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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >A novel mechanism of non-Abeta component of Alzheimer's disease amyloid (NAC) neurotoxicity. Interplay between p53 protein and cyclin-dependent kinase 5 (Cdk5).
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A novel mechanism of non-Abeta component of Alzheimer's disease amyloid (NAC) neurotoxicity. Interplay between p53 protein and cyclin-dependent kinase 5 (Cdk5).

机译：阿尔茨海默氏病淀粉样蛋白（NAC）神经毒性的非Abeta成分的新型机制。 p53蛋白与细胞周期蛋白依赖性激酶5（Cdk5）之间的相互作用。

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摘要

The non-Abeta component of Alzheimer's disease (AD) amyloid (NAC) is produced from the precursor protein NACP/alpha-synuclein (ASN) by till now unknown mechanism. Previous study showed that like ASN, NAC peptide induced oxidativeitrosative stress and apoptosis. Our present study focused on the mechanisms of PC12 cells death evoked by NAC peptide, with particular consideration on the role of p53 protein. On the basis of molecular and transmission electron microscopic (TEM) analysis it was found that exogenous NAC peptide (10 muM) caused mitochondria dysfunction, enhanced free radical generation, and induced both apoptotic and autophagic cell death. Morphological and immunocytochemical evidence from TEM showed marked changes in expression and in translocation of proapoptotic protein Bax. We also observed time-dependent enhancement of Tp53 gene expression after NAC treatment. Free radicals scavenger N-tert-butyl-alpha-phenylnitrone (PBN, 1 mM) and p53 inhibitor (alpha-Pifithrin, 20 muM) significantly protected PC12 cells against NAC peptide-evoked cell death. In addition, exposure to NAC peptide resulted in higher expression of cyclin-dependent kinase 5 (Cdk5), one of the enzymes responsible for p53 phosphorylation and activation. Concomitantly, we observed the increase of expression of Cdk5r1 and Cdk5r2 genes, coding p35 and p39 peptides that are essential regulators of Cdk5 activity. Moreover, the specific Cdk5 inhibitor (BML-259, 10 muM) protected large population of cells against NAC-evoked cell death. Our findings indicate that NAC peptide exerts its toxic effect by activation of p53/Cdk5 and Bax-dependent apoptotic signaling pathway.
机译：迄今为止未知的机制是由前体蛋白NACP /α-突触核蛋白（ASN）产生的阿尔茨海默氏病（AD）淀粉样蛋白（NAC）的非Abeta成分。先前的研究表明，与ASN一样，NAC肽也可以诱导氧化/亚硝基应激和细胞凋亡。我们目前的研究集中在NAC肽引起的PC12细胞死亡的机制上，特别考虑了p53蛋白的作用。在分子和透射电子显微镜（TEM）分析的基础上，发现外源NAC肽（10μM）引起线粒体功能障碍，增强自由基生成，并诱导凋亡和自噬细胞死亡。 TEM的形态学和免疫细胞化学证据表明，凋亡原蛋白Bax的表达和易位发生了明显变化。我们还观察到NAC治疗后Tp53基因表达的时间依赖性增强。自由基清除剂N-叔丁基-α-苯基硝酮（PBN，1 mM）和p53抑制剂（α-Pifithrin，20 muM）显着保护PC12细胞免受NAC肽引起的细胞死亡。此外，暴露于NAC肽会导致细胞周期蛋白依赖性激酶5（Cdk5）的更高表达，这是负责p53磷酸化和激活的酶之一。同时，我们观察到了Cdk5r1和Cdk5r2基因的表达增加，这些基因编码的p35和p39肽是Cdk5活性的重要调节因子。此外，特定的Cdk5抑制剂（BML-259，10μM）保护大量细胞免受NAC引起的细胞死亡。我们的发现表明，NAC肽通过激活p53 / Cdk5和Bax依赖性凋亡信号通路发挥其毒性作用。

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