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

Jasmina B. Mackic, Monique Stins, J. Gordon McComb, Miguel Calero, Jorge Ghiso, Kwang Sik Kim, Shi Du Yan, David Stern, Ann Marie Schmidt, Blas Frangione, Berislav V. Zlokovic

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Abstract

A soluble monomeric form of Alzheimer's amyloid-β (1-40) peptides (SAβ 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 sAβ 1- 40 using an in vitro model of human BBB. 125 I-sAβ 1-40 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 125 I-sAβ 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 125 I-sAβ 1-40 . The internalized peptide remains intact > 94%. Transcytosis of 125 I-sAβ 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 sAB 1-40 at the apical side of human BBB, and that RAGE is also involved in sAβ 1-40 transcystosis.

Original languageEnglish (US)
Pages (from-to)734-743
Number of pages10
JournalJournal of Clinical Investigation
Volume102
Issue number4
DOIs
StatePublished - Aug 15 1998

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Transcytosis
Scavenger Receptors
Endocytosis
Blood-Brain Barrier
Amyloid
Endothelial Cells
Peptides
Brain
Vascular Endothelium
Cultured Cells
Temperature
Antibodies

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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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. / Mackic, Jasmina B.; Stins, Monique; McComb, J. Gordon; Calero, Miguel; Ghiso, Jorge; Kim, Kwang Sik; Yan, Shi Du; Stern, David; Schmidt, Ann Marie; Frangione, Blas; Zlokovic, Berislav V.

In: Journal of Clinical Investigation, Vol. 102, No. 4, 15.08.1998, p. 734-743.

Research output: Contribution to journalArticle

Mackic, Jasmina B. ; Stins, Monique ; McComb, J. Gordon ; Calero, Miguel ; Ghiso, Jorge ; Kim, Kwang Sik ; Yan, Shi Du ; Stern, David ; Schmidt, Ann Marie ; Frangione, Blas ; Zlokovic, Berislav V. / 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. In: Journal of Clinical Investigation. 1998 ; Vol. 102, No. 4. pp. 734-743.
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abstract = "A soluble monomeric form of Alzheimer's amyloid-β (1-40) peptides (SAβ 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 sAβ 1- 40 using an in vitro model of human BBB. 125 I-sAβ 1-40 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 125 I-sAβ 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 125 I-sAβ 1-40 . The internalized peptide remains intact > 94{\%}. Transcytosis of 125 I-sAβ 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 sAB 1-40 at the apical side of human BBB, and that RAGE is also involved in sAβ 1-40 transcystosis.",
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AU - Mackic, Jasmina B.

AU - Stins, Monique

AU - McComb, J. Gordon

AU - Calero, Miguel

AU - Ghiso, Jorge

AU - Kim, Kwang Sik

AU - Yan, Shi Du

AU - Stern, David

AU - Schmidt, Ann Marie

AU - Frangione, Blas

AU - Zlokovic, Berislav V.

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AB - A soluble monomeric form of Alzheimer's amyloid-β (1-40) peptides (SAβ 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 sAβ 1- 40 using an in vitro model of human BBB. 125 I-sAβ 1-40 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 125 I-sAβ 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 125 I-sAβ 1-40 . The internalized peptide remains intact > 94%. Transcytosis of 125 I-sAβ 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 sAB 1-40 at the apical side of human BBB, and that RAGE is also involved in sAβ 1-40 transcystosis.

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