Increased Aβ1-42 Production Sensitizes Neuroblastoma Cells for ER Stress Toxicity
Increased Aβ1-42 Production Sensitizes Neuroblastoma Cells for ER Stress Toxicity
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DOI：
10.2174/156720508785908883
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发表时间：
2008-10-01
影响因子：
2.1
通讯作者：
Scheper, Wiep
中科院分区：
文献类型：
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作者：
Chafekar, Sidhartha M.;Zwart, Rob;Scheper, Wiep
阿尔茨海默病（AD）的特征是错误折叠的β -淀粉样蛋白（A β）肽的聚集和随后的沉积。未折叠蛋白反应（UPR）是由内质网（ER）中错误折叠的蛋白应激激活的。在先前的研究中，我们证明了细胞外应用寡聚物而不是纤原A β可以轻度激活UPR（1-42）。此外，我们发现低聚A β(1-42)被细胞内化，而原纤维A β(1-42)留在细胞外部。因此，在本研究中，我们利用过表达野生型APP695（APPwt）或APP695(V717F) （APPmut）的人神经母细胞瘤细胞，研究了细胞内产生的A β与内质网应激反应之间的联系。两种细胞系都比亲本细胞系分泌更高水平的A β(1-40)和A β(1-42)。此外，APPmut比APPwt产生更多的A β(1-42)。尽管UPR标记的基础水平没有差异，但我们发现，与亲本细胞系相比，两种APP过量细胞系在内质网应激下的UPR诱导增强，其中APPmut细胞的UPR激活最强。此外，内质网应激毒性在APPmut细胞中最高，强烈提示与a β的产生有关（1-42）。经γ -分泌酶抑制剂预处理后，APPwt和APPmut细胞系内质网应激介导的毒性差异得以缓解，这表明其依赖于A β的产生，尤其是A β(1-42)。我们的数据表明，增加的A β(1-42)产生使神经母细胞瘤细胞对内质网应激毒性敏感。
Alzheimer's disease ( AD) is characterized by the aggregation and subsequent deposition of misfolded beta-amyloid (A beta) 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 A beta(1-42). In addition, we showed that oligomeric A beta(1-42) is internalized by cells, whereas fibrillar A beta(1-42) remains on the outside of the cell. Inhibition of A beta uptake specifically inhibits toxicity of A beta(1-42) oligomers, underscoring the toxic potential of intracellular A beta Therefore, in the present study, we investigated the connection between intracellularly produced A beta 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 A beta(1-40) and A beta(1-42) compared to the parental line. In addition, APPmut produces more A beta(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 A beta(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 A beta production and in particular on A beta(1-42). Our data indicate that increased A beta(1-42) production sensitizes neuroblastoma cells for ER stress toxicity.