Amyloid precursor protein (APP) is a representative gene related to Alzheimer's disease (AD). Androgens function by binding to the androgen receptor (AR). Both androgen and RNA-binding protein PSF play a role in the pathology of AD. However, the involvement of AR and PSF in APP regulation in neuron has not been investigated. Here, we explored the regulatory mechanism of APP expression by AR and PSF using neuron-derived cells. We demonstrated that androgen up-regulates the production of APP at the mRNA and protein levels. This induction is enhanced by AR over-expression and inhibited by its silencing. One candidate AR-binding region was identified in the intron region of APP and validated its activity as AR-dependent enhancer by the luciferase assay. Furthermore, the public transcriptome data of brain tissues of mice indicated that APP is regulated by PSF post-transcriptionally. We observed a decreased expression of APP after PSF knockdown and interaction of PSF with the APP transcript. Moreover, we revealed that silencing of PSF inhibited the stability of the APP mRNA. Thus, these results presented a new regulatory mechanism of APP expression by androgen through AR-mediated transcription and PSF at the post-transcriptional level that might be associated with the occurrence of AD.

中文翻译：

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淀粉样蛋白前体蛋白是雄激素调节基因，在神经元细胞中被RNA结合蛋白PSF / SFPQ靶向。

淀粉样前体蛋白（APP）是与阿尔茨海默氏病（AD）有关的代表性基因。雄激素通过与雄激素受体（AR）结合而起作用。雄激素和RNA结合蛋白PSF均在AD的病理中起作用。但是，尚未研究AR和PSF在神经元APP调节中的参与。在这里，我们探讨了使用神经元衍生细胞通过AR和PSF调控APP表达的机制。我们证明雄激素在mRNA和蛋白质水平上调APP的产生。AR的过度表达增强了这种诱导作用，而沉默则抑制了这种诱导作用。在APP的内含子区域中鉴定了一个候选的AR结合区域，并通过荧光素酶测定法验证了其作为AR依赖性增强子的活性。此外，小鼠脑组织的公共转录组数据表明，APP在转录后受到PSF的调控。我们观察到PSF敲低后PS表达降低以及PSF与APP转录物相互作用。此外，我们揭示了PSF的沉默抑制了APP mRNA的稳定性。因此，这些结果提出了雄激素通过AR介导的转录和PSF在转录后水平上与APP的发生有关的APP表达的新调节机制。