Role And Mechanism Of Matrix Metallprotenaine 9 On Vascular Cognitive Impairment

BackgroundsPost-stroke cognitive impairment(PSCI),a common cognitive dysfunction after stroke(ischemic or hemorrhagic),may happen in approximately one third of stroke survivors.Various cognitive tools were used to screen and assess cognitive function to detect and diagnose PSCI early.But they are not available to all patients with stroke.A sensitive biomarker is urgently needed in disable stroke.Matrix metalloproteinase 9(MMP9)is not only involved in the regulation of hippocampal synaptic plasticity and working memory,but also activated during a series of pathological events,including extracellular matrix damage,inflammation and disruption of blood brain barrier in vascular dementia.Thus,the expression of MMP9 may relate to be some relationship between the expression of MMP9 and cognitive function impairment in PSCI.In addition,MMP9/C1562T(rs3918242)gene polymorphisms are associated with atherosclerosis and ischemic cerebral infarction.So it is necessary to further explore the relationship between MMP9/C1562T(rs3918242)gene polymorphisms and the occurrence of PSCI.Objectives:1.To screen and assess cognitive function of PSCI occurred in acute and recovery stage of cerebral infarction and investigate the possible risk factors of PSCI.2.To investigate the relationship between PSCI and MMP9/C1562T(rs3918242)gene polymorphisms.3.To investigate the effect of serum MMP9 level on cognitive function in patients with ischemic stroke.Methods:1.1250 patients with acute ischemic stroke were consecutively enrolled from the Department of Neurology,the First Affiliated Hospital of Xinxiang Medical University,Henan,China,from June 2013 to September 2016.Demographic data,clinical data,cerebrovascular risk factors and blood samples were collected.The signed written informed consents were obtained from each ischemic stroke patient and control subject prior to enrollment in this study.2.All patients with stroke enrolled in this study were screened to assess cognitive function with cognitive assess tools,the Mini-Mental State Examination(MMSE)and Beijing version of Montreal Cognitive Assessment(MoCA-BJ)after 2 weeks and 3 months onset respectively.3.Polymerase chain reaction(PCR)coupled with restriction fragment length polymorphism(RFLP)were used to measure MMP9/C1562T(rs3918242)gene polymorphisms.The levels of MMP9 in serum were detected by enzyme-linked immunosorbent assay(ELISA).Results:1.The incidence of PSCI in acute cerebral infarction was 7.9%,and25.59% in the recovery stage,totally 27.57% within 3 months onset.2.The multivariate analysis of risk factors for cerebrovascular disease showed that hyperhomocysteinemia and obstructive sleep apnea syndrome(OSAS)increased the risk of cerebral infarction as well as the following PSCI.The occurrence of PSCI was not related to the severity of neurological deficit and the classification of cerebral infarction.3.MMP9/C1562T(rs3918242)gene polymorphisms were associated with the incidence of cerebral infarction but not PSCI,and the C allele is a risk factor for cerebral infarction.4.The levels of serum MMP9 were negatively correlated with the scores of MoCA and positively correlated with the levels of homocysteine.5 The levels of serum MMP9 were not associated with MMP9/C1562T(rs3918242)gene polymorphisms.Conclusions:MMP9/C1562T(rs3918242)gene polymorphism in the C allele plays a critical role in the pathogenesis of cerebral infarction,but not as a risk factor for the onset of PSCI.The overexpression of MMP9 in serum is related to the cognitive impairment after stroke,and MMP9 in serum could be used as a biomarker for PSCI.Hyperhomocysteinemia and obstructive sleep apnea syndrome are independent risk factors for PSCI.Backgrounds: The activation of NMDA receptor regulates the postsynaptic Ca2+ channels and mediates the Ca2+ influx,which is involved in learning and memory and synaptic plasticity.Studies have shown that MMP9 enhances the long-term potentiation(LTP)of the CA3-CA1 pathway by acting on NMDA receptors in the hippocampus.But MMP9 overexpressed in the hippocampal region in mice with vascular dementia or vascular cognitive impairment(VCI).Therefore,the role of the MMP9/NMDAR pathway in vascular cognitive function impairment after chronic cerebral hypoperfusion needs to be further investigated.Objectives: To investigate the effect of the MMP9/NMDAR pathway on LTP of hippocampus CA3-CA1 pathway in VCI.Methods: 1 The model of chronic cerebral hypoperfusion was established to evaluate learning and memory.2 The LTP of the CA3-CA1 pathway in the hippocampus was recorded in vitro.MMP9 inhibitor and NMDA antagonist were used to test the effects of the MMP9/NMDAR pathway on VCI.Results: 1 LTP was damaged in the hippocampus of mice with chronic cerebral hypoperfusion(P < 0.01),learning and memory were impaired accordingly(P< 0.01).2 MMP9 increased LTP of CA1 area in the normal hippocampus(P<0.01),while interfered LTP after VCI(P<0.01).MMP9 inhibitor or NMDA receptor antagonist improved the damaged LTP in VCI(P < 0.01)3 The effect of MMP9 inhibitors combined with NMDA receptor antagonists was better than the sum of two in VCI(P<0.01).Conclusions: MMP9 is involved physiologically in synaptic plasticity and improve learning and memory by interacting with NMDAR located in postsynaptic.The synergistic effect of the MMP9/NMDAR pathway would impair the synaptic plasticity,lead to vascular cognitive impairment in chronic cerebral hypoperfusion.