LRP promotes endocytosis and degradation, but not transcytosis, of the amyloid-beta peptide in a blood-brain barrier in vitro model.
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.
Nazer
Babak
B
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Hong
Soyon
S
Selkoe
Dennis J
DJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D019921:Biotinylation / Q000379:methods; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002461:Cell Line, Transformed; D004285:Dogs; D004705:Endocytosis / Q000502:physiology*; D004847:Epithelial Cells; D006727:Hormone Antagonists / Q000494:pharmacology; D007456:Iodine Isotopes / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000502:physiology*; D015735:Mifepristone / Q000494:pharmacology; D008954:Models, Biological; D010446:Peptide Fragments / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D006727:Hormone Antagonists; D007456:Iodine Isotopes; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D015735:Mifepristone; D014700:Verapamil