title: A Role for P-Glycoprotein in Clearance of Alzheimer Amyloid β -Peptide from the Brain.
abstract: Most data indicates that Alzheimer's disease involves an accumulation of amyloid β - peptide (Aβ) in the CNS and that sporadic cases arise from a deficiency in Aβ clearance. Considerable attention has been given to mechanisms by which Aβ might be transported between the brain and blood, and evidence suggests that p-glycoprotein, also known as the multi-drug resistance (MDR) protein (product of the ABCB1 gene), plays a role in Aβ transport across the blood-brain barrier (BBB). We tested this possibility through two approaches: First, wild-type and MDR1A-knockout mice were compared after intravenous injection of [(125)I]-labeled Aβ; after 60 min, homogenates of brain parenchyma were subjected to γ-counting of TCA-precipitable material, and histological sections of brain were subjected to autoradiography. Second, MDR1Aknockout mice were crossed with Tg2576 APP transgenic mice, a line that routinely accumulates Aβ in the brain; SDS and formic acid extracts of brain homogenates were assessed for Aβ levels by ELISA. Each of these approaches yielded data indicating that Aβ accumulates to a greater degree in mice lacking MDR1A. These findings confirm other reports linking p-glycoprotein to Aβ clearance across the BBB and have important implications for Alzheimer's disease genetics, pharmacology, and epidemiology.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Angela M
authors.initials: AM
authors.lastname: Bodles-Brakhop
authors.affiliation: Reynolds Institute on Aging, #807, 629 Jack Stephens Drive, Little Rock AR 72205, USA. bargerstevenw@uams.edu.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Barger
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C095122:multidrug resistance protein 3