ER Stress-Mediated Apoptotic Pathway Induced by A beta Peptide Requires the Presence of Functional Mitochondria

作者：Costa R O; Ferreiro E; Cardoso S M; Oliveira C R; Pereira C M F^*

来源：Journal of Alzheimer's Disease, 2010, 20(2): 625-636.

DOI：10.3233/JAD-2010-091369

• Alzheimer's disease
• amyloid-beta
• ER stress
• mitochondria
• rho0 cells

Amyloid-beta (A beta) peptide plays a significant role in the pathogenesis of Alzheimer's disease (AD). Previously we found that A beta 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 A beta peptide. Using mitochondrial DNA-depleted rho 0 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 A beta(1-40) 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 A beta. 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 rho 0 cells. Our results strongly support the close communication between ER and mitochondria during apoptotic cell death induced by the A beta peptide and provide insights into the molecular cascade of cell death in AD.

• 出版日期2010