Therapeutic drugs modulate ATP-Binding cassette transporter-mediated transport of amyloid beta(1-42) in brain microvascular endothelial cells

Abstract

Deposition of amyloid-β peptide (Aβ_(1-42)) is a hallmark of Alzheimer's disease. Clearance of Aβ_(1-42), across the blood-brain barrier (BBB), is mediated by ATP-binding Cassette (ABC) efflux transporters. Many therapeutic drugs inhibit ABC transporters, but little is known of the effect of therapeutic drugs on Aβ_(1-42) transport across BBB endothelial cells. The effects of selected, widely prescribed, therapeutic drugs on ABCB1, ABCC5 and ABCG2 activities were determined by measuring intracellular levels of calcein, GS-MF, and Hoechst 33342 respectively in primary porcine brain endothelial cells (PBECs). The ability of ABCB1, ABCC5 and ABCG2 to transport Aβ_(1-42) was determined using fluorescent Aβ_(1-42). The ability of the ABCB1, ABCC5 and ABCG2 inhibitor telmisartan to modify transcellular Aβ_(1-42) transport was investigated using PBEC monolayers housed in Transwell® inserts. Treatment of PBECs with ABC transporter inhibitory drugs (indomethacin, olanzapine, chlorpromazine, telmisartan, pantoprazole, quinidine, sulfasalazine and nefazodone) increased Aβ_(1-42) intracellular accumulation. Inhibition of ABCB1, ABCC5 and ABCG2 by telmisartan increased Aβ_(1-42) transport in the apical to basal direction and reduced its transport in basal to apical direction in PBEC monolayers. ABCB1, ABCC5 and ABCG2 mediate the efflux transport of Aβ_(1-42) in BBB endothelial cells. Inhibition of ABC transporters by therapeutic drugs, at plasma concentrations, could decrease Aβ_(1-42) clearance from brain, across BBB endothelial cells into blood, and potentially influence levels of the Aβ_(1-42) peptide within the brain.

Keywords: ABCB1; ABCC5; ABCG2; Alzheimer's disease; Amyloid-beta; Porcine brain endothelial cells; Therapeutic drugs.