Apoptosis signal-regulating kinase 1 in amyloid β peptide-induced cerebral endothelial cell apoptosis
Apoptosis signal-regulating kinase 1 in amyloid β peptide-induced cerebral endothelial cell apoptosis
复制标题
DOI：
10.1523/jneurosci.1874-06.2007
复制
发表时间：
2007-05-23
影响因子：
5.3
通讯作者：
Lin, Chien-Huang
中科院分区：
文献类型：
--
作者：
Hsu, Ming-Jen;Hsu, Chung Y.;Lin, Chien-Huang
阿尔茨海默病的病理学特征是老年斑中淀粉样肽（A β）的积累。由于A β对包括脑内皮细胞（CECs）在内的非神经元细胞的细胞毒性作用，它也与脑淀粉样血管病的血管变性有关。我们探讨凋亡信号调节激酶1 （ASK1）在A β诱导的小鼠CECs原代培养中的作用。A β诱导ASK1去磷酸化，可通过选择性抑制蛋白磷酸酶2A （PP2A）而非PP2B来阻止。ASK1去磷酸化导致其从14-3-3解离。ASK1从14-3-3抑制中释放，激活p38丝裂原活化蛋白激酶（p38MAPK），导致p53磷酸化。p53，一种促凋亡转录因子，反过来反激活Bax，一种促凋亡蛋白的表达。转染各种显性阴性突变体（DNs），包括ASK1DN和p38MAPK DN，可以抑制A β诱导的p38MAPK激活、p53磷酸化和Bax上调，并部分阻止CEC死亡。使用Bax小干扰RNA策略敲除Bax也降低了Bax表达和随后的CEC死亡。这些结果表明，A β激活ASK1-p38MAPK-p53-Bax级联，以pp2a依赖的方式导致CEC死亡。
A pathological hallmark of Alzheimer's disease is accumulation of amyloid-beta peptide ( A beta) in senile plaques. A beta has also been implicated in vascular degeneration in cerebral amyloid angiopathy because of its cytotoxic effects on non-neuronal cells, including cerebral endothelial cells ( CECs). We explore the role of apoptosis signal-regulating kinase 1 ( ASK1) in A beta-induced death in primary cultures of murine CECs. A beta induced ASK1 dephosphorylation, which could be prevented by selective inhibition of protein phosphatase 2A ( PP2A) but not PP2B. ASK1 dephosphorylation resulted in its dissociation from 14-3-3. ASK1, released from 14-3-3 inhibition, activated p38 mitogen-activated protein kinase ( p38MAPK), leading to p53 phosphorylation. p53, a proapoptotic transcription factor, in turn transactivated the expression of Bax, a proapoptotic protein. Transfection with various dominant-negative mutants ( DNs), including ASK1DN and p38MAPK DN, suppressed A beta-induced p38MAPK activation, p53 phosphorylation, and Bax upregulation and partially prevented CEC death. Bax knockdown using a bax small interfering RNA strategy also reduced Bax expression and subsequent CEC death. These results suggest that A beta activates the ASK1-p38MAPK-p53-Bax cascade to cause CEC death in a PP2A-dependent manner.