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

Katarzyna D Kania; Hasini C Wijesuriya; Stephen B Hladky; Margery A Barrand

doi:10.1016/j.brainres.2011.08.044

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

Brain Res. 2011 Oct 18:1418:1-11. doi: 10.1016/j.brainres.2011.08.044. Epub 2011 Aug 23.

Authors

Katarzyna D Kania¹, Hasini C Wijesuriya, Stephen B Hladky, Margery A Barrand

Affiliation

¹ Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.

PMID: 21920506
DOI: 10.1016/j.brainres.2011.08.044

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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 / genetics
ATP-Binding Cassette Transporters / metabolism
Amyloid beta-Peptides / pharmacology*
Biological Transport / drug effects
Brain / cytology*
Cell Line, Transformed
Endothelial Cells / drug effects*
Gene Expression Regulation / drug effects*
Humans
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism*
Multidrug Resistance-Associated Proteins / genetics
Multidrug Resistance-Associated Proteins / metabolism
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism
RNA, Messenger / metabolism
Rhodamine 123 / metabolism
Signal Transduction / drug effects
Tetrazolium Salts
Thiazoles
Wnt Proteins / genetics
Wnt Proteins / metabolism
beta Catenin / metabolism

Substances

ABCC4 protein, human
ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters
Amyloid beta-Peptides
DKK1 protein, human
Intercellular Signaling Peptides and Proteins
Multidrug Resistance-Associated Proteins
Neoplasm Proteins
RNA, Messenger
Tetrazolium Salts
Thiazoles
Wnt Proteins
beta Catenin
Rhodamine 123
thiazolyl blue