ER stress-mediated apoptotic pathway induced by Abeta peptide requires the presence of functional mitochondria.
Amyloid-beta (Abeta) peptide plays a significant role in the pathogenesis of Alzheimer's disease (AD). Previously we found that Abeta induces both mitochondrial and endoplasmic reticulum (ER) dysfunction leading to apoptosis, and now we address the relevance of ER-mitochondria crosstalk in apoptotic cell death triggered by Abeta peptide. Using mitochondrial DNA-depleted rho0 cells derived from the human NT2 teratocarcinoma cell line, characterized by the absence of functional mitochondria, and the parental rho+ cells, we report here that treatment with the synthetic Abeta1-40 peptide, or the classical ER stressors thapsigargin or brefeldin A, increases GRP78 expression levels and caspase activity, two ER stress markers, and also depletes ER calcium stores. Significantly, we show that the presence of functional mitochondria is required for ER stress-mediated apoptotic cell death triggered by toxic insults such as Abeta. We found that the increase in the levels of the pro-apoptotic transcription factor GADD153/CHOP, which mediates ER stress-induced cell death, as well as caspase-9 and -3 activation and increased number of TUNEL-positive cells, occurs in treated parental rho+ cells but is abolished in rho0 cells. Our results strongly support the close communication between ER and mitochondria during apoptotic cell death induced by the Abeta peptide and provide insights into the molecular cascade of cell death in AD.
Costa
Rui O
RO
Faculty of Medicine, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
Ferreiro
Elisabete
E
Cardoso
Sandra M
SM
Oliveira
Catarina R
CR
Pereira
Cláudia M F
CM
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects*; D020126:Brefeldin A / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D008928:Mitochondria / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D018243:Teratocarcinoma / Q000473:pathology / Q000648:ultrastructure; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors
D016229:Amyloid beta-Peptides; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D010446:Peptide Fragments; D011500:Protein Synthesis Inhibitors; C078592:amyloid beta-protein (1-40); D020126:Brefeldin A; D019284:Thapsigargin; D020169:Caspases