Barros-Viegas Ana Teresa, Carmona Vítor, Ferreiro Elisabete, Guedes Joana, Cardoso Ana Maria, Cunha Pedro, Pereira de Almeida Luís, Resende de Oliveira Catarina, Pedro de Magalhães João, Peça João, Cardoso Ana Luísa
Doctoral Programme in Health Sciences, Faculty of Medicine, University of Coimbra, Coimbra, 3000-548, Portugal; CNC- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
CNC- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
Mol Ther Nucleic Acids. 2020 Mar 6;19:1219-1236. doi: 10.1016/j.omtn.2020.01.010. Epub 2020 Jan 17.
Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by progressive memory impairment, behavioral changes, and, ultimately, loss of consciousness and death. Recently, microRNA (miRNA) dysfunction has been associated with increased production and impaired clearance of amyloid-β (Aβ) peptides, whose accumulation is one of the most well-known pathophysiological markers of this disease. In this study, we identified several miRNAs capable of targeting key proteins of the amyloidogenic pathway. The expression of one of these miRNAs, miR-31, previously found to be decreased in AD patients, was able to simultaneously reduce the levels of APP and Bace1 mRNA in the hippocampus of 17-month-old AD triple-transgenic (3xTg-AD) female mice, leading to a significant improvement of memory deficits and a reduction in anxiety and cognitive inflexibility. In addition, lentiviral-mediated miR-31 expression significantly ameliorated AD neuropathology in this model, drastically reducing Aβ deposition in both the hippocampus and subiculum. Furthermore, the increase of miR-31 levels was enough to reduce the accumulation of glutamate vesicles in the hippocampus to levels found in non-transgenic age-matched animals. Overall, our results suggest that miR-31-mediated modulation of APP and BACE1 can become a therapeutic option in the treatment of AD.
阿尔茨海默病（AD）是全球最常见的痴呆形式，其特征为进行性记忆障碍、行为改变，最终导致意识丧失和死亡。最近，微小RNA（miRNA）功能障碍与淀粉样β（Aβ）肽的产生增加和清除受损有关，Aβ肽的积累是该疾病最著名的病理生理标志物之一。在本研究中，我们鉴定了几种能够靶向淀粉样蛋白生成途径关键蛋白的miRNA。其中一种miRNA，即miR-31，先前发现在AD患者中表达降低，它能够同时降低17月龄AD三重转基因（3xTg-AD）雌性小鼠海马中APP和Bace1 mRNA的水平，从而显著改善记忆缺陷，并减轻焦虑和认知灵活性下降。此外，慢病毒介导的miR-31表达在该模型中显著改善了AD神经病理学，大幅减少了海马和下托中的Aβ沉积。此外，miR-31水平的升高足以将海马中谷氨酸囊泡的积累减少到与非转基因年龄匹配动物中发现的水平。总体而言，我们的结果表明，miR-31介导的APP和BACE1调节可能成为治疗AD的一种治疗选择。
