Introduction: Vascular dementia (VaD) induces white matter (WM) damage, however, the molecular mechanisms underlying WM dysfunction and VaD remain unclear. The present study investigated the role of miR-219 in VaD-induced WM damage. Methods: MiR-219 mediates oligodendrocyte progenitor cell (OPC) function. To investigate the potential role of miR-219 in VaD-induced WM damage, we generated an inducible transgenic mouse line with specific ablation of miR-219 in oligodendrocyte progenitor cells (NG2-Cre ERT2 ; miR-219 flox ; Tau/GFP, miR-219 KO). VaD was induced by intracarotid administration of cholesterol crystals to provoke multiple microinfarcts (MMI) in mice. Cognitive and depression-like behaviors were evaluated by the forced swim, Morris water maze, and passive avoidance tests conducted at 21-30 days post MMI. Results: RT-PCR confirmed a significant down regulation of miR-219 in the WM of miR-219 KO mice compared to WT mice. Immunohistochemistry revealed that wild-type MMI mice (WT+MMI) significantly reduced NG2 + OPCs and diminished myelin basic protein (MBP) in the corpus callosum (CC). However, compared to WT-MMI, miR-219 KO MMI mice had significant reduction of NG2 + OPCs and MBP + myelin (p<0.01, n=3-5/group). Western blot showed that miR-219 KO+MMI mice significantly reduced marker proteins of mature oligodendrocytes (OLs) including APC (adenomatous polyposis coli) by 67%, CNPase by 47%, and MBP by 43% (p<0.05 vs WT+MMI, n=3/group). RNA-seq data revealed that deregulated genes in miR-219 KO+MMI mice were highly associated with OPC generation and differentiation, myelination, and myelin sheath compared to genes in WT+MMI mice. Downregulation of miR-219 increased its target genes of PDGFRα (Platelet-derived growth factor receptor alpha) and Foxj3 (Forkhead box J3) in the CC and striatum, which are known to regulate OPC function. Additionally, WT+MMI mice exhibited significantly increased escape latency in the passive avoidance test, reduced time spent in the target platform quadrant in the Morris water maze test, and decreased active time in the forced swim test compared to sham controls, indicating cognitive and behavioral deficits. MiR-219 KO+MMI mice exhibited an exacerbated cognitive decline and increased depression-like behavior compared to WT+MMI mice. Conclusions: Ablation of miR-219 in OPCs aggravates MMI- induced WM damage and cognitive and behavioral deficits, suggesting that therapy targeting augmentation of miR-219 can reduce VaD-induced WM damage.
Gao et al. (Thu,) studied this question.