Amyloid beta-induced ER stress is enhanced under mitochondrial dysfunction conditions

作者：Costa Rui O; Ferreiro Elisabete; Martins Isaura; Santana Isabel; Cardoso Sandra M; Oliveira Catarina R; Pereira Claudia M F^*

来源：Neurobiology of Aging, 2012, 33(4): 824.e5.

DOI：10.1016/j.neurobiolaging.2011.04.011

• Endoplasmic reticulum
• Alzheimer%26apos
• s disease
• Amyloid-beta
• Mitochondria
• Cytochrome c oxidase
• Cybrids

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%26apos;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.

• 出版日期2012-4