Role of ATP-binding cassette transporters in efflux of amyloid-ß at the human blood-brain barrier
Yasuteru Sano1, Kazuyuki Saito2, Masaaki Abe1, Hideaki Nishihara1, and Takashi Kanda1
1Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan
2Department of Neurology and Neurological Science, Tokyo Medical and Dental University Graduate School, Tokyo, Japan

The clearance of amyloid β (Aß) from the brain could be a novel therapeutic target for Alzheimer's disease (AD). Although several reports demonstrate that low-density lipoprotein receptor-related protein-1 (LRP1) is a major Aβ transporter at the blood-brain barrier (BBB), the role of ATP-binding cassette transporters in efflux of Aβ at the human BBB has not yet been elucidated. In addition, conflicting data exist regarding the contribution of ATP-binding cassette transporters to the clearance of Aß through the BBB. Therefore, we examined the role of efflux transporters on Aß transport using a new established conditionally immortalized human brain microvascular endothelial cell line.
Uptake of 125I Aß1-40 by a new conditionally immortalized human brain microvascular endothelial cell line, TY09, were examined with or without down-regulation of p-glycoprotein (P-gp), breast cancer resistance protein (BCRP), Multidrug resistance-associated protein 1 (MRP1), and MRP4 using siRNAs specific to each molecules. Apical-to-basolateral permeability of TY09 to 125I Aß1-40 was also evaluated. Down-regulation of BCRP increased the uptake of 125I Aß1-40 by TY09 as well as apical-to-basolateral permeability of TY09 to 125I Aß1-40. Down-regulation of P-gp, MRP1, and MRP4 did not influence the uptake and permeability of 125I Aß1-40 with TY09.
Our results using a new human in vitro BBB model suggest that BCRP act to prevent the blood-borne Aß from entering brain at the human BBB.
This study was supported in part by research grant (23790994) from the Japan Society for the Promotion of Science, Tokyo, Japan.