Document Detail

ER stress-mediated apoptotic pathway induced by Abeta peptide requires the presence of functional mitochondria.
MedLine Citation:
PMID:  20182029     Owner:  NLM     Status:  MEDLINE    
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.
Rui O Costa; Elisabete Ferreiro; Sandra M Cardoso; Catarina R Oliveira; Cláudia M F Pereira
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of Alzheimer's disease : JAD     Volume:  20     ISSN:  1875-8908     ISO Abbreviation:  J. Alzheimers Dis.     Publication Date:  2010  
Date Detail:
Created Date:  2010-05-27     Completed Date:  2010-09-07     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9814863     Medline TA:  J Alzheimers Dis     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  625-36     Citation Subset:  IM    
Faculty of Medicine, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
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MeSH Terms
Amyloid beta-Protein / pharmacology*
Analysis of Variance
Apoptosis / drug effects*
Brefeldin A / pharmacology
Caspases / metabolism
Cell Line, Tumor
Endoplasmic Reticulum / drug effects*
In Situ Nick-End Labeling / methods
Mitochondria / drug effects*
Oxidative Stress / drug effects*
Peptide Fragments / pharmacology*
Protein Synthesis Inhibitors / pharmacology
Teratocarcinoma / pathology,  ultrastructure
Thapsigargin / pharmacology
Time Factors
Reg. No./Substance:
0/Amyloid beta-Protein; 0/Peptide Fragments; 0/Protein Synthesis Inhibitors; 0/amyloid beta-protein (1-40); 20350-15-6/Brefeldin A; 67526-95-8/Thapsigargin; EC 3.4.22.-/Caspases

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