Brain Research, Oct 18, 2011, Vol.1418, p.1(11)
To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.brainres.2011.08.044 Byline: Katarzyna D. Kania, Hasini C. Wijesuriya, Stephen B. Hladky, Margery A. Barrand Keywords: Human brain endothelial cell; ABCB1; ABCG2; ABCC4; Wnt/[beta]-catenin signalling; [beta]-Amyloid Abbreviations: A[beta], [beta]-amyloid; ABC, ATP-Binding Cassette; AD, Alzheimer's disease; BIO, 6-bromoindirubin-3'-oxime; Dkk-1, Dickkopf-1; Fzd-1, Frizzled-1; GSK-3[beta], glycogen synthase kinase-3[beta]; LEF, lymphoid enhancer-binding factor; LRP, low density lipoprotein receptor-related protein; MTT, 3-(4,5-dimethylthiazol-2-)-2,5-diphenyl tetrazolium bromide; ROS, reactive oxygen species; SEAP, secreted alkaline phosphatase; TCF, T-cell factor 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 [beta]-amyloid (A[beta]) occur. The present study examines in vitro the effects of A[beta] using immortalised brain endothelial cells (hCMEC/D3). Significantly lower expression of ABCB1 but not ABCC4 or ABCG2 was found following exposure to A[beta].sub.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. A[beta] exposure also affected Wnt/[beta]-catenin signalling, decreasing levels of [beta]-catenin protein, reducing activation of TOPFLASH and increasing transcript levels of endogenous inhibitor, Dkk-1. Application of Wnt3a reversed the A[beta]-induced changes to ABCB1 protein. These results suggest that A[beta] may impair Wnt/[beta]-catenin signalling at the blood-brain barrier but that activation of this pathway may restore ABCB1. Article History: Accepted 17 August 2011
Bromine Compounds ; Genetic Research ; Endothelium ; Glycogen ; Phosphatases ; Alzheimer's Disease ; Glycogen Synthesis
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