title: Amyloid β-induced ER stress is enhanced under mitochondrial dysfunction conditions.
abstract: Previously we reported that endoplasmic reticulum (ER)-mitochondria crosstalk is involved in amyloid-β (Aβ)-induced apoptosis. Now we show that mitochondrial dysfunction affects the ER stress response triggered by Aβ 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 Aβ 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 Aβ-induced caspase-3 activation in both cybrid cell lines was prevented by dantrolene, thus implicating ER Ca(2+) release in ER stress-mediated apoptosis. Our results demonstrate that mitochondrial dysfunction occurring in AD patients due to COX inhibition potentiates cell susceptibility to Aβ-induced ER stress. This study further supports the close communication between ER and mitochondria during apoptosis in AD.
authors.affiliation: Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Rui O
authors.initials: RO
authors.lastname: Costa
authors.forename: Elisabete
authors.initials: E
authors.lastname: Ferreiro
authors.forename: Isaura
authors.initials: I
authors.lastname: Martins
authors.forename: Isabel
authors.initials: I
authors.lastname: Santana
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Cardoso
authors.forename: Catarina R
authors.initials: CR
authors.lastname: Oliveira
authors.forename: Cláudia M F
authors.initials: CM
authors.lastname: Pereira
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D001792:Blood Platelets / Q000166:cytology; D020126:Brefeldin A / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002459:Cell Fusion / Q000379:methods; D045744:Cell Line, Tumor / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects / Q000648:ultrastructure*; D020287:In Situ Nick-End Labeling; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013778:Tetrazolium Salts; D019284:Thapsigargin / Q000494:pharmacology; D013844:Thiazoles
chemical_list: D016229:Amyloid beta-Peptides; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D010446:Peptide Fragments; D011500:Protein Synthesis Inhibitors; D013778:Tetrazolium Salts; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); D020126:Brefeldin A; D019284:Thapsigargin; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; C022616:thiazolyl blue