Effect of endothelial cell polarity on β-amyloid-induced migration of monocytes across normal and AD endothelium

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Abstract
During normal aging and amyloid β-peptide (Aβ) disorders such as Alzheimer's disease (AD), one finds increased deposition of Aβ and activated monocytes/microglial cells in the brain. Our previous studies show that Aβ interaction with a monolayer of normal human brain microvascular endothelial cells results in increased adherence and transmigration of monocytes. Relatively little is known of the role of Aβ accumulated in the AD brain in mediating trafficking of peripheral blood monocytes (PBM) across the blood-brain barrier (BBB) and concomitant accumulation of monocytes/microglia in the AD brain. In this study, we showed that interaction of Aβ1—40 with apical surface of monolayer of brain endothelial cells (BEC), derived either from normal or AD individuals, resulted in increased transendothelial migration of monocytic cells (HL-60 and THP-1) and PBM. However, transmigration of monocytes across the BEC monolayer cultivated in a Transwell chamber was increased 2.5-fold when Aβ was added to the basolateral side of AD compared with normal individual BEC. The Aβ-induced transmigration of monocytes was inhibited in both normal and AD-BEC by antibodies to the putative Aβ receptor, receptor for advanced glycation end products (RAGE), and to the endothelial cell junction molecule, platelet-endothelial cell adhesion molecule-1 (PECAM-1). We conclude that interaction of Aβ with the basolateral surface of AD-BEC induces cellular signaling, promoting transmigration of monocytes from the apical to basolateral direction. We suggest that Aβ in the AD brain parenchyma or cerebrovasculature initiates cellular signaling that induces PBM to transmigrate across the BBB and accumulate in the brain.