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摘要
大量的证据表明了半胱天冬酶在神经障碍性疾病发展中的作用,包括阿尔茨海默病(AD)。因此,调节半胱天冬酶的活性已经被认为是药物作用靶点 。然而,由于不可控制的副作用,所有关于AD治疗剂pan-caspase抑制剂 的应用都以失败告终。或者,通过敲除caspase-3 基因特定干预RNA (RNAi),可以作为一种极具有潜力的治疗策略。当前研究的目的是,利用慢病毒载体介导的半胱氨酸天冬氨酸蛋白酶短发卡RNA(LV-Caspase-3 shRNA)来下调半胱氨酸天冬氨酸蛋白酶。利用原代大脑皮层神经元和C57BL/6J 小鼠验证,研究了 LV-Caspase-3 shRNA在由铝诱导的凋亡中的作用。这些结果表明凋亡蛋白的增加和半胱氨酸天冬氨酸蛋白酶在原代大脑皮层神经元中的表达和暴露在Al中的小鼠皮质,都可以通过LV-Caspase-3 shRNA来下调。此外,LV-Caspase-3 shRNA降低了神经元细胞的死亡和增强Al处理的C57BL/6J 小鼠的学习和记忆能力。我们的结果表明LV-Caspase-3 shRNA是一个潜在的治疗药物用于防止在铝暴露的动物模型中的神经退行性病变和认知障碍。这些发现提供了一个合理的AD基因治疗策略。
关键词: 细胞凋亡,阿尔茨海默病,半胱天冬酶3,调节caspase-3 shRNA的慢病毒载体,RNA干扰
Current Alzheimer Research
Title:Caspase-3 Short Hairpin RNAs: A Potential Therapeutic Agent in Neurodegeneration of Aluminum-Exposed Animal Model
Volume: 11 Issue: 10
Author(s): Qinli Zhang, Na Li, Xia Jiao, Xiujun Qin, Ramanjit Kaur, Xiaoting Lu, Jing Song, Linping Wang, Junming Wang and Qiao Niu
Affiliation:
关键词: 细胞凋亡,阿尔茨海默病,半胱天冬酶3,调节caspase-3 shRNA的慢病毒载体,RNA干扰
摘要: There is abundant evidence supporting the role of caspases in the development of neurodegenerative disease, including Alzheimer’s disease (AD). Therefore, regulating the activity of caspases has been considered as a therapeutic target. However, all the efforts on AD therapy using pan-caspase inhibitors have failed because of uncontrolled adverse effects. Alternatively, the specific knockdown of caspase-3 gene through RNA interference (RNAi) could serve as a future potential therapeutic strategy. The aim of the present study is to down-regulate the expression of caspase-3 gene using lentiviral vector-mediated caspase-3 short hairpin RNA (LV-Caspase-3 shRNA). The effect of LV-Caspase-3 shRNA on apoptosis induced by aluminum (Al) was investigated in primary cultured cortical neurons and validated in C57BL/6J mice. The results indicated an increase in apoptosis and caspase-3 expression in primary cultured neurons and the cortex ofmice exposed to Al, which could be down-regulated by LV-Caspase-3 shRNA. Furthermore, LV-Caspase-3 shRNA reduced neural cell death and improved learning and memory in C57BL/6J mice treated with Al. Our results suggest that LV-caspase-3 shRNA is a potential therapeutic agent to prevent neurodegeneration and cognitive dysfunction in aluminum- exposed animal models. The findings provide a rational gene therapy strategy for AD.
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Cite this article as:
Qinli Zhang, Na Li, Xia Jiao, Xiujun Qin, Ramanjit Kaur, Xiaoting Lu , Jing Song, Linping Wang, Junming Wang and Niu Qiao, Caspase-3 Short Hairpin RNAs: A Potential Therapeutic Agent in Neurodegeneration of Aluminum-Exposed Animal Model, Current Alzheimer Research 2014; 11 (10) . https://dx.doi.org/10.2174/1567205011666141107150938
DOI https://dx.doi.org/10.2174/1567205011666141107150938 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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