title: MDR1-P-Glycoprotein (ABCB1) Mediates Transport of Alzheimer's amyloid-beta peptides--implications for the mechanisms of Abeta clearance at the blood-brain barrier.
abstract: 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.
authors.affiliation: Department of Pharmacology, Research Center of Pharmacology and Experimental Therapeutics, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Kuhnke
authors.forename: Gabriele
authors.initials: G
authors.lastname: Jedlitschky
authors.forename: Markus
authors.initials: M
authors.lastname: Grube
authors.forename: Markus
authors.initials: M
authors.lastname: Krohn
authors.forename: Mathias
authors.initials: M
authors.lastname: Jucker
authors.forename: Igor
authors.initials: I
authors.lastname: Mosyagin
authors.forename: Ingolf
authors.initials: I
authors.lastname: Cascorbi
authors.forename: Lary C
authors.initials: LC
authors.lastname: Walker
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Warzok
authors.forename: Silke
authors.initials: S
authors.lastname: Vogelgesang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002451:Cell Compartmentation / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D018374:LLC-PK1 Cells; D008657:Metabolic Clearance Rate / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D020112:Rhodamine 123 / Q000378:metabolism; D013552:Swine; D014162:Transfection; D022161:Transport Vesicles / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D020112:Rhodamine 123