Park Junghyung, Kim Bokyung, Chae Unbin, Lee Dong Gil, Kam Min Kyoung, Lee Sang-Rae, Lee Seunghoon, Lee Hyun-Shik, Park Jeen-Woo, Lee Dong-Seok
1 School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University , Daegu, Republic of Korea.
2 College of Natural Sciences, Kyungpook National University , Daegu, Republic of Korea.
Antioxid Redox Signal. 2017 Oct 10;27(11):715-726. doi: 10.1089/ars.2016.6810. Epub 2017 Mar 30.
Aberrant Cdk5 (cyclin-dependent kinase 5) and oxidative stress are crucial components of diverse neurodegenerative disorders, including Alzheimer's disease (AD). We previously reported that a change in peroxiredoxin (Prx) expression is associated with protection from neuronal death. The aim of the current study was to analyze the role of Prx in regulating Cdk5 activation in AD.
We found that of the six Prx subtypes, Prx5 was increased the most in cellular (N2a-APPswe cells) model of AD. Prx5 in the brain of APP (amyloid precursor protein) transgenic mouse (Tg2576) was more increased than a nontransgenic mouse. We evaluated Prx5 function by using overexpression (Prx5-WT), a mutation in the catalytic residue (Prx5-C48S), and knockdown. Increased neuronal death and Cdk5 activation by amyloid beta oligomer (AβO) were rescued by Prx5-WT expression, but not by Prx5-C48S or Prx5 knockdown. Prx5 plays a role in Cdk5 regulation by inhibiting the conversion of p35 to p25, which is increased by AβO accumulation. Prx5 is also upregulated in both the cytosol and mitochondria and it protects cells from AβO-mediated oxidative stress by eliminating intracellular and mitochondrial reactive oxygen species. Moreover, Prx5 regulates Ca and Ca-mediated calpain activation, which are key regulators of p35 cleavage to p25. Innovation and Conclusion: Our study represents the first demonstration that Prx5 induction is a key factor in the suppression of Cdk5-related neuronal death in AD and we show that it functions via regulation of Ca-mediated calpain activation. Antioxid. Redox Signal. 27, 715-726.
异常的细胞周期蛋白依赖性激酶5（Cdk5）和氧化应激是包括阿尔茨海默病（AD）在内的多种神经退行性疾病的关键组成部分。我们之前报道过，过氧化物酶（Prx）表达的变化与神经元死亡的保护作用相关。本研究的目的是分析Prx在AD中调节Cdk5激活的作用。
我们发现，在AD的细胞（N2a-APPswe细胞）模型中，六种Prx亚型中Prx5增加最多。淀粉样前体蛋白（APP）转基因小鼠（Tg2576）大脑中的Prx5比非转基因小鼠增加得更多。我们通过过表达（Prx5-WT）、催化残基突变（Prx5-C48S）和敲低来评估Prx5的功能。Prx5-WT表达可挽救淀粉样β寡聚体（AβO）引起的神经元死亡增加和Cdk5激活，但Prx5-C48S或Prx5敲低则不能。Prx5通过抑制p35向p25的转化在Cdk5调节中发挥作用，而AβO积累会使这种转化增加。Prx5在细胞质和线粒体中也上调，它通过消除细胞内和线粒体活性氧来保护细胞免受AβO介导的氧化应激。此外，Prx5调节钙以及钙介导的钙蛋白酶激活，而钙蛋白酶是p35裂解为p25的关键调节因子。创新与结论：我们的研究首次证明Prx5的诱导是AD中抑制Cdk5相关神经元死亡的关键因素，并且我们表明它通过调节钙介导的钙蛋白酶激活发挥作用。《抗氧化与氧化还原信号》27卷，715 - 726页。
