Evaluation of Mitochondrial Oxidative Stress in the Brain of a Transgenic Mouse Model of Alzheimer's Disease by in vitro Electron Paramagnetic Resonance Spectroscopy.
Evaluation of Mitochondrial Oxidative Stress in the Brain of a Transgenic Mouse Model of Alzheimer's Disease by in vitro Electron Paramagnetic Resonance Spectroscopy.
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DOI：
10.3233/jad-180985
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发表时间：
2019
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通讯作者：
T. Manabe;A. Matsumura;Kazuki Yokokawa;Taro Saito;M. Fujikura;N. Iwahara;T. Matsushita;Syuuichirou Suzuki;S. Hisahara;J. Kawamata;Hiromi Suzuki;M. Emoto;H. Fujii;S. Shimohama
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作者：
T. Manabe;A. Matsumura;Kazuki Yokokawa;Taro Saito;M. Fujikura;N. Iwahara;T. Matsushita;Syuuichirou Suzuki;S. Hisahara;J. Kawamata;Hiromi Suzuki;M. Emoto;H. Fujii;S. Shimohama
阿尔茨海默病(AD)是导致进行性痴呆最常见的神经退行性疾病之一。淀粉样蛋白(Aβ，Aβ)在脑内沉积是AD最重要的病理生理标志。此外，最近的证据表明，线粒体产生的活性氧物种(ROS)参与了AD的病理过程。因此，我们假设在AD转基因小鼠模型(APDE9)的脑线粒体中Aβ积聚，氧化应激增加。测定了6、9、15、18个月龄小鼠脑线粒体Aβ含量和抗氧化酶超氧化物歧化酶活性。我们还使用顺磁性氮氧化物[(2-(2，2，6，6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)一水合三苯基氯化膦作为线粒体靶向氧化还原敏感探针，通过电子顺磁共振光谱定量了APDE9和WT小鼠脑线粒体部分氧化还原状态随年龄的变化。在APDE9小鼠中，Aβ在脑线粒体中的积累早于在脑中非线粒体部分的积累。此外，体外超氧化物歧化酶测定和电子顺磁共振波谱分析表明，APdE9小鼠脑线粒体氧化应激增加。EPR结合线粒体氧化还原敏感的氮氧化物探针是一种潜在的强有力的工具，有助于阐明AD的病因，促进AD新治疗策略的开发。
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases responsible for progressive dementia. Deposition of amyloid-β (Aβ) in the brain is the most important pathophysiological hallmark of AD. In addition, recent evidence indicates that reactive oxygen species (ROS) derived from mitochondria contribute to progression of AD pathology. We thus hypothesized that Aβ accumulates and oxidative stress increases in the brain mitochondria of a transgenic mouse model of AD (APdE9). We measured the quantity of Aβ and the activity of the antioxidant enzyme superoxide dismutase (SOD) in brain mitochondrial fractions prepared from APdE9 and wild-type (WT) mice aged 6, 9, 15, and 18 months. We also quantified the age-related changes in redox status in the mitochondrial fractions obtained from both APdE9 and WT mouse brains by electron paramagnetic resonance (EPR) spectrometry using a paramagnetic nitroxide "Mito-Tempo" [(2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride monohydrate] as a mitochondria-targeted redox-sensitive probe. In APdE9 mice, Aβ accumulated in brain mitochondria earlier than in the non-mitochondrial fraction of the brain. Furthermore, increased oxidative stress was demonstrated in brain mitochondria of APdE9 mice by in vitro SOD assay as well as EPR spectroscopy. EPR combined with a mitochondria-targeted redox-sensitive nitroxide probe is a potentially powerful tool to elucidate the etiology of AD and facilitate the development of new therapeutic strategies for AD.