Vascular endothelial barrier dysfunction mediated by amyloid-beta proteins.
Neuronal inflammation is very common in Alzheimer's disease (AD). This inflammation can be caused by infiltration of neutrophils across the blood brain barrier. Endothelial permeability changes are required for the infiltration of high molecular weight components to the brain. Deposition of toxic amyloid-beta (A beta) fibrils in the cerebral vasculature, as well as in brain neurons, has been implicated in the development of AD. This study investigates the effect of A beta fibrils on the permeability of the endothelium and the mechanism for the observed permeability changes. A beta(1-40) and A beta(1-42) fibrils, but not monomers, were found to increase permeability of bovine pulmonary arterial endothelial cells in a dose- and time dependent manner as detected by transendothelial electrical resistance. This increase in permeability is only partially (25%) inhibited by catalase and is not associated with an increase in cytosolic Ca+2 or tyrosine phosphorylation. These results indicate that hydrogen peroxide is not the primary mediator for the permeability changes. Treatment of cells with both amyloid fibrils resulted in stress fiber formation, disruption and aggregation of actin filaments, and cellular gap formation. The results of this study reveal that A beta increases the permeability of endothelium by inducing change in the cytoskeleton network.
Nagababu
Enika
E
Molecular Dynamics Section, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Usatyuk
Peter V
PV
Enika
Divya
D
Natarajan
Viswanathan
V
Rifkind
Joseph M
JM
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D017097:Electric Impedance; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D010755:Organophosphates / Q000378:metabolism; D011108:Polymers / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology; D013997:Time Factors
D016229:Amyloid beta-Peptides; D003598:Cytoskeletal Proteins; D010755:Organophosphates; D011108:Polymers; C542009:tyrosine polyphosphate; D002118:Calcium