title: Down-regulation of the ATP-binding cassette transporter 2 (Abca2) reduces amyloid-β production by altering Nicastrin maturation and intracellular localization.
abstract: Clinical, pharmacological, biochemical, and genetic evidence support the notion that alteration of cholesterol homeostasis strongly predisposes to Alzheimer disease (AD). The ATP-binding cassette transporter-2 (Abca2), which plays a role in intracellular sterol trafficking, has been genetically linked to AD. It is unclear how these two processes are related. Here we demonstrate that down-regulation of Abca2 in mammalian cells leads to decreased amyloid-β (Aβ) generation. In vitro studies revealed altered γ-secretase complex formation in Abca2 knock-out cells due to the altered levels, post-translational modification, and subcellular localization of Nicastrin. Reduced Abca2 levels in mammalian cells in vitro, in Drosophila melanogaster and in mice resulted in altered γ-secretase processing of APP, and thus Aβ generation, without affecting Notch cleavage.
authors.affiliation: Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Michaki
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Guix
authors.forename: Krist'l
authors.initials: K
authors.lastname: Vennekens
authors.forename: Sebastian
authors.initials: S
authors.lastname: Munck
authors.forename: Colin
authors.initials: C
authors.lastname: Dingwall
authors.forename: John B
authors.initials: JB
authors.lastname: Davis
authors.forename: Danyelle M
authors.initials: DM
authors.lastname: Townsend
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Tew
authors.forename: Fabian
authors.initials: F
authors.lastname: Feiguin
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Dotti
authors.forename: Tina
authors.initials: T
authors.lastname: Wahle
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015536:Down-Regulation / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D057809:HEK293 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats
chemical_list: C418186:ABCA2 protein, human; C545487:APP protein, human; D018528:ATP-Binding Cassette Transporters; C498824:Abca2 protein, mouse; C498825:Abca2 protein, rat; D016564:Amyloid beta-Protein Precursor; D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases
references.citation: Biochim Biophys Acta. 2010 Aug;1801(8):860-7
references.pmid: 20303415
references.citation: Neurobiol Dis. 2000 Aug;7(4):321-31
references.pmid: 10964604
references.citation: J Biol Chem. 1999 Apr 2;274(14):9627-35
references.pmid: 10092649
references.citation: J Neurosci. 2003 Jul 2;23(13):5645-9
references.pmid: 12843267
references.citation: J Cell Sci. 2003 Mar 15;116(Pt 6):1127-36
references.pmid: 12584255
references.citation: J Cell Biol. 2003 Jan 6;160(1):113-23
references.pmid: 12515826
references.citation: Expert Opin Ther Targets. 2008 Apr;12(4):491-504
references.pmid: 18348684
references.citation: J Neurochem. 2006 Apr;97(2):345-55
references.pmid: 16539677
references.citation: Neuron. 2004 Jan 8;41(1):7-10
references.pmid: 14715130
references.citation: Curr Biol. 2001 Aug 21;11(16):1288-93
references.pmid: 11525745
references.citation: J Neurocytol. 2003 Jun-Sep;32(5-8):619-47
references.pmid: 15034257
references.citation: J Biol Chem. 2003 Dec 26;278(52):53112-22
references.pmid: 14561753
references.citation: Neurobiol Dis. 2005 Feb;18(1):119-25
references.pmid: 15649702
references.citation: J Biol Chem. 2005 Jul 8;280(27):25892-900
references.pmid: 15886206
references.citation: J Neurochem. 2002 Dec;83(5):1065-71
references.pmid: 12437577
references.citation: Neurology. 2006 Jan 24;66(2 Suppl 1):S69-73
references.pmid: 16432149
references.citation: Nat Protoc. 2006;1(5):2406-15
references.pmid: 17406484
references.citation: J Biol Chem. 2002 Sep 20;277(38):35113-7
references.pmid: 12130643
references.citation: Traffic. 2010 Sep;11(9):1234-45
references.pmid: 20573067
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11735-40
references.pmid: 14504402
references.citation: Biochemistry. 2002 Mar 5;41(9):3128-36
references.pmid: 11863452
references.citation: Curr Alzheimer Res. 2010 Nov;7(7):566-77
references.pmid: 20704561
references.citation: Front Biosci. 2001 Mar 01;6:D505-14
references.pmid: 11229879
references.citation: J Neurosci. 2002 Mar 1;22(5):1679-89
references.pmid: 11880497
references.citation: J Lipid Res. 2001 Jul;42(7):1007-17
references.pmid: 11441126
references.citation: J Biol Chem. 2003 Feb 28;278(9):7374-80
references.pmid: 12471034
references.citation: J Biol Chem. 2009 Jan 16;284(3):1373-84
references.pmid: 19028695
references.citation: Eur J Biochem. 2004 Jan;271(2):375-85
references.pmid: 14717705
references.citation: FASEB J. 2004 Jul;18(10):1129-31
references.pmid: 15155565
references.citation: Nature. 1999 Apr 8;398(6727):518-22
references.pmid: 10206645
references.citation: J Cell Biol. 2004 Sep 27;166(7):1041-54
references.pmid: 15452145
references.citation: Annu Rev Cell Dev Biol. 2002;18:25-51
references.pmid: 12142279
references.citation: Neurodegener Dis. 2006;3(4-5):305-11
references.pmid: 17047372
references.citation: Nature. 1999 Apr 8;398(6727):522-5
references.pmid: 10206646
references.citation: Nat Rev Mol Cell Biol. 2007 Jan;8(1):74-84
references.pmid: 17183362
references.citation: FEBS Lett. 2002 Jun 5;520(1-3):117-21
references.pmid: 12044882
references.citation: J Biol Chem. 2008 Apr 25;283(17):11302-11
references.pmid: 18308724
references.citation: J Biol Chem. 2011 Apr 8;286(14):12271-82
references.pmid: 21296884
references.citation: Mol Cell Biol. 2007 Jan;27(1):44-53
references.pmid: 17060448
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1719-24
references.pmid: 15665098
references.citation: Hum Mol Genet. 2003 Oct 15;12(20):2669-78
references.pmid: 12944419
references.citation: Neurology. 2001 Sep 25;57(6):1089-93
references.pmid: 11571339
references.citation: J Neurochem. 2002 Jun;81(5):1011-20
references.pmid: 12065613
references.citation: J Biol Chem. 2004 Oct 22;279(43):44945-54
references.pmid: 15322084
references.citation: Biochim Biophys Acta. 1994 Feb 22;1225(3):235-43
references.pmid: 8312368
references.citation: Curr Drug Metab. 2007 Jan;8(1):47-57
references.pmid: 17266523
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2006 Jul 5;141B(5):534-6
references.pmid: 16752360
references.citation: PLoS One. 2007 Sep 05;2(9):e851
references.pmid: 17786222
references.citation: Biochim Biophys Acta. 1991 Jun 5;1096(4):328-37
references.pmid: 2065104
references.citation: J Biol Chem. 2005 Nov 4;280(44):36815-23
references.pmid: 16115865
references.citation: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6460-4
references.pmid: 9600988
references.citation: Neurology. 1992 Dec;42(12):2286-90
references.pmid: 1461380
references.citation: Handb Clin Neurol. 2008;89:245-60
references.pmid: 18631749
references.citation: J Biol Chem. 2002 Aug 2;277(31):28135-42
references.pmid: 12032140
references.citation: J Biol Chem. 2003 Aug 15;278(33):31261-8
references.pmid: 12761223
references.citation: Biochem J. 2005 Sep 1;390(Pt 2):549-61
references.pmid: 15896196
references.citation: Physiol Rev. 2001 Apr;81(2):741-66
references.pmid: 11274343
references.citation: J Surg Res. 2009 Jul;155(1):65-9
references.pmid: 19159910
references.citation: Nat Rev Neurosci. 2006 Feb;7(2):93-102
references.pmid: 16429119
references.citation: Development. 2000 Feb;127(4):851-60
references.pmid: 10648243
references.citation: Proc Natl Acad Sci U S A. 2001 May 8;98(10):5815-20
references.pmid: 11309494
references.citation: Biochim Biophys Acta. 1999 Dec 6;1461(2):237-62
references.pmid: 10581359
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8666-71
references.pmid: 12048259
references.citation: Science. 2004 Apr 30;304(5671):700-3
references.pmid: 15044753
references.citation: J Biol Chem. 2003 Oct 31;278(44):43430-6
references.pmid: 12885769
references.citation: Biochem J. 2000 Sep 15;350 Pt 3:865-72
references.pmid: 10970803
references.citation: Neurobiol Dis. 2002 Feb;9(1):11-23
references.pmid: 11848681
references.citation: Clin Transplant. 2009 Nov-Dec;23(6):897-903
references.pmid: 19566755
references.citation: J Biol Chem. 2001 May 4;276(18):14634-41
references.pmid: 11278841
references.citation: Mol Cell. 2000 Sep;6(3):625-36
references.pmid: 11030342
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9775-80
references.pmid: 18626010
references.citation: Biochim Biophys Acta. 2004 Jul 5;1683(1-3):89-100
references.pmid: 15238223
references.citation: Neurobiol Dis. 2008 Mar;29(3):422-37
references.pmid: 18086530
references.citation: J Cell Biol. 2004 Dec 6;167(5):953-60
references.pmid: 15583033