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Interactions with and Membrane Permeabilization of Brain Mitochondria by Amyloid Fibrils
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Localization and Processing of the Amyloid-β Protein Precursor in Mitochondria-Associated Membranes

Dolores Del Prete1,2, Jan M Suski3,4, Bénédicte Oulès5

  • 1Université Côte d'Azur, INSERM, CNRS, IPMC, France, Laboratory of Excellence DistALZ, Sophia-Antipolis, Valbonne, France.

Journal of Alzheimer'S Disease : JAD
|December 3, 2016
PubMed

Insights

Alzheimer's disease pathogenesis involves altered mitochondria-associated membranes (MAMs). Amyloid-beta precursor protein (AβPP) processing occurs in MAMs, impacting ER-mitochondria contacts and lipid accumulation.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Mitochondria-associated membranes (MAMs) are critical for cellular homeostasis.
  • Alterations in MAMs are implicated in the pathogenesis of Alzheimer's disease (AD).

Purpose of the Study:

  • To investigate the role of amyloid-beta protein precursor (AβPP) processing and its products within MAMs in AD.
  • To explore the protein interactome of AβPP and its catabolites in MAMs.

Main Methods:

  • Subcellular fractionation and analysis of AβPP and its products in MAMs.
  • Assessment of AβPP processing enzymes (β- and γ-secretases) in MAMs.
  • Proteomic analysis to identify AβPP interactors in MAMs.
  • Cellular models overexpressing wild-type or mutant AβPP, and AD transgenic mouse models were used.

Main Results:

  • AβPP and its catabolites are localized in MAMs in cellular and animal models of AD.
  • Both β- and γ-secretases are active in AβPP processing within MAMs.
  • Overexpression of APPswe increases ER-mitochondria contact sites and neutral lipid accumulation, which is reversed by secretase inhibition.
  • AβPP and its catabolites interact with key MAM proteins regulating mitochondrial and ER functions.

Conclusions:

  • AβPP processing and its interactome within MAMs contribute to MAM deregulation in Alzheimer's disease.
  • MAMs represent a significant site for AβPP metabolism and dysfunction in AD pathogenesis.
Keywords:
Alzheimer diseaseamyloid-β protein precursorlipidsmitochondria associated membranesproteomic

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