Soluble aggregates of the amyloid-beta protein selectively stimulate permeability in human brain microvascular endothelial monolayers.
Cerebral amyloid angiopathy associated with Alzheimer's disease is characterized by cerebrovascular deposition of the amyloid-beta protein (Abeta). Abeta elicits a number of morphological and biochemical alterations in the cerebral microvasculature, which culminate in hemorrhagic stroke. Among these changes, compromise of the blood-brain barrier has been described in Alzheimer's disease brain, transgenic animal models of Alzheimer's disease, and cell culture experiments. In the current study, presented data illustrates that isolated soluble Abeta(1-40) aggregates, but not unaggregated monomer or mature fibril, enhance permeability in human brain microvascular endothelial monolayers. Abeta(1-40)-induced changes in permeability are paralleled by both a decrease in transendothelial electrical resistance and a re-localization of the tight junction-associated protein zonula occludin-1 away from cell borders and into the cytoplasm. Small soluble Abeta(1-40) aggregates are confirmed to be the most potent stimulators of endothelial monolayer permeability by establishing an inverse relationship between average aggregate size and stimulated changes in diffusional permeability coefficients. These results support previous findings demonstrating that small soluble Abeta(1-40) aggregates are also primarily responsible for endothelial activation, suggesting that these same species may elicit other changes in the cerebrovasculature associated with cerebral amyloid angiopathy and Alzheimer's disease.
Gonzalez-Velasquez
Francisco J
FJ
Department of Chemical Engineering, University of South Carolina, Swearingen Engineering Center, Columbia, South Carolina, USA.
Kotarek
Joseph A
JA
Moss
Melissa A
MA
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology*; D001921:Brain / Q000166:cytology*; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D004727:Endothelium / Q000166:cytology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D062826:Zonula Occludens-1 Protein
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; C569042:TJP1 protein, human; D014409:Tumor Necrosis Factor-alpha; D062826:Zonula Occludens-1 Protein; C078592:amyloid beta-protein (1-40)