Abstract
Vascular dementia (VD) is the most common form of dementia in elderly people. However, little is understood about the role of microRNAs (miRNAs) involved in cognitive impairment in early VD. Here, a VD model induced by chronic cerebral ischemia and fetal bovine serum (FBS)-free cell model that detects synapse formation was established to investigate the function of miRNAs in early VD. The microarray analysis and real-time reverse transcription polymerase chain reaction (RT-PCR) showed that miR-210-5p increased significantly in the hippocampus of rats with 4 weeks of ischemia. The VD model rats also displayed significant cognitive deficits and synaptic loss. The overexpression of miR-210-5p decreased the synaptic number in primary hippocampal neurons, whereas specific suppression of miR-210-5p resulted in the formation of more synapses. Additionally, intracerebroventricular (ICV) injection of miR-210-5p agomir to VD rats aggravated phenotypes of cognitive impairment and synaptic loss. These VD-induced phenotypes were effectively attenuated by miR-210-5p antagomir. Moreover, bioinformatic prediction revealed that synaptosomal-associated protein of 25 KDa (Snap25) mRNA is targeted by miR-210-5p. The miR-210-5p decreased the luciferase activities of 3’ untranslated region (3’UTR) of Snap25 mRNA. Mutation of predicted miR-210-5p binding sites in the 3’ UTR of Snap25 mRNA abolished the miR-210-5p-induced decrease in luciferase activity. Western blot and immunofluorescence staining confirmed that miR-210-5p targets Snap25. Finally, RT-quantitative PCR (qPCR) and immunofluorescence staining detected that miR-210-5p agomir downregulated Snap25 expression in the cornu ammonis1 (CA1) region of hippocampi in VD rats, whereas miR-210-5p antagomir upregulated Snap25 expression. Altogether, miR-210-5p contributes to cognitive impairment in chronic ischemia-induced VD model through the regulation of Snap25 expression, which potentially provides an opportunity to develop a new therapeutic strategy for VD.
Highlights
Vascular dementia (VD), which is characterized by a decline in learning and memory, is widely considered as the second most common cause of dementia and is expected to increase in the coming years
The evidence demonstrated that miR-210-5p mediates the cognitive impairment effects of chronic cerebral ischemia-induced VD by suppressing the expression of Synaptosomal-associated protein of 25 KDa (Snap25), which leads to synaptic loss
The major findings of the present study were as follows: (1) Rats with 4 weeks of chronic ischemia displayed a significant synaptic loss and cognitive deficits; (2) miR-210-5p was increased significantly in the hippocampus of VD model rats and Snap25 mRNA is targeted by miR-210-5p; and (3) miR210-5p agomir aggregates cognitive impairment of VD model and leads to more synaptic loss, and miR-210-5p agomir downregulated Snap25 mRNA level and protein expression in vivo
Summary
Vascular dementia (VD), which is characterized by a decline in learning and memory, is widely considered as the second most common cause of dementia and is expected to increase in the coming years. Extensive research has indicated complex mechanisms of chronic cerebral ischemia-induced VD, such as autophagy (Liu et al, 2014; Hu et al, 2017), apoptosis (Ma et al, 2017b; Aski et al, 2018; Zhao et al, 2018; Zhu et al, 2018), and Aβ and Tau mediated inflammatory response (Miao et al, 2005; Miklossy, 2008; Zhang et al, 2008), leading to neuronal death, which results in cognitive impairment and behavioral disorders. The mechanism of chronic ischemia-induced cognitive impairment has been studied extensively (Choi et al, 2015; Wan et al, 2017; Wang et al, 2017, 2018b; Yao et al, 2018), whereas the mechanism of synapse dysfunction in the early stage of VD remains unclear
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