| Objectives: White matter injury induced by chronic cerebral hypoperfusion is a key factor for vascular dementia.Microglia is activated under chronic cerebral hypoperfusion and may participate in the white matter disintegration.However,the molecular mechanism of activated microglia in white matter injury induced by chronic ischemia is unclear.Here,we explored the effect of activated microglia on the white matter injury in a rat model of chronic brain ischemia.Methods: Adult male Sprague-Dawley rats underwent bilateral common carotid artery occlusion for 1,2,and 4 weeks.Cerebral vessel density and cerebral blood flow was determined by synchrotron radiation angiography and 3D arterial spin labeling.Neurobehavioral assessment was performed by Morris water maze test.Immunostaining,CLARITY imaging,and behavioral test were performed to elucidate: 1)M1 microglia activation,migration,and adhesion contributed to white matter injury induced by chronic cerebral ischemia;2)up-regulation of complement C3 and its receptors on microglia are key factors for white matter injury induced by chronic ischemia.Results: Synchrotron radiation angiography and 3D arterial spin labeling results showed that cerebral vessel density were significantly decreased and cerebral blood flow were decreased to 50% of the baseline in chronic ischemia rats compared with controls(p<0.05).Spatial learning and memory deficits began at 2 weeks and sustained to 4 weeks in chronic ischemic rats compared to the control(p<0.05).The myelin density and the expression of myelin basic protein decreased,while the proportion of M1 microglia increased in chronic ischemic rats(p<0.05).CLARITY imaging showed that the number of M1 microglia adhering to myelin increased(p<0.05).Furthermore,we found the up-regulation of chemokines including CCL2,CCL3,CCL5,and CX3CL1(p<0.05).Complement C3 and its receptors C3 a R and CR3 expressed on microglia were also upregulated in chronic ischemia(p<0.05).C3 a R antagonist SB290157 prevented downregulation of myelin basic protein induced by chronic ischemia(p<0.05),decreased expression of M1 phenotype microglia marker CD86 and i NOS(p<0.05),protected from chronic ischemia-induced spatial learning and memory impairments compared with those vehicle controls(p<0.05).Conclusions: Our results suggest that chronic cerebral hypoperfusion can lead to white matter injury resulting in vascular dementia.M1 microglia mediated white matter injury by adhering to and phagocytosing myelin in chronic ischemia,complement C3 mediated the transformation of microglia towards M1 phenotype.Complement C3-microglia axis plays an important role in chronic cerebral ischemic white matter injury inducing vascular dementia. |
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