A mouse model of subcortical vascular dementia reflecting degeneration of cerebral white matter and microcirculation

Abstract

Subcortical vascular dementia(SVaD) is associated with white matter damage, lacunar infarction, and degeneration of cerebral microcirculation. Currently available mouse models can mimic only partial aspects of human SVaD features. Here, we combined bilateral common carotid artery stenosis (BCAS) with a hyperlipidaemia model in order to develop a mouse model of SVaD; 10- to 12-week-old apolipoprotein E (ApoE)-deficient or wild-type C57BL/6J mice were subjected to sham operation or chronic cerebral hypoperfusion with BCAS using micro-coils. Behavioural performance (locomotion, spatial working memory, and recognition memory), histopathological findings (white matter damage, microinfarctions, astrogliosis), and cerebral microcirculation (microvascular density and blood-brain barrier (BBB) integrity) were investigated. ApoE-deficient mice subjected to BCAS showed impaired locomotion, spatial working memory, and recognition memory. They also showed white matter damage, multiple microinfarctions, astrogliosis, reduction in microvascular density, and BBB breakdown. The combination of chronic cerebral hypoperfusion and ApoE deficiency induced cognitive decline and cerebrovascular pathology, including white matter damage, multiple microinfarctions, and degeneration of cerebral microcirculation. Together, these features are all compatible with those of patients with SVaD. Thus, the proposed animal model is plausible for investigating SVaD pathophysiology and for application in preclinical drug studies.

Increased capillary stalling is associated with endothelial glycocalyx loss in subcortical vascular dementia

“…We thus investigated the relationship of stalling with SVaD pathological findings, such as gliosis and BBB integrity impairment. We observed significantly more reactive astrocytes and a higher degree of BBB leakage in SVaD mice, in agreement with the findings of previous studies 12,17,36 . Local hypoxia by stalling may contribute to BBB leakage or increased gliosis 37,38 .…”

“…IHC analysis was performed using the 5 control and 9 SVaD mice that had been used for the OCTA analysis. Figure 4C shows the significantly higher GFAP expression (control: 2.505 ± 0.749, SVaD: 8.018 ± 1.061, student's t test p = 0.0039) and IgG deposition (control: 326.2 ± 48.99, SVaD: 523.8 ± 29.51, Mann-Whitney test p = 0.007) in SVaD than in control mice, in agreement with previous observations in other SVaD models 12,17 . To examine the possible correlations between capillary stalling and the histopathological features of SVaD, we measured the correlation between the severity of capillary stalling and GFAP (or IgG) expression.…”

“…Here, we investigated capillary stalling in a model of subcortical vascular dementia (SVaD). SVaD is the most frequent type of vascular dementia, impairing microcirculation and appearing as white matter hyperintensity in magnetic resonance imaging 12,13 . Since the deficits in SVaD develop over time, a longitudinal investigation is required to properly understand the disease.…”

“…Since the deficits in SVaD develop over time, a longitudinal investigation is required to properly understand the disease. However, no study has examined microcirculation changes, such as alterations in capillary stalling, in SVaD over several months 7,12 .…”

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

“…However, it is unclear whether sexdependent differences extend to the cerebral microcirculation. Cerebral microvessels (MVs) are more susceptible to injury than large arteries during aging, injury, and pathology and recent evidence implicates derangement of the microcirculation as a major contributor to the development of neurological diseases such as cognitive impairment (Lee et al, 2019a;Iadecola et al, 2019), vascular dementia (van Leijsen et al, 2017;Wardlaw et al, 2019), and Alzheimer's disease (AD) (Hansra et al, 2019). Although the mechanisms linking cerebral MV disease with neurological diseases are not fully known, mitochondria in the microcirculation appear to play a central role in disease progression and present an accessible, possible target for sex-specific therapies.…”