Localization and Processing of the Amyloid-β Protein Precursor in Mitochondria-Associated Membranes

J Alzheimers Dis. 2017;55(4):1549-1570. doi: 10.3233/JAD-160953.


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.

Keywords: Alzheimer disease; amyloid-β protein precursor; lipids; mitochondria associated membranes; proteomic.

MeSH terms

  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • CHO Cells
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism*
  • Cell Membrane / ultrastructure
  • Cricetulus
  • Electron Transport Complex IV / metabolism
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Humans
  • Immunoprecipitation
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Mutation / genetics
  • Neuroblastoma / pathology
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism
  • Pyrazoles / pharmacology
  • Quinolines / pharmacology
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Transfection
  • Voltage-Dependent Anion Channel 1 / metabolism


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Enzyme Inhibitors
  • Presenilin-1
  • Pyrazoles
  • Quinolines
  • Ryanodine Receptor Calcium Release Channel
  • (R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo(4,3-c)quinoline
  • Voltage-Dependent Anion Channel 1
  • cytochrome C oxidase subunit II
  • Electron Transport Complex IV
  • Amyloid Precursor Protein Secretases