Abstract
Alzheimers disease (AD) is characterized by the aggregation and subsequent deposition of misfolded β- amyloid (Aβ) 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 Aβ1-42. In addition, we showed that oligomeric Aβ1-42 is internalized by cells, whereas fibrillar Aβ1-42 remains on the outside of the cell. Inhibition of Aβ uptake specifically inhibits toxicity of Aβ1-42 oligomers, underscoring the toxic potential of intracellular Aβ. Therefore, in the present study, we investigated the connection between intracellularly produced Aβ and the ER stress response, using human neuroblastoma cells overexpressing either wild type APP695 (APPwt) or APP695V717F (APPmut). Both cell lines secrete higher levels of Aβ1-40 and Aβ1-42 compared to the parental line. In addition, APPmut produces more Aβ1-42 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 Aβ1-42. The difference in ER stress mediated toxicity between the APPwt and APPmut cell lines is alleviated by pretreatment with γ-secretase inhibitor, indicating that it is dependent on Aβ production and in particular on Aβ1-42. Our data indicate that increased Aβ1-42 production sensitizes neuroblastoma cells for ER stress toxicity.
Keywords: Alzheimer's disease, β-Amyloid, intracellular, endoplasmic reticulum, unfolded protein response
Current Alzheimer Research
Title: Increased Aβ1-42 Production Sensitizes Neuroblastoma Cells for ER Stress Toxicity
Volume: 5 Issue: 5
Author(s): Sidhartha M. Chafekar, Rob Zwart, Robert Veerhuis, H. Vanderstichele, Frank Baas and Wiep Scheper
Affiliation:
Keywords: Alzheimer's disease, β-Amyloid, intracellular, endoplasmic reticulum, unfolded protein response
Abstract: Alzheimers disease (AD) is characterized by the aggregation and subsequent deposition of misfolded β- amyloid (Aβ) 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 Aβ1-42. In addition, we showed that oligomeric Aβ1-42 is internalized by cells, whereas fibrillar Aβ1-42 remains on the outside of the cell. Inhibition of Aβ uptake specifically inhibits toxicity of Aβ1-42 oligomers, underscoring the toxic potential of intracellular Aβ. Therefore, in the present study, we investigated the connection between intracellularly produced Aβ and the ER stress response, using human neuroblastoma cells overexpressing either wild type APP695 (APPwt) or APP695V717F (APPmut). Both cell lines secrete higher levels of Aβ1-40 and Aβ1-42 compared to the parental line. In addition, APPmut produces more Aβ1-42 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 Aβ1-42. The difference in ER stress mediated toxicity between the APPwt and APPmut cell lines is alleviated by pretreatment with γ-secretase inhibitor, indicating that it is dependent on Aβ production and in particular on Aβ1-42. Our data indicate that increased Aβ1-42 production sensitizes neuroblastoma cells for ER stress toxicity.
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Chafekar M. Sidhartha, Zwart Rob, Veerhuis Robert, Vanderstichele H., Baas Frank and Scheper Wiep, Increased Aβ1-42 Production Sensitizes Neuroblastoma Cells for ER Stress Toxicity, Current Alzheimer Research 2008; 5 (5) . https://dx.doi.org/10.2174/156720508785908883
DOI https://dx.doi.org/10.2174/156720508785908883 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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