title: ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro.
abstract: ATP-binding cassette transporter A7 (ABCA7) is expressed in the brain and, like its closest homolog ABCA1, belongs to the ABCA subfamily of full-length ABC transporters. ABCA1 promotes cellular cholesterol efflux to lipid-free apolipoprotein acceptors and also inhibits the production of neurotoxic beta-amyloid (Abeta) peptides in vitro. The potential functions of ABCA7 in the brain are unknown. This study investigated the ability of ABCA7 to regulate cholesterol efflux to extracellular apolipoprotein acceptors and to modulate Abeta production. The transient expression of ABCA7 in human embryonic kidney cells significantly stimulated cholesterol efflux (fourfold) to apolipoprotein E (apoE) discoidal lipid complexes but not to lipid-free apoE or apoA-I. ABCA7 also significantly inhibited Abeta secretion from Chinese hamster ovary cells stably expressing human amyloid precursor protein (APP) or APP containing the Swedish K670M671-->N670L671 mutations when compared with mock-transfected cells. Studies with fluorogenic substrates indicated that ABCA7 had no impact on alpha-, beta-, or gamma-secretase activities. Live cell imaging of Chinese hamster ovary cells expressing APP-GFP indicated an apparent retention of APP in a perinuclear location in ABCA7 co-transfected cells. These studies indicate that ABCA7 has the capacity to stimulate cellular cholesterol efflux to apoE discs and regulate APP processing resulting in an inhibition of Abeta production.
authors.affiliation: Prince of Wales Medical Research Institute, Randwick, New South Wales, Australia.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Chan
authors.forename: Woojin Scott
authors.initials: WS
authors.lastname: Kim
authors.forename: John B
authors.initials: JB
authors.lastname: Kwok
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Hill
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.forename: Brett
authors.initials: B
authors.lastname: Garner
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D053829:Amyloid Precursor Protein Secretases / Q000145:classification / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002461:Cell Line, Transformed; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010446:Peptide Fragments / Q000494:pharmacology; D014162:Transfection / Q000379:methods
chemical_list: C411895:ABCA7 protein, human; D018528:ATP-Binding Cassette Transporters; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D049452:Green Fluorescent Proteins; D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases