Differential expression of apoptotic protease-activating factor-1 and caspase-3 genes and susceptibility to apoptosis during brain development and after traumatic brain injury
Differential expression of apoptotic protease-activating factor-1 and caspase-3 genes and susceptibility to apoptosis during brain development and after traumatic brain injury
复制标题
DOI：
10.1523/jneurosci.21-19-07439.2001
复制
发表时间：
2001-10-01
影响因子：
5.3
通讯作者：
Faden, AI
中科院分区：
文献类型：
--
作者：
Yakovlev, AG;Ota, K;Faden, AI
神经元凋亡在早期脑发育中起重要作用，并导致急性脑损伤后继发性神经元丢失。最近的研究提供了证据表明，神经元对创伤或缺血性损伤诱导的细胞凋亡的易感性在脑发育过程中降低。然而，这种年龄依赖性现象的分子机制仍不清楚。在这里，我们证明，在大脑成熟过程中，内在的凋亡途径的潜力是逐步减少，这种抑制与凋亡蛋白酶激活因子-1（Apaf-1）和caspase-3基因表达下调。在培养的原代大鼠皮层神经元中也发现了与Apaf-1表达下调相关的凋亡易感性的类似下降，其为发育年龄的函数。损伤诱导的caspase-9细胞色素c特异性裂解，随后在成熟脑中激活caspase-3，这与Apaf-1和caspase-3 mRNA和蛋白表达的显著增加相关。这些结果表明，Apaf-1和caspase-3基因的差异表达可能是调节脑发育过程中的凋亡易感性的基础，以及在成熟脑急性损伤后，通过caspase激活的内在途径。
Neuronal apoptosis plays an essential role in early brain development and contributes to secondary neuronal loss after acute brain injury. Recent studies have provided evidence that neuronal susceptibility to apoptosis induced by traumatic or ischemic injury decreases during brain development. However, the molecular mechanisms responsible for this age-dependent phenomenon remain unclear. Here we demonstrate that, during brain maturation, the potential of the intrinsic apoptotic pathway is progressively reduced and that such repression is associated with downregulation of apoptotic protease-activating factor-1 (Apaf-1) and caspase-3 gene expression. A similar decline in apoptotic susceptibility associated with downregulation of Apaf-1 expression as a function of developmental age was also found in cultured primary rat cortical neurons. Injury-induced cytochrome c-specific cleavage of caspase-9 followed by activation of caspase-3 in mature brain correlated with marked increases in Apaf-1 and caspase-3 mRNA and protein expression. These results suggest that differential expression of Apaf-1 and caspase-3 genes may underlie regulation of apoptotic susceptibility during brain development, as well as after acute injury to mature brain, through the intrinsic pathway of caspase activation.