期刊
BIOMEDICINES
卷 9, 期 8, 页码 -出版社
MDPI
DOI: 10.3390/biomedicines9080881
关键词
Alzheimer's disease; subcellular fractions; ER-mitochondria contacts; Ca2+ signaling; mitochondrial dysfunction
资金
- European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme [CENTRO-01-0145-FEDER-000012-HealthyAging2020]
- COMPETE 2020-Operational Programme for Competitiveness and Internationalization
- Portuguese national funds via FCT-FundacAo para a Ciencia e a Tecnologia, I.P. [POCI-01-0145-FEDER-028214, POCI-01-0145-FEDER-029369, UIDB/04539/2020, UIDP/04539/2020]
- European Social Fund [SFRH/BPD/101028/2014]
- FCT [SFRH/BD/148801/2019]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/148801/2019] Funding Source: FCT
Alzheimer's disease is characterized by the accumulation of plaques in the brain, and this study found that abnormalities in the crosstalk between the endoplasmic reticulum and mitochondria may play a crucial role in the pathophysiology of AD.
Alzheimer's disease (AD) is characterized by the accumulation of extracellular plaques composed by amyloid-beta (A beta) 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.
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