A soluble monomeric form of Alzheimer's amyloid-β (1-40) peptides (SAβ1-40) 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 sAβ1- 40 using an in vitro model of human BBB. 125I-sAβ1-40 binding to the brain microvascular endothelial cell monolayer was time dependent, polarized to the apical side, and saturable wi'th high- and low-affinity dissociation constants of 7.8±1.2 and 52.8±6.2 nM, respectively. Binding of 125I-sAβ1-40 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-sAβ1-40. The internalized peptide remains intact > 94%. Transcytosis of 125I-sAβ1-40 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 sAB1-40 at the apical side of human BBB, and that RAGE is also involved in sAβ1-40 transcystosis.
|Original language||English (US)|
|Number of pages||10|
|Journal||Journal of Clinical Investigation|
|State||Published - Aug 15 1998|
- Central nervous system
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