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

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

Author information

1
Université Côte d'Azur, INSERM, CNRS, IPMC, France, Laboratory of Excellence DistALZ, Sophia-Antipolis, Valbonne, France.
2
Albert Einstein College of Medicine, Bronx, NY, USA.
3
Department of Biochemistry, Nencki Institute of Experimental Biology, Warsaw, Poland.
4
CCMA-Université de Nice-Sophia-Antipolis, Nice, France.
5
Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK.
6
Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy.
7
INSERM U 807, Paris V University, Paris, France.

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.

KEYWORDS:

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

PMID:
27911326
PMCID:
PMC5181669
DOI:
10.3233/JAD-160953
[Indexed for MEDLINE]
Free PMC Article

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