Increased Abeta(1-42) Production Sensitizes Neuroblastoma Cells for ER Stress Toxicity.
Curr Alzheimer Res. 2008 Oct;5(5):469-74
Authors: Chafekar SM, Zwart R, Veerhuis R, Vanderstichele H, Baas F, Scheper W
Alzheimer's disease (AD) is characterized by the aggregation and subsequent deposition of misfolded beta-amyloid (Abeta) peptide. The unfolded protein response (UPR) is activated by misfolded protein stress in the endoplasmic reticulum (ER). In previous studies we demonstrated mild activation of the UPR by extracellularly applied oligomeric but not fibrillar Abeta(1-42). In addition, we showed that oligomeric Abeta(1-42) is internalized by cells, whereas fibrillar Abeta(1-42) remains on the outside of the cell. Inhibition of Abeta uptake specifically inhibits toxicity of Abeta(1-42) oligomers, underscoring the toxic potential of intracellular Abeta. Therefore, in the present study, we investigated the connection between intracellularly produced Abeta and the ER stress response, using human neuroblastoma cells overexpressing either wild type APP695 (APPwt) or APP695(V717F) (APPmut). Both cell lines secrete higher levels of Abeta (1-40) and Abeta(1-42) compared to the parental line. In addition, APPmut produces more Abeta(1-42) than APPwt. Whereas the basal levels of UPR markers are not different, we find augmented UPR induction in response to ER stress in both APP overproducing cell lines compared to the parental cell line, with the strongest UPR activation in APPmut cells. In addition, ER stress toxicity was highest in APPmut cells, strongly suggesting a connection with the production of Abeta(1-42). The difference in ER stress mediated toxicity between the APPwt and APPmut cell lines is alleviated by pretreatment with gamma-secretase inhibitor, indicating that it is dependent on Abeta production and in particular on Abeta(1-42). Our data indicate that increased Abeta(1-42) production sensitizes neuroblastoma cells for ER stress toxicity.
PMID: 18855588 [PubMed - in process]