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

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.

ABC efflux transporters in brain vasculature of Alzheimer's subjects.

Multidrug efflux transporters of the ATP-Binding cassette (ABC) family, P-glycoprotein (Pgp), multidrug-resistance associated protein 4 (MRP4) and breast cancer resistance protein (BCRP), located on endothelial cells lining brain vasculature play important roles in limiting movement of substances into and enhancing their efflux from the brain. Signals from the surrounding brain normally maintain such barrier function but these may become altered in CNS pathologies such as Alzheimer's disease (AD). Previous studies have reported decreases in the glucose transporter, Glut-1, in brain vasculature of AD patients.

Decreased expression of multidrug efflux transporters in the brains of GSK-3beta transgenic mice.

Multidrug efflux transporters protect cells in the brain from potentially harmful substances but also from therapeutically useful drugs. Thus any condition that causes changes in their expression is of some importance with regard to drug access. In this study, changes in efflux transporter expression are investigated in mice containing a mutant constitutively active glycogen synthase kinase-3 (GSK-3beta) transgene, driven by the Thy-1 promoter so limiting its localization predominantly to neurons and some glial cells.

Activation of beta-catenin signalling by GSK-3 inhibition increases p-glycoprotein expression in brain endothelial cells.

This study investigates involvement of beta-catenin signalling in regulation of p-glycoprotein (p-gp) expression in endothelial cells derived from brain vasculature. Pharmacological interventions that enhance or that block beta-catenin signalling were applied to primary rat brain endothelial cells and to immortalized human brain endothelial cells, hCMEC/D3, nuclear translocation of beta-catenin being determined by immunocytochemistry and by western blot analysis to confirm effectiveness of the manipulations. Using the specific glycogen synthase kinase-3 (GSK-3) inhibitor 6-bromoindirubin-3'-oxime enhanced beta-catenin and increased p-gp expression including activating the MDR1 promoter.