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MDR1‐P‐Glycoprotein (ABCB1) Mediates Transport of Alzheimer’s Amyloid‐β Peptides—Implications for the Mechanisms of Aβ Clearance at the Blood–Brain Barrier

2007; Wiley; Volume: 17; Issue: 4 Linguagem: Inglês

10.1111/j.1750-3639.2007.00075.x

1750-3639

Diana Kuhnke, Gabriele Jedlitschky, Markus Grube, Markus Krohn, Mathias Jucker, Igor Mosyagin, Ingolf Cascorbi, Lary C. Walker, Heyo K. Kroemer, R Warzok, Silke Vogelgesang,

Trace Elements in Health

Amyloid-beta (Abeta) 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 Abeta from the brain. In the present study, MDR1-transfected LLC cells growing in a polarized cell layer were used to characterize the interaction of Abeta1-40/1-42 with P-gp. In this system, P-gp-mediated transport can be followed by the efflux of the fluorescent dye rhodamine-123, or of Abeta itself from the cells into the apical extracellular space. Abeta significantly decreased the apical efflux of rhodamine-123, and the transcellular transport of Abeta1-40 and Abeta1-42 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 Abeta from brain, and thus may represent a target protein for the prevention and/or treatment of neurodegenerative disorders such as AD.