Boscher Emmanuelle, Goupil Claudia, Petry Serena, Keraudren Rémi, Loiselle Andréanne, Planel Emmanuel, Hébert Sébastien S
Centre de Recherche du CHU de Québec - Université Laval, CHUL, Axe Neurosciences, Quebec City, QC, Canada.
Faculté de Médecine, Département de Psychiatrie et de Neurosciences, Université Laval, Quebec City, QC, Canada.
Front Neurosci. 2021 Jan 14;14:591138. doi: 10.3389/fnins.2020.591138. eCollection 2020.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by changes in cognitive and behavioral functions. With the exception or rare mutations in PSEN and APP genes causing early-onset autosomal dominant AD (EOADAD), little is known about the genetic factors that underlie the vast majority (>95%) of early onset AD (EOAD) cases. We have previously identified copy number variations (CNVs) in microRNA genes in patients with EOAD, including a duplication of the MIR-138-2 gene. Overexpression of miR-138 in cultured cells increased Aβ production and tau phosphorylation, similar to what is seen in AD brain. In this study, we sought to determine if miR-138 overexpression could recapitulate certain features of disease in non-transgenic mice. A mild overexpression of pre-miR-138 in the brain of C57BL/6J wildtype mice altered learning and memory in a novel object recognition test and in the Barnes Maze. Increased levels of anxiety were also observed in the open-field test. MiR-138 upregulation caused an increase in endogenous Aβ42 production as well as changes in synaptic and inflammation markers. Tau expression was significantly lower with no overt effects on phosphorylation. We finally observed that Sirt1, a direct target of miR-138 involved in Aβ production, learning and memory as well as anxiety, is decreased following miR-138 overexpression. In sum, this study further strengthens a role for increased gene dosage of MIR-138-2 gene in modulating AD risk, possibly by acting on different biological pathways. Further studies will be required to better understand the role of CNVs in microRNA genes in AD and related neurodegenerative disorders.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征为认知和行为功能发生改变。除了导致早发性常染色体显性AD（EOADAD）的PSEN和APP基因中的罕见突变外，对于绝大多数（>95%）早发性AD（EOAD）病例的潜在遗传因素知之甚少。我们之前已经在EOAD患者中鉴定出微小RNA基因中的拷贝数变异（CNV），包括MIR-138-2基因的重复。在培养细胞中miR-138的过表达增加了Aβ的产生和tau磷酸化，这与在AD大脑中观察到的情况相似。在本研究中，我们试图确定miR-138的过表达是否能在非转基因小鼠中重现疾病的某些特征。在C57BL/6J野生型小鼠大脑中轻度过表达前体miR-138会在新物体识别测试和巴恩斯迷宫中改变学习和记忆。在旷场试验中也观察到焦虑水平增加。miR-138上调导致内源性Aβ42产生增加以及突触和炎症标志物发生变化。Tau表达显著降低，对磷酸化没有明显影响。我们最终观察到，作为miR-138直接靶点且参与Aβ产生、学习和记忆以及焦虑的Sirt1，在miR-138过表达后减少。总之，本研究进一步强化了MIR-138-2基因剂量增加在调节AD风险中的作用，可能是通过作用于不同的生物学途径。需要进一步研究以更好地理解CNV在AD及相关神经退行性疾病微小RNA基因中的作用。
