Effect of endothelial cell polarity on beta-amyloid-induced migration of monocytes across normal and AD endothelium.
During normal aging and amyloid beta-peptide (Abeta) disorders such as Alzheimer's disease (AD), one finds increased deposition of Abeta and activated monocytes/microglial cells in the brain. Our previous studies show that Abeta 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 Abeta 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 Abeta(1--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 Abeta was added to the basolateral side of AD compared with normal individual BEC. The Abeta-induced transmigration of monocytes was inhibited in both normal and AD-BEC by antibodies to the putative Abeta 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 Abeta with the basolateral surface of AD-BEC induces cellular signaling, promoting transmigration of monocytes from the apical to basolateral direction. We suggest that Abeta in the AD brain parenchyma or cerebrovasculature initiates cellular signaling that induces PBM to transmigrate across the BBB and accumulate in the brain.
Giri
Ranjit
R
Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles 90033, USA.
Selvaraj
Suresh
S
Miller
Carol A
CA
Hofman
Florence
F
Yan
S D
SD
Stern
David
D
Zlokovic
Berislav V
BV
Kalra
Vijay K
VK
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000906:Antibodies / Q000494:pharmacology; D001921:Brain / Q000098:blood supply; D002465:Cell Movement / Q000187:drug effects; D016764:Cell Polarity; D002478:Cells, Cultured; D015194:Diffusion Chambers, Culture; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D009000:Monocytes / Q000166:cytology / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D016229:Amyloid beta-Peptides; D000906:Antibodies; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C078592:amyloid beta-protein (1-40)