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

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