Beta amyloid effects on expression of multidrug efflux transporters in brain endothelial cells

• Published in: Brain research Vol. 1418; pp. 1 - 11
• Main Authors: Kania, Katarzyna D., Wijesuriya, Hasini C., Hladky, Stephen B., Barrand, Margery A.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 18.10.2011; Elsevier
• Subjects: ABCB1; ABCC4; ABCG2; Alzheimer disease; amyloid; Amyloid beta-Peptides; Amyloid beta-Peptides - pharmacology; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Sub-Family B Member 4; ATP-Binding Cassette Transporters; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; beta Catenin; beta Catenin - metabolism; Biological and medical sciences; Biological Transport; Biological Transport - drug effects; blood-brain barrier; brain; Brain - cytology; breast neoplasms; Cell Line, Transformed; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges; cytology; diagnostic use; drug effects; endothelial cells; Endothelial Cells - drug effects; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Gene Expression Regulation - drug effects; genetics; Human brain endothelial cell; Humans; Intercellular Signaling Peptides and Proteins; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; luciferase; metabolism; Multidrug Resistance-Associated Proteins; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; multiple drug resistance; Neoplasm Proteins; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neurology; pharmacology; reporter genes; Rhodamine 123; Rhodamine 123 - metabolism; RNA, Messenger; RNA, Messenger - metabolism; Signal Transduction; Signal Transduction - drug effects; Tetrazolium Salts; Thiazoles; transcription (genetics); transporters; Vertebrates: nervous system and sense organs; Wnt Proteins; Wnt Proteins - genetics; Wnt Proteins - metabolism; Wnt/β-catenin signalling; xenobiotics; β-Amyloid; ABCC4; ABC; AD; ABCB1; Fzd-1; SEAP; BIO; LRP; LEF; MTT; Human brain endothelial cell; Wnt/β-catenin signalling; Aβ; GSK-3β; TCF; ROS; Dkk-1; β-Amyloid; ABCG2; Dickkopf-1; ATP-Binding Cassette; 3-(4,5-dimethylthiazol-2-)-2,5-diphenyl tetrazolium bromide; T-cell factor; low density lipoprotein receptor-related protein; reactive oxygen species; glycogen synthase kinase-3β; Alzheimer's disease; β-amyloid; Frizzled-1; 6-bromoindirubin-3′-oxime; secreted alkaline phosphatase; lymphoid enhancer-binding factor; Human; Endothelial cell; Central nervous system; Encephalon; β Amyloid protein; β Catenin; Carrier protein
• ISSN: 0006-8993; 1872-6240; 1872-6240
• DOI: 10.1016/j.brainres.2011.08.044

ABC (ATP Binding Cassette) efflux transporters at the blood–brain barrier, P-glycoprotein (ABCB1), multidrug resistance associated protein 4 (ABCC4) and breast cancer resistance protein (ABCG2), are important for protecting the brain from circulating xenobiotics. Their expression is regulated by signals from surrounding brain tissue that may alter in CNS pathologies. Differences have been reported in transporter expression on brain vasculature of Alzheimer's subjects where raised levels of β-amyloid (Aβ) occur. The present study examines in vitro the effects of Aβ using immortalised brain endothelial cells (hCMEC/D3). Significantly lower expression of ABCB1 but not ABCC4 or ABCG2 was found following exposure to Aβ 1–42 peptide but not its scrambled equivalent. This was evident at both protein and transcript level and was reflected in lower transcriptional activity of the ABCB1 promoter as judged from the luciferase reporter gene assay and in decreases in ABCB1-mediated efflux of rhodamine 123. Aβ exposure also affected Wnt/β-catenin signalling, decreasing levels of β-catenin protein, reducing activation of TOPFLASH and increasing transcript levels of endogenous inhibitor, Dkk-1. Application of Wnt3a reversed the Aβ-induced changes to ABCB1 protein. These results suggest that Aβ may impair Wnt/β-catenin signalling at the blood–brain barrier but that activation of this pathway may restore ABCB1. ► Can raised β-amyloid levels affect efflux transporters in brain endothelial cells? ► Lower expression of ABCB1 but not ABCC4 or ABCG2 seen following exposure to Aβ 1–42. ► Aβ effects reflected in decreased ABCB1-mediated efflux capacity. ► Aβ exposure also decreased Wnt/β-catenin signalling. ► Application of Wnt3a reversed the Aβ-induced changes to ABCB1 protein.