title: Localization and Processing of the Amyloid-β Protein Precursor in Mitochondria-Associated Membranes.
abstract: Alteration of mitochondria-associated membranes (MAMs) has been proposed to contribute to the pathogenesis of Alzheimer's disease (AD). We studied herein the subcellular distribution, the processing, and the protein interactome of the amyloid-β protein precursor (AβPP) and its proteolytic products in MAMs. We reveal that AβPP and its catabolites are present in MAMs in cellular models overexpressing wild type AβPP or AβPP harboring the double Swedish or London familial AD mutations, and in brains of transgenic mice model of AD. Furthermore, we evidenced that both β- and γ-secretases are present and harbor AβPP processing activities in MAMs. Interestingly, cells overexpressing APPswe show increased ER-mitochondria contact sites. We also document increased neutral lipid accumulation linked to Aβ production and reversed by inhibiting β- or γ-secretases. Using a proteomic approach, we show that AβPP and its catabolites interact with key proteins of MAMs controlling mitochondria and ER functions. These data highlight the role of AβPP processing and proteomic interactome in MAMs deregulation taking place in AD.
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, IPMC, France, Laboratory of Excellence DistALZ, Sophia-Antipolis, Valbonne, France.|Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Dolores
authors.initials: D
authors.lastname: Del Prete
authors.affiliation: Department of Biochemistry, Nencki Institute of Experimental Biology, Warsaw, Poland.|CCMA-Université de Nice-Sophia-Antipolis, Nice, France.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Suski
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Oulès
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, IPMC, France, Laboratory of Excellence DistALZ, Sophia-Antipolis, Valbonne, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Debayle
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, IPMC, France, Laboratory of Excellence DistALZ, Sophia-Antipolis, Valbonne, France.
authors.forename: Anne Sophie
authors.initials: AS
authors.lastname: Gay
authors.affiliation: CCMA-Université de Nice-Sophia-Antipolis, Nice, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lacas-Gervais
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, IPMC, France, Laboratory of Excellence DistALZ, Sophia-Antipolis, Valbonne, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Bussiere
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, IPMC, France, Laboratory of Excellence DistALZ, Sophia-Antipolis, Valbonne, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bauer
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.affiliation: INSERM U 807, Paris V University, Paris, France.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Paterlini-Bréchot
authors.affiliation: Department of Biochemistry, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Mariusz R
authors.initials: MR
authors.lastname: Wieckowski
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, IPMC, France, Laboratory of Excellence DistALZ, Sophia-Antipolis, Valbonne, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Checler
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, IPMC, France, Laboratory of Excellence DistALZ, Sophia-Antipolis, Valbonne, France.
authors.forename: Mounia
authors.initials: M
authors.lastname: Chami
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D003412:Cricetulus; D003576:Electron Transport Complex IV / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014162:Transfection; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D053764:Presenilin-1; D011720:Pyrazoles; D011804:Quinolines; D019837:Ryanodine Receptor Calcium Release Channel; C573127:(R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo(4,3-c)quinoline; D050995:Voltage-Dependent Anion Channel 1; C117108:cytochrome C oxidase subunit II; D003576:Electron Transport Complex IV; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer disease; amyloid-β protein precursor; lipids; mitochondria associated membranes; proteomic