Potential In Vivo Amelioration by N-Acetyl-L-Cysteine of Oxidative Stress in Brain in Human Double Mutant APP/PS-1 Knock-In Mice: Toward Therapeutic Modulation of Mild Cognitive Impairment
Potential In Vivo Amelioration by N-Acetyl-L-Cysteine of Oxidative Stress in Brain in Human Double Mutant APP/PS-1 Knock-In Mice: Toward Therapeutic Modulation of Mild Cognitive Impairment
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DOI：
10.1002/jnr.22422
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发表时间：
2010-09-01
影响因子：
4.2
通讯作者：
Butterfield, D. Allan
中科院分区：
文献类型：
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作者：
Huang, Quanzhen;Aluise, Christopher D.;Butterfield, D. Allan
阿尔茨海默病（AD）是老年人中最常见的痴呆形式。虽然根本原因尚未确定，但大量数据表明，氧化应激与AD以及AD的临床前阶段（如轻度认知障碍（MCI））有关。在AD和MCI受试者脑中观察到的氧化应激可能完全或部分归因于淀粉样β肽（A β）介导的自由基增加。通过使用双人类突变APP/PS-1基因敲入小鼠作为AD模型，本工作证明APP/PS-1双突变导致9月龄和12月龄小鼠脑中蛋白质氧化（以蛋白质羰基为指标）、蛋白质硝化（以3-硝基酪氨酸为指标）以及脂质过氧化（以蛋白质结合的4-羟基-2-壬烯醛为指标）升高。APP/PS-1小鼠在研究的两个年龄组中也表现出较低的脑谷胱甘肽过氧化物酶（GPx）水平，而脑谷胱甘肽还原酶（GR）水平不受突变的影响。APP/PS-1小鼠脑中这两种抗氧化酶的活性均显著降低，而葡萄糖-6-磷酸脱氢酶（G6 PDH）的活性相对于两个年龄组的对照组均增加。在9个月和12个月大的APP/PS-1小鼠脑中，肽基脯氨酰异构酶1（Pin 1）的水平显著降低。通过饮用水给予APP/PS-1小鼠N-乙酰-L-半胱氨酸（NAC）（一种谷胱甘肽前体）抑制了蛋白质氧化和硝化的增加，并显著增加了两个年龄组脑中GPx的水平和活性。口服NAC也增加了GR的活性降低，并保护9个月大的APP/PS-1小鼠的脑中的脂质过氧化作用。Pin 1水平，GR水平，和G6 PDH活性在大脑中不受口服NAC在两个年龄组。这些结果进行了讨论，参考治疗MCI和AD的治疗潜力，这种大脑可访问的谷胱甘肽前体。(C)2010 Wiley-Liss，Inc.
Alzheimer's disease (AD) is the most prevalent form of dementia among the elderly. Although the underlying cause has yet to be established, numerous data have shown that oxidative stress is implicated in AD as well as in preclinical stages of AD, such as mild cognitive impairment (MCI). The oxidative stress observed in brains of subjects with AD and MCI may be due, either fully or in part, to increased free radicals mediated by amyloid-beta peptide (A beta). By using double human mutant APP/PS-1 knock-in mice as the AD model, the present work demonstrates that the APP/PS-1 double mutation results in elevated protein oxidation (as indexed by protein carbonyls), protein nitration (as indexed by 3-nitrotyrosine), as well as lipid peroxidation (as indexed by protein-bound 4-hydroxy-2-nonenal) in brains of mice aged 9 months and 12 months. APP/PS-1 mice also exhibited lower levels of brain glutathione peroxidase (GPx) in both age groups studied, whereas glutathione reductase (GR) levels in brain were unaffected by the mutation. The activities of both of these antioxidant enzymes were significantly decreased in APP/PS-1 mouse brains, whereas the activity of glucose-6-phosphate dehydrogenase (G6PDH) was increased relative to controls in both age groups. Levels of peptidyl prolyl isomerase 1 (Pin1) were significantly decreased in APP/PS-1 mouse brain aged 9 and 12 months. Administration of N-acetyl-L-cysteine (NAC), a glutathione precursor, to APP/PS-1 mice via drinking water suppressed increased protein oxidation and nitration and also significantly augmented levels and activity of GPx in brain from both age groups. Oral administration of NAC also increased the diminished activity of GR and protected against lipid peroxidation in brains of 9-month-old APP/PS-1 mice only. Pin1 levels, GR levels, and G6PDH activity in brain were unaffected by oral administration of NAC in both age groups. These results are discussed with reference to the therapeutic potential of this brain-accessible glutathione precursor in the treatment of MCI and AD. (C) 2010 Wiley-Liss, Inc.