Early Induction of Oxidative Stress in Mouse Model of Alzheimer Disease with Reduced Mitochondrial Superoxide Dismutase Activity
Early Induction of Oxidative Stress in Mouse Model of Alzheimer Disease with Reduced Mitochondrial Superoxide Dismutase Activity
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DOI：
10.1371/journal.pone.0050296
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发表时间：
2012-01-19
期刊：
影响因子：
3.7
通讯作者：
Lee, Hyoung-gon
中科院分区：
文献类型：
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作者：
Lee, Hyun-Pil;Pancholi, Neel;Lee, Hyoung-gon
虽然氧化应激与阿尔茨海默病有关，但其潜在的病理生理学关系尚不清楚。为了研究这种关系，我们诱导氧化应激通过基因消融的一个拷贝的线粒体抗氧化剂超氧化物歧化酶2（SOD 2）等位基因突变的人淀粉样前体蛋白（hAPP）转基因小鼠。检查具有四种基因型，野生型（Sod 2（+/+））、半合子Sod 2（Sod 2（+/-））、hAPP/野生型（Sod 2（+/+））和hAPP/半合子（Sod 2（+/-））的年轻（5-7月龄）和老年（25-30月龄）小鼠的脑，以评估氧化应激标志物4-羟基-2-壬烯醛和血红素加氧酶-1的水平。年轻hAPP小鼠中的Sod 2减少导致海马锥体神经元中的氧化应激显著增加。有趣的是，虽然hAPP表达或Sod 2减少导致的差异在老年小鼠的神经元中不明显，但在Sod 2（+/+）或Sod 2（+/-）的老年hAPP小鼠的星形胶质细胞中氧化应激增加，而不是年轻的hAPP小鼠。我们的研究显示了氧化应激的具体变化以及与这些小鼠病理进展的因果关系。这些结果表明hAPP/Sod 2（+/-）小鼠中早期神经元对氧化应激的易感性可能有助于在该动物模型中观察到的病理和行为变化。
While oxidative stress has been linked to Alzheimer's disease, the underlying pathophysiological relationship is unclear. To examine this relationship, we induced oxidative stress through the genetic ablation of one copy of mitochondrial antioxidant superoxide dismutase 2 (Sod2) allele in mutant human amyloid precursor protein (hAPP) transgenic mice. The brains of young (5-7 months of age) and old (25-30 months of age) mice with the four genotypes, wild-type (Sod2(+/+)), hemizygous Sod2 (Sod2(+/-)), hAPP/wild-type (Sod2(+/+)), and hAPP/hemizygous (Sod2(+/-)) were examined to assess levels of oxidative stress markers 4-hydroxy-2-nonenal and heme oxygenase-1. Sod2 reduction in young hAPP mice resulted in significantly increased oxidative stress in the pyramidal neurons of the hippocampus. Interestingly, while differences resulting from hAPP expression or Sod2 reduction were not apparent in the neurons in old mice, oxidative stress was increased in astrocytes in old, but not young hAPP mice with either Sod2(+/+) or Sod2(+/-). Our study shows the specific changes in oxidative stress and the causal relationship with the pathological progression of these mice. These results suggest that the early neuronal susceptibility to oxidative stress in the hAPP/Sod2(+/-) mice may contribute to the pathological and behavioral changes seen in this animal model.