Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200023, China.
Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Brain Res Bull. 2022 Jun 1;183:73-83. doi: 10.1016/j.brainresbull.2022.03.001. Epub 2022 Mar 4.
Vascular cognitive impairment (VCI) is the most common type of dementia after Alzheimer's disease (AD). Effective treatments for VCI are currently lacking. MicroRNA (miR)- 140-5p is associated with cerebral ischemia and poststroke depression, but its relationship with VCI remains unknown. A VCI model was established by bilateral common carotid artery occlusion (BCCAO) for 17 min in mice. Neurogenesis was evaluated by immunostaining for Nestin/bromodeoxyuridine (BrdU), NeuN/BrdU, and doublecortin (DCX)/BrdU. Neuroplasticity was assessed by quantifying synapsin-I and postsynaptic density protein 95 (PSD-95) protein levels. Predicted target genes were screened and verified using the dual luciferase reporter gene system. MiR-140-5p was upregulated in the hippocampus of the BCCAO mice 2 weeks following ischemia. Compared with control groups, the AAV-miR-140-5p group exhibited poorer cognitive performance alongside lower numbers of DCX/BrdU and NeuN/BrdU and less synapsin-I and PSD-95 in the dentate gyrus (P < 0.05). MiR-140-5p overexpression decreased the predicted target gene Prox1. Dual luciferase reporter system confirmed that Prox1 was a direct target site for miR-140-5p. In conclusion, our results suggest that miR-140-5p inhibits neurogenesis and neuroplasticity via downregulation of Prox1 and aggravates VCI. Our findings highlight that miR-140-5p is involved in the pathological process of VCI and provides information for the development of new treatments, which may need further inhibition tests to verify.
血管性认知障碍（VCI）是仅次于阿尔茨海默病（AD）的最常见痴呆类型。目前缺乏针对 VCI 的有效治疗方法。微小 RNA（miR）-140-5p 与脑缺血和中风后抑郁有关，但与 VCI 的关系尚不清楚。通过双侧颈总动脉闭塞（BCCAO）在小鼠中建立 17 分钟的 VCI 模型。通过巢蛋白/溴脱氧尿苷（BrdU）、神经元核抗原/ BrdU 和双皮质素（DCX）/ BrdU 的免疫染色评估神经发生。通过定量突触素-I 和突触后密度蛋白 95（PSD-95）蛋白水平评估神经可塑性。使用双荧光素酶报告基因系统筛选和验证预测的靶基因。缺血后 2 周，BCCAO 小鼠海马 miR-140-5p 上调。与对照组相比，AAV-miR-140-5p 组的认知表现较差，齿状回中的 DCX/BrdU 和 NeuN/BrdU 数量较少，突触素-I 和 PSD-95 较少（P<0.05）。miR-140-5p 过表达降低了预测的 Prox1 靶基因。双荧光素酶报告系统证实 Prox1 是 miR-140-5p 的直接靶位点。总之，我们的研究结果表明，miR-140-5p 通过下调 Prox1 抑制神经发生和神经可塑性，加重 VCI。我们的研究结果表明，miR-140-5p 参与了 VCI 的病理过程，为新的治疗方法的发展提供了信息，可能需要进一步的抑制试验来验证。
