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Apical-to-Basolateral Transport of Amyloid-β Peptides through Blood-Brain Barrier Cells is Mediated by the Receptor for Advanced Glycation End-Products and is Restricted by P-Glycoprotein
Abstract
Several studies have highlighted the close relationship between Alzheimer's disease (AD) and alterations in the bidirectional transport of amyloid-β (Aβ) peptides across the blood-brain barrier (BBB). The brain capillary endothelial cells (BCECs) that compose the BBB express the receptors and transporters that enable this transport process. There is significant in vivo evidence to suggest that P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) restrict Aβ peptides entry into the brain, whereas the receptor for advanced glycation end-products (RAGE) seems to mediate apical-to-basolateral passage across the BBB. However, deciphering the molecular mechanisms underlying these in vivo processes requires further in vitro characterization. Using an in vitro BBB model and specific competition experiments against RAGE, we have observed a significant decrease in apical-to-basolateral (but not basolateral-to-apical) transport of Aβ1-40 and Aβ1-42 peptides through BCECs. This transport is a caveolae-dependent process and fits with the apical location of RAGE observed in confocal microscopy experiments. Inhibition of P-gp and BCRP using different inhibitors increases transport of Aβ peptides suggesting that these efflux pumps are involved in Aβ peptide transport at the BCECs level. Taken as a whole, these results demonstrate the involvement of the caveolae-dependent transcytosis of Aβ peptides through the BBB in a RAGE-mediated transport process, reinforcing the hypothesis…
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RAGE is involved in the blood-to-brain transport of Aβ.
“The receptor for advanced glycation end-products (RAGE, expressed at the EC luminal membrane) is involved in the blood-tobrain transport of A [32,34]”
The BBB participates in the regulation of the brain pool of Aβ peptides and the re-entry of these peptides into the brain.
“The BBB also participates in the regulation of the brain pool of A peptides in general and the re-entry of these peptides into the brain in particular [32][33][34][35][36].”
RAGE and ABCB1 play a role in the re-entry of Aβ peptides into the CNS.
“Given that we have previously characterized the role of RAGE and ABCB1 in the re-entry of A peptides into the CNS [29,34,42]”
ABCB1 is involved in Aβ peptide transport across the BBB.
“but it is now clear that ABCB1 is also involved in A peptide transport across the BBB.”
Other studies have demonstrated that ABCB1 restricts the re-entry of Aβ peptides into the CNS.
“others have demonstrated that this transporter restricts the re-entry of these peptides into the CNS [34,45].”
The bexarotene-induced decrease in apical-to-basolateral Aβ peptide transport across the BBB is ABCB1-mediated.
“The results of our experiments with the specific ABCB1 inhibitor elacridar [34,45] definitively confirmed that the process was ABCB1-mediated, since the compound restored apical-to-basolateral A peptide transport across the BBB.”
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Metadata
- Authors
- Candela, P., Gosselet, F., Saint-Pol, J., Sevin, E., Boucau, M.-C., Boulanger, E., Cecchelli, R., & Fenart, L.
- Affiliations
- Univ Lille Nord de France, Lille, France
- Department of Vascular Aging Biology, Medical School, Lille, France
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2010-11-25
- Volume
- 22
- Issue
- 3
- Pages
- 849-859
- ISSN
- 1875-8908
- 1387-2877
- Cited by
- 128
- References
- 0
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