The Role And Mechanisms Of MiRNA-451/MIF Pathway Mediates Neurovascular Unit Injury In Cognitive Impairment Of Parkinson's Disease

Objective:To investigate the role of mi RNA-451/MIF and its downstream signaling pathway on cognitive impairment in Parkinson's disease(PD),focusing on the blood-brain barrier injury,neuroinflammatory activation and neuron injury,and to elucidate the function and mechanism of neurovascular units on cognitive impairment in PD.Methods:The PD cell model was constructed by Mpp~+.PD animal model were constructed by MPTP and the cognition was evaluated by Morris water maze.According to the severity of cognitive impairments,mice were divided into NC group,control group,MPTP group-1 and MPTP group-2.The expression of mi RNA-451 was measured by fluorescence quantitative PCR to explore its relationship with cognitive impairment in PD.Expression of tyrosine hydroxylase(TH)in dopaminergic neurons was measured by IHC.MN9D cells were transfected with lentivirus.After overexpressing or downregulating of mi RNA-451,the cell was then induced by Mpp~+,and the expression of MIF protein and TH were measured by Western blot.Intraperitoneal injection with MPTP to induce and lateral ventricle stereotactic injection with mi RNA-451 antagomir and mi RNA-451 antagomir control to down-regulate of mi RNA-451.The mice were divided into NC group,Sham group,mi R-in group and mi R-in con group.And their cognitive function was evaluated by Morris water maze test before sacrificed.Data were collected as followed:(1)Learning and memory ability and space exploration ability of mice(2)The expression levels of MIF and mi RNA-451 were measured by quantitative PCR(3)The IHC technique of TH and the iba-1(4)The apoptosis degree by TUNEL fluorescence(5)the damage degree of neurons by Nissl staining(6)The damage degree of the blood-brain barrier and the activation level of apoptotic pathway protein were measured by western blot.Results:(1)The expression of mi RNA-451 increased in Parkinson's disease cell model and Parkinson's disease animal model.(2)The expression of mi RNA-451 related to the dopaminergic neuron damage and correlated with the severity of cognitive impairment.(3)MIF is a target of mi RNA-451 in Parkinson's disease cell model and animal model.(4)Down-regulating mi RNA-451 alleviated damage in Parkinson's cell model.(5)Down-regulating mi RNA-451 level improved the learning and memory ability of Parkinson's disease mice model.(6)TH positive cell loss and microglial activation were reduced in mi R-in group.(7)Apoptosis was reduced in mi R-in group(8)Neuron damage was reduced in mi R-in group.(9)The levels of occludin and cleaved-caspase 3 in mi R-in group were significantly higher than those in Sham group and mi R-in con group.Conclusion:mi RNA-451 may be a potential biomarker of cognitive impairment of Parkinson's disease.mi RNA-451/MIF pathway can affect neurovascular unit through cell apoptosis,and it involved in the process of cognitive impairment in Parkinson's disease.