β-Amyloid-induced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1

In patients with amyloid beta -related cerebrovascular disorders, e.g., Alzheimer'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 monocytes across the blood-brain barrier (BBB). Our studies show that interaction of A beta (1-40) with monolayer of human brain endothelial cells results in augmented adhesion and transendothelial migration of monocytic cells (THP-1 and HL-60) and peripheral blood monocytes. The A beta -mediated migration of monocytes was inhibited by antibody to A beta receptor (RAGE) and platelet 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 initiates cellular signaling leading to the transendothelial migration of monocytes. We suggest that increased diapedesis of monocytes across the BBB in response to A beta present either in the peripheral circulation or in the brain parenchyma may play a role in the pathophysiology of A beta -related vascular disorder.