Santiard-Baron D, Gosset P, Nicole A, Sinet P M, Christen Y, Ceballos-Picot I
CNRS URA1335, CHU Necker-Enfants Malades, Paris, France.
Exp Neurol. 1999 Jul;158(1):206-13. doi: 10.1006/exnr.1999.7076.
Alzheimer's disease is a neurodegenerative disorder characterized by the extracellular deposition in the brain of amyloid beta-peptide (A beta), presumed to play a pathogenic role. However, the precise molecular mechanisms of its neurotoxicity are not fully understood. Recent studies have suggested that it may exert its toxic effect via activation of transcription factors. We investigated A beta-responsive genes in human preneuron NT2 cells, at early stages of A beta (25-35) exposure, by RNA differential display. A beta induced the expression of (i) the growth arrest and DNA damage-inducible gene (gadd45) implicated in the DNA excision-repair process; (ii) a stress-signaling kinase gene encoding the mitogen-activated protein kinase/Erk kinase kinase-1 (MEKK1); (iii) a new growth factor-inducible immediate-early gene, CYR61, the product of which functions as an extracellular matrix signaling molecule; (iv) other immediate-early genes, such as c-jun and c-fos; (v) the gene encoding the basic fibroblast growth factor (bFGF); (vi) a gene encoding a constituent of the mitochondrial pyruvate dehydrogenase complex, the dihydrolipoamide dehydrogenase-binding protein (E3-BP); and (vii) an unidentified human gene (KIAA0099). A beta not only activates but also respresses genes: (i) the gene encoding "hinge" protein, a subunit of the mitochondrial cytochrome-c reductase and (ii) the SRp55 gene encoding a splicing factor involved in constitutive pre-mRNA splicing and alternative splice site selection. Our results underscored A beta-responsive genes that play key roles in the response (damage/recovery) of neuron cells to A beta exposure. In particular, the strong upregulation of gadd45, indicating DNA damage, was detected early in A beta cytotoxicity. This suggests that DNA strand breaks occurred rapidly in cells exposed to A beta, which may be a critical event in A beta neurotoxicity.
阿尔茨海默病是一种神经退行性疾病，其特征是大脑中淀粉样β肽（Aβ）的细胞外沉积，推测其具有致病作用。然而，其神经毒性的确切分子机制尚未完全明确。最近的研究表明，它可能通过激活转录因子发挥毒性作用。我们通过RNA差异显示技术，在人神经元前体细胞NT2中，于Aβ（25 - 35）暴露的早期阶段，研究了Aβ反应性基因。Aβ诱导了以下基因的表达：（i）参与DNA切除修复过程的生长停滞和DNA损伤诱导基因（gadd45）；（ii）编码丝裂原活化蛋白激酶/细胞外信号调节激酶激酶-1（MEKK1）的应激信号激酶基因；（iii）一种新的生长因子诱导型即刻早期基因CYR61，其产物作为细胞外基质信号分子发挥作用；（iv）其他即刻早期基因，如c-jun和c-fos；（v）编码碱性成纤维细胞生长因子（bFGF）的基因；（vi）编码线粒体丙酮酸脱氢酶复合体成分二氢硫辛酰胺脱氢酶结合蛋白（E3-BP）的基因；以及（vii）一个未鉴定的人类基因（KIAA0099）。Aβ不仅激活基因，还抑制基因：（i）编码线粒体细胞色素c还原酶亚基“铰链”蛋白的基因，以及（ii）编码参与组成型前体mRNA剪接和可变剪接位点选择的剪接因子的SRp55基因。我们的结果强调了Aβ反应性基因在神经元细胞对Aβ暴露的反应（损伤/恢复）中起关键作用。特别是，gadd45的强烈上调表明DNA损伤，在Aβ细胞毒性早期即可检测到。这表明暴露于Aβ的细胞中DNA链断裂迅速发生，这可能是Aβ神经毒性中的一个关键事件。
