MDR1-P-glycoprotein (ABCB1) mediates transport of Alzheimer's amyloid-β peptides -: Implications for the mechanisms of Aβ clearance at the blood-brain barrier

Amyloid-beta (A beta) is the major component of the insoluble amyloid plaques that accumulate intracerebrally in patients with Alzheimer's disease (AD). It has been suggested that MDR1-P-glycoprotein (ABCB1, P-gp) plays a substantial role in the elimination of A beta from the brain. In the present study, MDR1-transfected LLC cells growing in a polarized cell layer were used to characterize the interaction of A beta 1-40/1-42 with P-gp. In this system, P-gp-mediated transport can be followed by the efflux of the fluorescent dye rhodamine-123, or of A beta itself from the cells into the apical extracellular space. A beta significantly decreased the apical efflux of rhodamine-123, and the transcellular transport of A beta 1-40 and A beta 1-42 into the apical chamber could be demonstrated using both ELISA and fluorescence (FITC)-labeled peptides. This transport was inhibited by a P-gp modulator. Furthermore, ATP-dependent, P-gp-mediated transport of the fluorescence-labeled peptides could be demonstrated in isolated, inside-out membrane vesicles. Our data support the concept that P-gp is important for the clearance of A beta from brain, and thus may represent a target protein for the prevention and/or treatment of neurodegenerative disorders such as AD.