The pathogenesis of Alzheimer's disease is characterized by aggregation of the amyloid-beta protein (Abeta) into neurotoxic plaques. Recent in vivo studies have suggested the non-proteolytic clearance of Abeta via receptor-mediated transport across the blood-brain barrier (BBB). The aim of this study was to investigate the role of P-glycoprotein (Pgp) and the low-density lipoprotein receptor-related protein (LRP) in Abeta efflux across the BBB. We developed an in vitro BBB-like model using Madin-Darby Canine Kidney (MDCK) cells seeded on filters separating apical (blood) and basolateral (brain) compartments. MDCK cells were stably transfected with Pgp or mLRP4, an LRP mini-receptor. When compared to empty vector-transfected cells, MDCK-Pgp cells did not transcytose radiolabeled Abeta in the basolateral-to-apical direction. MDCK-mLRP4 cells were found to endocytose and degrade, but not to trasncytose intact radiolabeled Abeta. These results implicate LRP as a mediator of Abeta degradation, but indicate that overexpression of LRP or Pgp alone is insufficient for non-proteolytic transcytosis of intact Abeta.