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Brain Dicer1 Is Down-Regulated in a Mouse Model of Alzheimer's Disease Via Aβ42-Induced Repression of Nuclear Factor Erythroid 2-Related Factor 2.
Molecular Neurobiology ( IF 5.1 ) Pub Date : 2020-07-31 , DOI: 10.1007/s12035-020-02036-8
Yan Wang 1, 2 , Meiling Lian 1, 2 , Jing Zhou 1, 2 , Shengzhou Wu 1, 2
Affiliation  

Dicer1 is a microRNA-processing enzyme which plays critical roles in neuronal survival and neuritogenesis. Dicer1 deletion induces neurodegeneration or degeneration in retinal pigment epithelium, which is associated with oxidative stress. Oxidative stress is thought to be central in the pathogenesis of Alzheimer’s disease (AD). Therefore, we hypothesize that Dicer1 may play roles in AD. Using immunoblotting and quantitative real-time PCR, Dicer1 protein and mRNA were reduced in the hippocampi of the AD mouse model APPswe/PSEN1dE9 compared with littermate controls. SiRNA-mediated Dicer1 knockdown induced oxidative stress and apoptosis and reduced mitochondrial membrane potential in cultured neurons. Chronic Aβ42 exposure decreased Dicer1 and nuclear factor erythroid 2-related factor 2 (Nrf2) which were reversed by N-acetyl-cystein. Nrf2 overexpression increased Dicer1 mRNA and protein and reverted the Aβ42-induced Dicer1 reduction. We further cloned Dicer1 promoter variants harboring the Nrf2-binding site, the antioxidant response elements (ARE), into a luciferase reporter and found that simultaneous transfection of Nrf2-expressing plasmid increased luciferase expression from these promoter constructs. ChIP assays indicated that Nrf2 directly interacted with the ARE motifs in the Dicer1 promoter. Furthermore, Dicer1 overexpression in cultured neurons reverted Aβ42-induced neurite deficits. Notably, injection of Dicer1-expressing adenovirus into the hippocampus of the mice significantly improved spatial learning. Altogether, we found novel roles of Dicer1 in AD and a novel regulatory pathway for Dicer1. These results suggest that Dicer1 is a target in AD therapy, especially at the early stage of this disorder.



中文翻译:

通过Aβ42诱导的核因子类红细胞2相关因子2的阻遏,在阿尔茨海默氏病小鼠模型中Brain Dicer1下调。

Dicer1是一种microRNA加工酶,在神经元存活和神经形成中起关键作用。Dicer1缺失引起视网膜色素上皮神经变性或变性,这与氧化应激有关。氧化应激被认为是阿尔茨海默氏病(AD)发病机理的中心。因此,我们假设Dicer1可能在AD中起作用。使用免疫印迹和定量实时PCR,与同窝对照相比,AD小鼠模型APPswe / PSEN1dE9的海马中Dicer1蛋白和mRNA减少。SiRNA介导的Dicer1敲低诱导了神经元中的氧化应激和凋亡,并降低了线粒体膜电位。慢性Aβ42暴露使Dicer1和核因子类红细胞2相关因子2(Nrf2)降低,N逆转-乙酰半胱氨酸。Nrf2过表达增加Dicer1 mRNA和蛋白,并逆转Aβ42诱导的Dicer1减少。我们进一步克隆了携带Nrf2结合位点,抗氧化剂响应元件(ARE)的Dicer1启动子变异体到荧光素酶报道分子中,发现同时转染表达Nrf2的质粒增加了这些启动子构建体的荧光素酶表达。ChIP分析表明Nrf2直接与Dicer1中的ARE基序相互作用启动子。此外,Dicer1在培养的神经元中的过表达恢复了Aβ42诱导的神经突缺陷。值得注意的是,将表达Dicer1的腺病毒注射入小鼠海马区可显着改善空间学习。总而言之,我们发现Dicer1在AD中的新作用以及Dicer1的新型调节途径。这些结果表明,Dicer1是AD治疗的靶标,尤其是在该疾病的早期。

更新日期:2020-09-24
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