Human blood-brain barrier receptors for Alzheimer's amyloid-β 1-40 -: Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer

被引:212
作者
Mackic, JB
Stins, M
McComb, JG
Calero, M
Ghiso, J
Kim, KS
Yan, SD
Stern, D
Schmidt, AM
Frangione, B
Zlokovic, BV
机构
[1] Univ So Calif, Sch Med, Dept Neurol Surg, Los Angeles, CA 90033 USA
[2] Univ So Calif, Sch Med, Div Infect Dis, Los Angeles, CA 90033 USA
[3] Univ So Calif, Sch Med, Div Neurosurg, Childrens Hosp, Los Angeles, CA 90033 USA
[4] NYU, Med Ctr, Dept Pathol, New York, NY 10016 USA
[5] Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA
[6] Columbia Univ Coll Phys & Surg, Dept Physiol, New York, NY 10032 USA
[7] Columbia Univ Coll Phys & Surg, Dept Surg, New York, NY 10032 USA
关键词
A beta-peptide; cerebrovascular; transporter; central nervous system; amyloidosis;
D O I
10.1172/JCI2029
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
A soluble monomeric form of Alzheimer's amyloid-beta (1-40) peptide (sA beta(1-40)) 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 sA beta(1-40) using an in vitro model of human BBB. I-125-sA beta(1-40) 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 I-125-sA beta(1-40) 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 I-125-sA beta(1-40). The internalized peptide remains intact > 94%. Transcytosis of I-125-sA beta(1-40) 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 sA beta(1-40) at the apical side of human BBB, and that RAGE is also involved in sA beta(1-40) transcytosis.
引用
收藏
页码:734 / 743
页数:10
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