beta-Amyloid-induced migration of monocytes across human brain endothelialcells involves RAGE and PECAM-1

In patients with amyloid beta -related cerebrovascular disorders, e.g., Alz heimer's disease, one finds increased deposition of amyloid peptide (A beta ) and increased presence of monocyte/microglia cells in the brain. However, relatively little is known of the role of A beta in the trafficking of mon ocytes across the blood-brain barrier (BBB). Our studies show that interact ion of A beta (1-40) with monolayer of human brain endothelial cells result s in augmented adhesion and transendothelial migration of monocytic cells ( THP-1 and HL-60) and peripheral blood monocytes. The A beta -mediated migra tion of monocytes was inhibited by antibody to A beta receptor (RAGE) and p latelet endothelial cell adhesion molecule (PECAM-1). Additionally, A beta -induced transendothelial migration of monocytes were inhibited by protein kinase C inhibitor and augmented by phosphatase inhibitor. We conclude that interaction of A beta with RAGE expressed on brain endothelial cells initi ates cellular signaling leading to the transendothelial migration of monocy tes. We suggest that increased diapedesis of monocytes across the BBB in re sponse to A beta present either in the peripheral circulation or in the bra in parenchyma may play a role in the pathophysiology of A beta -related vas cular disorder.