title: Wild type and Tangier disease ABCA1 mutants modulate cellular amyloid-β production independent of cholesterol efflux activity.
abstract: Cerebral amyloid-β (Aβ) deposition is a critical feature of Alzheimer's disease. Aβ is derived from the amyloid-β protein precursor (AβPP) via two sequential cleavages that are mediated by β-secretase and the γ-secretase complex. Such amyloidogenic AβPP processing occurs in lipid raft microdomains of cell membranes and it is thought that modulating the distribution of lipids in rafts may regulate AβPP processing and Aβ production. Certain ATP-binding cassette (ABC) transporters regulate lipid transport across cell membranes and, as recent studies reveal, within membrane microdomains. ABCA1 also regulates Aβ metabolism in the brain although its direct impact on AβPP remains an open question. Here we assessed the capacity of three ABCA1 mutants (that do not promote lipid efflux) to modulate AβPP processing. Unexpectedly, these non-functional mutants also reduced Aβ production similar to wild type ABCA1. ABCA1 expression did not alter AβPP localization in lipid rafts, and co-immunoprecipitation experiments indicated ABCA1 and AβPP physically interact. These data suggest that ABCA1 may regulate AβPP processing independent of its impact on membrane lipid homeostasis.
authors.affiliation: Neuroscience Research Australia, Sydney, NSW, Australia.
authors.forename: Woojin S
authors.initials: WS
authors.lastname: Kim
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Hill
authors.forename: Michael L
authors.initials: ML
authors.lastname: Fitzgerald
authors.forename: Mason W
authors.initials: MW
authors.lastname: Freeman
authors.forename: Genevieve
authors.initials: G
authors.lastname: Evin
authors.forename: Brett
authors.initials: B
authors.lastname: Garner
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D001692:Biological Transport / Q000235:genetics; D016466:CHO Cells; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008563:Membrane Lipids / Q000502:physiology; D021962:Membrane Microdomains / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D013631:Tangier Disease / Q000235:genetics / Q000378:metabolism*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016564:Amyloid beta-Protein Precursor; D008563:Membrane Lipids; D002784:Cholesterol