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Title: Amyloid beta transport and effects on permeability in a human brain endothelial cell line
Author: Tai, Leon M.
ISNI:       0000 0001 3496 0761
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2009
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The clearance of neurotoxic amyloid beta (Aβ) from the brain represents a novel therapeutic target for Alzheimer's disease (AD). The ability of two blood-brain barrier (BBB) drug transporters, P-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP), to transport Aβ was investigated using a human brain endothelial cell (BEC) line, hCMEC/D3. P-gp expression by hCMEC/D3 cells was stable over a high passage number, polarised on the apical membrane, consistent with the blood side in vivo, and comparable, albeit slightly reduced, to primary isolated human BECs. The P-gp inhibitors tariquidar and vinblastine prevented the efflux of rhodamine 123 from hCMEC/D3 cells, indicative of functional P-gp expression. hCMEC/D3 cells therefore constituted a suitable model to investigate P-gp substrate interactions in vitro. P-gp, and to a lesser extent BCRP, inhibition, increased the net influx and decreased the efflux of 0.1 nM¹²⁵ I Aβ 1-40 in hCMEC/D3 cells. Both P-gp and BCRP inhibition increased the apical-to-basolateral but not the basolateral-to-apical permeability of hCMEC/D3 cells to nM¹²⁵ I Aβ 1-40. This data is consistent with P-gp and BCRP, acting in vivo to prevent blood-borne Aβ peptides entering the brain but not to clear Aβ load from the brain.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral