MicroRNA-140–5p exacerbates vascular cognitive impairment by inhibiting neurogenesis in the adult mouse hippocampus after global cerebral ischemia

Abstract

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.