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A soluble monomeric form of Alzheimer's amyloid-beta (1-40) peptide (sAbeta1-40) is present in the circulation and could contribute to neurotoxicity if it crosses the brain capillary endothelium, which comprises the blood-brain barrier (BBB) in vivo. This study characterizes endothelial binding and transcytosis of a synthetic peptide homologous to human sAbeta1-40 using an in vitro model of human BBB. 125I-sAbeta1-40 binding to the brain microvascular endothelial cell monolayer was time dependent, polarized to the apical side, and saturable with high- and low-affinity dissociation constants of 7.8+/-1.2 and 52.8+/-6.2 nM, respectively. Binding of 125I-sAbeta1-40 was inhibited by anti-RAGE (receptor for advanced glycation end products) antibody (63%) and by acetylated low density lipoproteins (33%). Consistent with these data, transfected cultured cells overexpressing RAGE or macrophage scavenger receptor (SR), type A, displayed binding and internalization of 125I-sAbeta1-40. The internalized peptide remains intact > 94%. Transcytosis of 125I-sAbeta1-40 was time and temperature dependent, asymmetrical from the apical to basolateral side, saturable with a Michaelis constant of 45+/-9 nM, and partially sensitive to RAGE blockade (36%) but not to SR blockade. We conclude that RAGE and SR mediate binding of sAbeta1-40 at the apical side of human BBB, and that RAGE is also involved in sAbeta1-40 transcytosis.


J B Mackic ... B Frangione, B V Zlokovic


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Citations to this article in year 2012 (12)

Title and authors Publication Year
Aβ42 production in brain capillary endothelial cells after oxygen and glucose deprivation
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Future Medicinal Chemistry 2012
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R Deane, I Singh, AP Sagare, RD Bell, NT Ross, B LaRue, R Love, S Perry, N Paquette, RJ Deane, M Thiyagarajan, T Zarcone, G Fritz, AE Friedman, BL Miller, BV Zlokovic
Journal of Clinical Investigation 2012
Microglial Scavenger Receptors and Their Roles in the Pathogenesis of Alzheimer's Disease
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AP Sagare, R Deane, BV Zlokovic
Pharmacology & Therapeutics 2012
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ML Giuffrida, F Tomasello, F Caraci, S Chiechio, F Nicoletti, A Copani
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SD Skaper
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Cilostazol Strengthens Barrier Integrity in Brain Endothelial Cells
S Horai, S Nakagawa, K Tanaka, Y Morofuji, PO Couraud, MA Deli, M Ozawa, M Niwa
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Aβ-induced formation of autophagosomes is mediated by RAGE-CaMKKβ-AMPK signaling
SM Son, ES Jung, HJ Shin, J Byun, I Mook-Jung
Neurobiology of Aging 2012
Neurovascular dysfunction and faulty amyloid β-peptide clearance in Alzheimer disease
Abhay P Sagare, Robert D Bell, Berislav V Zlokovic
Neurovascular Dysfunction and Faulty Amyloid ?-Peptide Clearance in Alzheimer Disease
Abhay P. Sagare, Robert D. Bell, Berislav V. Zlokovic
Neurovascular defects and faulty amyloid-β vascular clearance in Alzheimer's disease
Abhay P Sagare, Robert D Bell, Berislav V Zlokovic
Journal of Alzheimer's disease : JAD 2012