelial adhesion or transmigration. Correlations between average Abeta 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 Abeta aggregates, including Abeta-derived diffusible ligands, oligomers, and protofibrils, and further show that soluble aggregates also selectively exhibit activity in a vascular cell model.
authors.affiliation: Department of Chemical Engineering, University of South Carolina, Swearingen Engineering Center, Columbia, South Carolina 29208, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Gonzalez-Velasquez
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Moss
mesh_terms: D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D002448:Cell Adhesion / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009000:Monocytes / Q000502:physiology*; D062793:Occludin; D010446:Peptide Fragments / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation / Q000187:drug effects; D062826:Zonula Occludens-1 Protein
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D010446:Peptide Fragments; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; C078592:amyloid beta-protein (1-40)