Localization and Processing of the Amyloid-? 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-? protein precursor (A?PP) and its proteolytic products in MAMs. We reveal that A?PP and its catabolites are present in MAMs in cellular models overexpressing wild type A?PP or A?PP harboring the double Swedish or London familial AD mutations, and in brains of transgenic mice model of AD. Furthermore, we evidenced that both ?- and ?-secretases are present and harbor A?PP processing activities in MAMs. Interestingly, cells overexpressing APPswe show increased ER-mitochondria contact sites. We also document increased neutral lipid accumulation linked to A? production and reversed by inhibiting ?- or ?-secretases. Using a proteomic approach, we show that A?PP and its catabolites interact with key proteins of MAMs controlling mitochondria and ER functions. These data highlight the role of A?PP processing and proteomic interactome in MAMs deregulation taking place in AD.

SUBMITTER: Del Prete D 

PROVIDER: S-EPMC5181669 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature