Presenilin-dependent γ-secretase-mediated control of p53-associated cell death in Alzheimer's disease
Presenilin-dependent γ-secretase-mediated control of p53-associated cell death in Alzheimer's disease
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DOI：
10.1523/jneurosci.0651-06.2006
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发表时间：
2006-06-07
影响因子：
5.3
通讯作者：
Checler, F
中科院分区：
文献类型：
--
作者：
da Costa, CA;Sunyach, C;Checler, F
早老素（PS）是γ-分泌酶复合物的一部分，其从其前体[β-淀粉样前体蛋白（β APP）]产生淀粉样β-肽（A β）。导致家族性阿尔茨海默病（FAD）的PS突变增加了A β的产生并触发p53依赖性细胞死亡。我们证明，PS缺陷，催化失活的PS突变体，γ-分泌酶抑制剂，β APP或淀粉样前体蛋白样蛋白2（APLP 2）耗尽都降低了p53的表达和活性，并降低其启动子和mRNA表达的反式激活。在PS或β APP缺陷小鼠的脑中，p53表达也减少。β APP的γ-和ε-分泌酶衍生的淀粉样蛋白胞内C-末端结构域（AICD）片段（分别为AICDC 59和AICDC 50）触发p53依赖性细胞死亡并增加p53活性和mRNA。最后，PS1突变增强人胚肾293细胞中的p53活性和FAD影响的大脑中的p53表达。因此，我们的研究表明，AICD控制p53在转录水平，在体外和体内，FAD突变增加p53在细胞和人脑中的表达和活性。
Presenilins ( PSs) are part of the gamma-secretase complex that produces the amyloid beta-peptide ( A beta) from its precursor [ beta-amyloid precursor protein ( beta APP)]. Mutations in PS that cause familial Alzheimer's disease ( FAD) increase A beta production and trigger p53-dependent cell death. We demonstrate that PS deficiency, catalytically inactive PS mutants, gamma-secretase inhibitors, and beta APP or amyloid precursor protein-like protein 2 ( APLP2) depletion all reduce the expression and activity of p53 and lower the transactivation of its promoter and mRNA expression. p53 expression also is diminished in the brains of PS- or beta APP-deficient mice. The gamma- and epsilon-secretase-derived amyloid intracellular C-terminal domain ( AICD) fragments ( AICDC59 and AICDC50, respectively) of beta APP trigger p53-dependent cell death and increase p53 activity and mRNA. Finally, PS1 mutations enhance p53 activity in human embryonic kidney 293 cells and p53 expression in FAD-affected brains. Thus our study shows that AICDs control p53 at a transcriptional level, in vitro and in vivo, and that FAD mutations increase p53 expression and activity in cells and human brains.