Localization and Processing of the Amyloid-β 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-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.

In vivo Ca2+ imaging of astrocytic microdomains reveals a critical role of the amyloid precursor protein for mitochondria

“…Additionally, the KPI domain of APP, which is predominantly expressed in astrocytes, has been shown to be important for APP localization to mitochondrial (Wang et al, ). More specifically, APP localizes at the translocase of the outer mitochondrial membrane (TOMM) complex, where it affects the import of nuclear encoded proteins into mitochondria (Del Prete et al, ). Intriguingly, this mechanism appears disrupted in AD and APP tends to accumulate around TOMM complexes under pathophysiological conditions (Anandatheerthavarada, Biswas, Robin, & Avadhani, ; Del Prete et al, ; Devi, Prabhu, Galati, Avadhani, & Anandatheerthavarada, ).…”

The Role of Ca2+ Signaling in Aging and Neurodegeneration: Insights from Caenorhabditis elegans Models

“…These regions constitute an almost direct pathway for Ca 2+ transfer from the ER to mitochondria, thanks to the presence of IP 3 R in the ER, voltage-dependent anion channels in the outer mitochondrial membrane, and mitochondrial Ca 2+ uniporters in the inner mitochondrial membrane, together with many other proteins that form long-lasting structures that keep ER and mitochondrial membranes at distances of 10-30 nm. It has been shown that presenilins and APP are ER integral membrane proteins that are enriched in the MAMs [56][57][58], so they can easily interact with all the machinery for ER-mitochondria Ca 2+ transfer. In fact, several Alzheimer's disease inducers or presenilin mutations enhance ER to mitochondria Ca 2+ transfer through these structures [59].…”

In Vivo Elevation of Mitochondrial Activity and Amyloid Deposition, but Inversely Correlated, in Early-stage Senescence-Accelerated Mice: A Positron Emission Tomography Study

“…Interestingly, the proteolytic activity of PreP is decreased in the AD brain [31]. Aβ can be localized to the inner mitochondrial membrane [32], and constituents of the γ-secretase complex, such as nicastrin, APH-1, PEN-2, and presenilin-1, which function in APP processing, are also localized within the mitochondria-associated membrane [33,34]. It has been reported that mitochondrial dysfunction and neurodegeneration occur in model mice with deleted HtrA2, a serine protease that interacts with Aβ, APP, and presenilin-1 within the intermembrane space [35].…”