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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 2002 (6)

Title and authors Publication Year
Sporadic and Familial Cerebral Amyloid Angiopathies
T Revesz, JL Holton, T Lashley, G Plant, A Rostagno, J Ghiso, B Frangione
Brain Pathology 2002
Circulating amyloid-β peptide crosses the blood–brain barrier in aged monkeys and contributes to Alzheimer's disease lesions
JB Mackic, J Bading, J Ghiso, L Walker, T Wisniewski, B Frangione, BV Zlokovic
Vascular Pharmacology 2002
Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer's disease brain and damage the blood-brain barrier
M Fiala, QN Liu, J Sayre, V Pop, V Brahmandam, MC Graves, HV Vinters
European Journal of Clinical Investigation 2002
Heparin attenuates cytotoxic and inflammatory activity of Alzheimer amyloid-β in vitro
L Bergamaschini, C Donarini, E Rossi, AD Luigi, C Vergani, MG de Simoni
Neurobiology of Aging 2002
Intracellular accumulation of β-amyloid1–42 in neurons is facilitated by the α7 nicotinic acetylcholine receptor in Alzheimer’s disease
RG Nagele, MR D’Andrea, WJ Anderson, HY Wang
Neuroscience 2002
BSE: a consequence of cattle feeding with glycated molecules host-unknown?
J Boratyński, A Górski
Medical Hypotheses 2002

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