Journal
NEUROBIOLOGY OF AGING
Volume 33, Issue 4, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2011.04.011
Keywords
Endoplasmic reticulum; Alzheimer's disease; Amyloid-beta; Mitochondria; Cytochrome c oxidase; Cybrids
Categories
Funding
- Fundacao para a Ciencia e a Tecnologia (FCT) [Prize L'Oreal/FCT/UNESCO 2004, PIC/IC/83206/2007, SFRH/BD/28403/2006, SFRH/BD/14108/2003]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/28403/2006, SFRH/BD/14108/2003] Funding Source: FCT
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Previously we reported that endoplasmic reticulum (ER)-mitochondria crosstalk is involved in amyloid-beta (A beta)-induced apoptosis. Now we show that mitochondrial dysfunction affects the ER stress response triggered by A beta using cybrids that recreate the defect in mitochondrial cytochrome c oxidase (COX) activity detected in platelets from Alzheimer's disease (AD) patients. AD and control cybrids were treated with A beta or classical ER stressors and the ER stress-mediated apoptotic cell death pathway was accessed. Upon treatment, we found increased glucose-regulated protein 78 (GRP78) levels and caspase-4 activation (ER stress markers) which were more pronounced in AD cybrids. Treated AD cybrids also exhibited decreased cell survival as well as increased caspase-3-like activity, poli-ADP-ribose-polymerase (PARP) levels and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells. Finally, we showed that A beta-induced caspase-3 activation in both cybrid cell lines was prevented by dantrolene, thus implicating ER Ca2+ release in ER stress-mediated apoptosis. Our results demonstrate that mitochondrial dysfunction occurring in AD patients due to COX inhibition potentiates cell susceptibility to A beta-induced ER stress. This study further supports the close communication between ER and mitochondria during apoptosis in AD. (C) 2012 Elsevier Inc. All rights reserved.
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