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Abstract

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.

Authors

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

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Citations to this article in year 2008 (8)

Title and authors Publication Year
SYMPOSIUM: Clearance of Aβ from the Brain in Alzheimer's Disease: Aβ-Degrading Enzymes in Alzheimer's Disease
JS Miners, S Baig, J Palmer, LE Palmer, PG Kehoe, S Love
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RAGE recycles at the plasma membrane in S100B secretory vesicles and promotes Schwann cells morphological changes
L Perrone, G Peluso, MA Melone
Journal of Cellular Physiology 2008
The role of the cell surface LRP and soluble LRP in blood-brain barrier Abeta clearance in Alzheimer's disease
R Deane, A Sagare, BV Zlokovic
Current pharmaceutical design 2008
A role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis
JM Englert, LE Hanford, N Kaminski, JM Tobolewski, RJ Tan, CL Fattman, L Ramsgaard, TJ Richards, I Loutaev, PP Nawroth, M Kasper, A Bierhaus, TD Oury
The American Journal of Pathology 2008
Apolipoprotein E, Amyloid-??, and Blood-Brain Barrier Permeability in Alzheimer Disease
JE Donahue, CE Johanson
Journal of Neuropathology and Experimental Neurology 2008
Effects of ginkgo biloba extract EGb761 on expression of RAGE and LRP-1 in cerebral microvascular endothelial cells under chronic hypoxia and hypoglycemia
FL Yan, Y Zheng, FD Zhao
Acta Neuropathologica 2008
Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests
KA Bates, G Verdile, QX Li, D Ames, P Hudson, CL Masters, RN Martins
Molecular Psychiatry 2008
The role of peptides in blood-brain barrier nanotechnology
M Teixidó, E Giralt
Journal of Peptide Science 2008

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