Development of a mouse model for chronic cerebral hypoperfusion: Analysis of its impact on neurovascular unit and cognitive impairment

Abstract

Recent evidence suggest a strong link between vascular risk factors and neurodegeneration, cognitive impairment and dementia. Cerebral hypoperfusion is a common pathophysiological mechanism for vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). It leads to white matter attenuation, and is associated with cerebral small vessel disease. Cerebral small vessel disease affects small arteries, arterioles, venules and capillaries in the brain leading to arteriolar occlusion, lacuna and white matter changes. Although chronic cerebral hypoperfusion may affect neurodegenerative disease pathogenesis, the mechanism remains elusive. In the present study, we develop a rodent model of chronic cerebral hypoperfusion. C57BL/6 J mice were subjected to gradual bilateral common carotid arteries (CCA) stenosis with ameroid constrictors for slowly progressive cerebral hypoperfusion. Ameroid constrictors are ring-shaped titanium coated with hygroscopic-casein. Once implanted on mice CCA, casein will absorb interstitial liquids and swell, leading to gradual constriction of the CCA then inducing cerebral hypoperfusion. At the experimental endpoint, mice were euthanized, perfused and brains were collected for immunostaining and histology. Three cohorts have been implanted with ameroid constrictors with decreasing internal diameters: 0,75, 0,5 and 0,25 mm and we analyzed the histological impact of cerebral hypoperfusion in each groups. Histological analysis of the AC-mice brain have shown several ischemia, white matter loss, demyelinization, hippocampal neuronal apoptosis, lacunes and microbleeds apparition. We now need to analyze whether learning and memory will be significantly impaired in the hypoperfusion group using new object recognition behavioral test. Based on this pattern of data, we argued that this mouse model would be a useful tool to investigate the therapeutic interventions for the treatment of vascular dementia.