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Title: Structural and Functional Alterations in Mitochondria-Associated Membranes (MAMs) and in Mitochondria Activate Stress Response Mechanisms in an In Vitro Model of Alzheimer's Disease
Authors: Fernandes, Tânia 
Resende, Rosa Maria Branco de Matos Costa 
Silva, Diana F
Marques, Ana P. 
Santos, Armanda Emanuela Castro e 
Cardoso, Sandra Morais 
Domingues, M. Rosário M. 
Moreira, Paula I. 
Pereira, Cláudia F
Keywords: Alzheimer’s disease; Ca2+ signaling; ER-mitochondria contacts; mitochondrial dysfunction; subcellular fractions
Issue Date: 24-Jul-2021
Publisher: MDPI
Project: European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme: project CENTRO-01-0145-FEDER-000012-HealthyAging2020 
COMPETE 2020—Operational Programme for Competitiveness and Internationalization 
FCT—Fundação para a Ciência e a Tecnologia, I.P.: projects POCI-01-0145-FEDER-028214 and POCI-01-0145-FEDER-029369 and UIDB/04539/2020 and UIDP/04539/2020 
European Social Fund (Post-Doctoral Researcher Contract SFRH/BPD/101028/2014 to Rosa Resende) 
Tânia Fernandes is a recipient of the PhD fellow from the FCT (SFRH/BD/148801/2019). 
Volume: 9
Issue: 8
Abstract: Alzheimer's disease (AD) is characterized by the accumulation of extracellular plaques composed by amyloid-β (Aβ) and intracellular neurofibrillary tangles of hyperphosphorylated tau. AD-related neurodegenerative mechanisms involve early changes of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) and impairment of cellular events modulated by these subcellular domains. In this study, we characterized the structural and functional alterations at MAM, mitochondria, and ER/microsomes in a mouse neuroblastoma cell line (N2A) overexpressing the human amyloid precursor protein (APP) with the familial Swedish mutation (APPswe). Proteins levels were determined by Western blot, ER-mitochondria contacts were quantified by transmission electron microscopy, and Ca2+ homeostasis and mitochondria function were analyzed using fluorescent probes and Seahorse assays. In this in vitro AD model, we found APP accumulated in MAM and mitochondria, and altered levels of proteins implicated in ER-mitochondria tethering, Ca2+ signaling, mitochondrial dynamics, biogenesis and protein import, as well as in the stress response. Moreover, we observed a decreased number of close ER-mitochondria contacts, activation of the ER unfolded protein response, reduced Ca2+ transfer from ER to mitochondria, and impaired mitochondrial function. Together, these results demonstrate that several subcellular alterations occur in AD-like neuronal cells, which supports that the defective ER-mitochondria crosstalk is an important player in AD physiopathology.
ISSN: 2227-9059
DOI: 10.3390/biomedicines9080881
Rights: openAccess
Appears in Collections:I&D CIBB - Artigos em Revistas Internacionais

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