RAGE Regulation Of Endothelial Cell-cell Junctions And Permeability And Actin Cytoskeleton By Increase Of β-catenin And Decrease Of ZO-1

RAGE (receptor for advanced glycation end products), an immunoglobin superfamily cell surface receptor, has been implicated in the pathogenesis of multiple age-associated disorders, including Alzheimer's disease (AD), diabetic complications, and inflammatory conditions. It contributes to Aβtranslocation across the endothelial blood brain barrier (BBB), leading to increased Aβaccumulation and amyloid plaque burden in the brain parenchyma. However, mechanisms underlying RAGE regulation of Aβtransport across BBB remains largely unclear. Here, using human umbilical vascular endothelial cell line (ECV304) over expressing human RAGE, we report that RAGE expression leads to impaired cell-cell adhesions and altered paracellular permeability. Further studies demonstrate that RAGE expression inducesβ-catenin upregulation, resulting in remodeling of F-actin cytoskeleton and increase of immature adherens junctions (AJs). In addition, cell density dependent increase of ZO-1 was blocked in RAGE expressing ECV cells, corresponding with the impaired tight junctions (TJs) and increase of paracellular permeability. These events are RAGE dependent as they were not observed in ECV304 cells expressing mutant RAGE that lacks of its intracellular domain. These results suggest a role for RAGE to remodel actin cytoskeleton and regulate cell-cell junctions and permeability, revealing a potential novel cellular mechanism underlying RAGE involvement of AD and diabetic complication associated vascular pathology.