Immortalized cortical neurons expressing caspase-cleaved tau are sensitized to endoplasmic reticulum stress induced cell death
Immortalized cortical neurons expressing caspase-cleaved tau are sensitized to endoplasmic reticulum stress induced cell death
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DOI：
10.1016/j.brainres.2008.07.111
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发表时间：
2008-10-09
期刊：
影响因子：
2.9
通讯作者：
Johnson, Gail V. W.
中科院分区：
文献类型：
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作者：
Matthews-Roberson, Tori A.;Quintanilla, Rodrigo A.;Johnson, Gail V. W.
先前有报道称，Asp421切割形式的tau蛋白在细胞中表达时是有毒的。本研究的目的是了解caspase裂解产生的神经元中Asp421裂解tau蛋白是否以及以何种方式促进阿尔茨海默病（AD）的神经元死亡。在这些研究中，我们使用永生化的皮质神经元，诱导表达全长tau亚型（T4）或在Asp421处伪截断的亚型（T4C3），以模拟caspase-3切割。表达T4或T4C3的神经元用thapsigargin治疗，该药物已被证明可诱导内质网（ER）应激。在长期使用thapsigargin治疗后，表达T4C3的细胞表现出明显的细胞毒性增加，与表达T4的细胞相比，caspase-3的不同激活强调了这一点。此外，我们发现ERKI/2信号通路的抑制剂在每种细胞类型中都有不同程度的上调，可显著降低T4和T4C3细胞的毒性。我们的研究结果表明，Asp421裂解tau蛋白的存在可能使神经元对内质网应激源敏感，并可能在AD进展过程中增强细胞死亡过程。(C) 2008 Elsevier B.V.版权所有
It has been previously reported that an Asp421 cleaved form of tau is toxic when expressed in cells. The purpose of this study was to understand if, and in what manner, the presence of Asp421 cleaved tau in neurons, which is generated by caspase cleavage, might facilitate neuronal death in Alzheimer's disease (AD). For these studies we used immortalized cortical neurons that inducibly express either a full-length tau isoform (T4) or an isoform that has been pseudo-truncated at Asp421 (T4C3), to mimic caspase-3 cleavage. Neurons expressing either T4 or T4C3 were treated with thapsigargin, a drug, which has been shown to induce endoplasmic reticulum (ER) stress. Following long-term treatment with thapsigargin, cells expressing T4C3 presented with a marked increase in cell toxicity, underscored by differential activation of caspase-3 in comparison with cells expressing T4. Furthermore, we found that an inhibitor of the ERKI/2 signaling pathway, which is upregulated to different extents in each cell type, significantly reduced toxicity in both T4 and T4C3 cells. our results suggest that the presence of Asp421 cleaved tau may sensitize neurons to ER stressors and possibly potentiate cell death processes during AD progression. (C) 2008 Elsevier B.V. All rights reserved.