Amyloid beta peptide increases DP5 expression via activation of neutral sphingomyelinase and JNK in oligodendrocytes
Amyloid beta peptide increases DP5 expression via activation of neutral sphingomyelinase and JNK in oligodendrocytes
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DOI：
10.1111/j.1471-4159.2006.03774.x
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发表时间：
2006-05-01
影响因子：
4.7
通讯作者：
Xu, J
中科院分区：
文献类型：
--
作者：
Chen, SW;Lee, JM;Xu, J
越来越多的人认识到，白质病理是阿尔茨海默病的一个共同特征。我们之前报道过淀粉样蛋白β肽（A β）通过激活中性鞘磷脂酶（nSMase）和由此产生的神经酰胺诱导少突胶质细胞（OLG）凋亡。在本研究中，我们报道了A β和神经酰胺都增加了OLGs中促凋亡蛋白DP5/Hrk （DP5）的表达，以及细胞色素C从线粒体向细胞质的释放。我们提供的证据表明，Jun n -末端激酶（JNK）信号通路介导β和神经酰胺诱导的细胞凋亡：β和神经酰胺均激活JNK磷酸化，并随后激活AP-1 DNA结合活性；JNK siRNA降低AP-1 DNA结合，降低DP5表达，减少细胞死亡。此外，抑制nSMase可减弱A β诱导的JNK磷酸化、AP-1 DNA结合活性、DP5表达和细胞色素C释放。综上所述，这些结果表明，A β诱导的细胞凋亡涉及神经酰胺生成、JNK激活、AP-1 DNA结合和DP5表达的nSMase的顺序激活。
There is growing recognition that white matter pathology is a common feature in Alzheimer's disease. We have previously reported that the amyloid beta peptide (A beta) induces apoptosis in oligodendrocytes (OLG), via activation of neutral sphingomyelinase (nSMase) and resultant generation of ceramide. In the current study, we report that both A beta and ceramide increased expression of the proapoptotic protein DP5/Hrk (DP5), and release of cytochrome C from mitochondria to cytoplasm in OLGs. We provide evidence that the Jun N-terminal kinase (JNK) signaling pathway mediates A beta- and ceramide-induced apoptosis: Both A beta and ceramide activated JNK phosphorylation, and subsequent AP-1 DNA binding activity; JNK siRNA decreased AP-1 DNA binding, DP5 expression and reduced cell death. Furthermore, inhibition of nSMase attenuated A beta-induced JNK phosphorylation, AP-1 DNA binding activity, DP5 expression, and cytochrome C release. Collectively, these results suggest that A beta-induced apoptosis involves the sequential activation of nSMase with ceramide generation, JNK activation, AP-1 DNA binding, and DP5 expression.