Antisense oligonucleotide against GSK-3β in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: Involvement of transcription factor Nrf2 and implications for Alzheimer disease.
Antisense oligonucleotide against GSK-3β in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: Involvement of transcription factor Nrf2 and implications for Alzheimer disease.
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DOI：
10.1016/j.freeradbiomed.2013.11.014
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发表时间：
2014-02
影响因子：
7.4
通讯作者：
Butterfield, D. Allan
中科院分区：
文献类型：
--
作者：
Farr, Susan A.;Ripley, Jessica L.;Sultana, Rukhsana;Zhang, Zhaoshu;Niehoff, Michael L.;Platt, Thomas L.;Murphy, M. Paul;Morley, John E.;Kumar, Vijaya;Butterfield, D. Allan
关键词：
糖原合成酶激酶（Glycogen synthase kinase，GSK）-3β是一种多功能蛋白质，与阿尔茨海默病（Alzheimer's disease，AD）的病理特征有关，包括神经元缠结、β淀粉样蛋白（amyloid-beta，Aβ）和神经退行性变。在这项研究中，我们使用12个月大的SAMP 8小鼠（AD模型）来检查GSK-3β可能引起的与AD相关的认知障碍和氧化应激的影响。为了抑制GSK-3β的水平，用针对该激酶的反义寡核苷酸（GAO）处理SAMP 8小鼠。我们测量到小鼠皮质中GSK-3β水平降低，表明反义治疗成功。SAMP 8小鼠的学习和记忆评估在反义处理后使用厌恶性T-迷宫和物体识别测试进行测试，两者都显著改善。在SAMP 8小鼠的皮质样品中，测量到蛋白质羰基和蛋白质结合的HNE水平降低，表明氧化应激降低。核因子红细胞-2相关因子2（Nrf 2）是一种转录因子，已知可增加许多抗氧化剂（包括谷胱甘肽-S转移酶（GST））的水平，并受GSK-3β活性的负调控。我们的结果表明，Nrf 2的核定位和GST水平增加，表明GSK-3β抑制导致转录因子活性增加，与观察到的氧化应激降低一致。与改善的学习和记忆一致，并且与GSK-3b是tau激酶一致，我们观察到与RAO处理的SAMP 8小鼠相比，GAO处理的SAMP 8小鼠脑中tau磷酸化降低。最后，我们检查了GAO穿过血脑屏障的能力，并确定这是可能的。本研究中呈现的结果表明，用针对GSK-3的硫代磷酸化反义物减少GSK-3可以改善学习和记忆，减少氧化应激，这可能与Nrf 2的抗氧化转录活性水平增加一致，并减少tau磷酸化。我们的研究支持GAO作为AD的可能治疗方法的概念。
Glycogen synthase kinase (GSK) -3β is a multifunctional protein that has been implicated in the pathological characteristics of Alzheimer’s disease (AD), including the heightened levels of neurofibrillary tangles, amyloid-beta (Aβ) and neurodegeneration. In this study we used 12 month old SAMP8 mice, an AD model, to examine the effects GSK-3β may cause regarding the cognitive impairment and oxidative stress associated with AD. To suppress the level of GSK-3β, SAMP8 mice were treated with an antisense oligonucleotide (GAO) directed at this kinase. We measured a decreased level of GSK-3β in the cortex of the mice, indicating the success of the antisense treatment. Learning and memory assessments of the SAMP8 mice were tested post-antisense treatment using an aversive T-maze and object recognition test, both of which observably improved. In cortex samples of the SAMP8 mice, decreased levels of protein carbonyl and protein-bound HNE were measured indicating decreased oxidative stress. Nuclear factor erythroid -2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. Our results indicated the increased nuclear localization of Nrf2 and level of GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice. Lastly, we examined the ability of GAO to cross the blood-brain barrier and determined it to be possible. The results presented in this study demonstrate that reducing GSK-3 with a phosphorothionated antisense against GSK-3 improves learning and memory, reduces oxidative stress, possibly coincident with increased levels of the antioxidant transcriptional activity of Nrf2, and decreases tau phosphorylation. Our study supports the notion of GAO as a possible treatment for AD.
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阿尔茨海默氏病的GSK3假设。
影响因子：
4.7
作者：
Hooper C;Killick R;Lovestone S
通讯作者：
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影响因子：
10.5
作者：
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DOI：
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2002-09-03
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DOI：
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发表时间：
2010-05-26
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
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LaFerla FM
DOI：
10.1006/bbrc.1997.6943
发表时间：
1997-07-18
影响因子：
3.1
作者：
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通讯作者：
Nabeshima, Y