Gliovascular Disruption and Cognitive Deficits in a Mouse Model with Features of Small Vessel Disease

Abstract

Cerebral small vessel disease (SVD) is a major cause of age-related cognitive impairment and dementia. The pathophysiology of SVD is not well understood and is hampered by a limited range of relevant animal models. Here, we describe gliovascular alterations and cognitive deficits in a mouse model of sustained cerebral hypoperfusion with features of SVD (microinfarcts, hemorrhage, white matter disruption) induced by bilateral common carotid stenosis. Multiple features of SVD were determined on T2-weighted and diffusion-tensor magnetic resonance imaging scans and confirmed by pathologic assessment. These features, which were absent in sham controls, included multiple T2-hyperintense infarcts and T2-hypointense hemosiderin-like regions in subcortical nuclei plus increased cerebral atrophy compared with controls. Fractional anisotropy was also significantly reduced in several white matter structures including the corpus callosum. Investigation of gliovascular changes revealed a marked increase in microvessel diameter, vascular wall disruption, fibrinoid necrosis, hemorrhage, and blood-brain barrier alterations. Widespread reactive gliosis, including displacement of the astrocytic water channel, aquaporin 4, was observed. Hypoperfused mice also demonstrated deficits in spatial working and reference memory tasks. Overall, gliovascular disruption is a prominent feature of this mouse, which could provide a useful model for early-phase testing of potential SVD treatment strategies. Keywords: cognition; diffusion-tensor imaging; hypoperfusion; magnetic resonance imaging; small vessel disease INTRODUCTION Cerebral small vessel disease (SVD) is a major cause of age-related cognitive decline and dementia. Journal of Cerebral Blood1 Hypertension is proposed to be a common risk factor (although it explains only a small proportion of imaging-determined SVD) and cerebral amyloid angiopathy is commonly present on pathologic examination.2,3 Clinically, SVD is associated with early impairment of attention and executive function with slowing of information processing and motor deficits.1 These clinical manifestations result primarily from the occurrence of lesions in the cerebral white matter, multiple lacunes within subcortical structures, atrophy, and, in some cases, microbleeds in deep gray matter, white matter, or at the corticosubcortical junction, identified by neuroimaging.2,4 White matter lesions, associated with increased extracellular fluid, varying degrees of myelin and axonal pathology, and glial responses, are predominantly detected as hyperintense regions on fluid attenuation inversion recovery and T2-weighted magnetic resonance imaging (MRI).5 Lacunes, which present as hypointense regions on fluid attenuation inversion recovery or T1-weighted MRI or hyperintense on T2-weighted MRI, are small deep cavities

Animal Models of Vascular Cognitive Impairment and Dementia (VCID)

“…Blood-borne CD45-positive leukocytes were found distributed in the brain of SHR compared to controls indicating neuroinflammatory contributions to the development of cSVD (Kaiser et al 2014). BBB breakdown, evident by the leakage of immunoglobulin G (IgG) and dextran, as well as platelet aggregation in the vicinity of vascular stasis has been observed (Hainsworth et al 2012;Holland et al 2015). Furthermore, ultrastructural changes to astrocyte endfeet in the SHR model were indicative of gliovascular changes.…”

Emerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease

“…64 Although the bilateral common carotid artery stenosis model cannot replicate small vessel vasculopathy or lacunar infarcts or model SVD, it possesses advantages in terms of reproducibility of WM pathology, characterized by BBB disruption, glial activation, oxidative stress, and oligodendrocyte loss. [65][66][67][68][69] Although clinically there is no direct evidence of an association between carotid stenosis and SVD or cognitive decline, once confounding risk factors are corrected for, 13,70,71 altered hemodynamics following bilateral common carotid artery stenosis results in opening of the endothelial tight junction only 2 hours after manipulation, which can be suppressed by matrix metalloproteinase 2 (MMP2) inhibitors. 66,68 MMP2, an extracellular matrix degradation enzyme, is also known to degrade the tight junction proteins ZO-1, claudin-5, and occludin, as well as induce BBB breakdown.…”

“…Несмотря на то что модель двустороннего стеноза общей сонной артерии не позволяет воспроизвести васкулопатию мелких сосудов, лакунарные инфаркты или поражения, характерные для БМЦС, она обладает преимуществами с точки зрения воспроизводимости патологии БВГМ, характеризующей-ся нарушением ГЭБ, активацией глии, оксидантным стрессом и гибелью олигодендроцитов [65][66][67][68][69]. Несмотря на отсутствие прямых клинических доказательств связи стеноза и БМЦС или развития когнитивных нарушений, при внесении поправок на вмешивающиеся факторы [13,70,71] нарушение гемодинамики в результате двусто-роннего стеноза приводит к открытию эндотелиальных плотных контактов только через 2 часа после манипуля-ций, которое можно подавить с помощью ингибиторов матричной металлопротеиназы-2 (MMP2) [66,68].…”

Vascular Contributions to Cognitive Impairment and Dementia

“…In the radial maze and Barnes maze tasks, working memory was impaired at 30 days. Impaired reference memory was also detected at 5–6 months post-surgery 8, 9 .…”

“…After six months of stenosis the animals display significantly (30%) reduced fractional anisotropy on diffusion tensor imaging in white matter areas 9 . Histologically, they exhibit thickened basement membrane collagen IV (relative to one month post-BCAS and sham-operated animals) 9 and hippocampal atrophy with pyknotic and apoptotic cells from 6–8 months post-surgery 29 .…”