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

In patients with amyloid β-related cerebrovascular disorders, e.g., Alzheimer's disease, one finds increased deposition of amyloid peptide (Aβ) and increased presence of monocyte/microglia cells in the brain. However, relatively little is known of the role of Aβ in the trafficking of monocytes across the blood-brain barrier (BBB). Our studies show that interaction of Aβ_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 Aβ-mediated migration of monocytes was inhibited by antibody to Aβ receptor (RAGE) and platelet endothelial cell adhesion molecule (PECAM-1). Additionally, Aβ-induced transendothelial migration of monocytes were inhibited by protein kinase C inhibitor and augmented by phosphatase inhibitor. We conclude that interaction of Aβ 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 Aβ present either in the peripheral circulation or in the brain parenchyma may play a role in the pathophysiology of Aβ-related vascular disorder.