Abstract
Bilateral carotid artery stenosis (BCAS) is one experimental model of vascular dementia thought to preferentially impact brain white matter. Indeed, few studies report hippocampal and cortical pathology prior to 30 days post-stenosis; though it is unclear whether those studies examined regions outside the white matter. Since changes in the blood-brain barrier (BBB) permeability precede more overt brain pathology in various diseases, we hypothesized that changes within the BBB and/or BBB-associated extracellular matrix (ECM) could occur earlier after BCAS in the hippocampus, cortex and striatum and be a precursor of longer term pathology. Here, C57Bl/6 mice underwent BCAS or sham surgeries and changes in the BBB and ECM were analyzed by collagen IV (vascular basement membrane component), α5 integrin (marker of endothelial activation), claudin-5 and occludin (tight junction proteins), Evans blue (permeability marker), Ki-67 (cell proliferation marker), and GFAP and CD11b (glial cell markers) immunohistochemistry after 14 days. Significant changes in markers of cerebrovascular integrity and glial activation were detected, not only in the striatum, but also in the hippocampus and cortex. In conclusion, this study demonstrates for the first time that changes in the BBB/ECM occur shortly after BCAS and within multiple brain regions and suggests such changes might underlie the gradual development of BCAS non-white matter pathology.
Highlights
Vascular pathology is the second leading cause of dementia behind Alzheimer’s disease and will likely become more prominent in patients in the coming years [1]
To determine if Bilateral carotid artery stenosis (BCAS) leads to alterations of the blood-brain barrier (BBB)-associated extracellular matrix (ECM), we examined collagen IV staining in the cortex, hippocampus and striatum of sham and BCAS-treated mice (Fig 2A)
We demonstrate that alterations in BBB permeability, BBB-associated ECM components, inflammation and cellular proliferation occur at early time points following BCAS, in both the white matter and, unexpectedly, the hippocampus and cortex
Summary
Vascular pathology is the second leading cause of dementia behind Alzheimer’s disease and will likely become more prominent in patients in the coming years [1]. Vascular dementia (VaD) is thought to develop from chronic cerebral hypoperfusion, which with time leads to white matter lesions and cognitive impairment. Bilateral carotid artery stenosis (BCAS) is a commonly used model of cerebral hypoperfusion-induced cognitive impairment, using micro-coils wrapped. Blood-brain barrier changes occur early after bilateral carotid artery stenosis around the arteries to decrease blood flow to the brain [2]. Many rodent studies have shown this reduced carotid artery blood flow causes alterations within the corpus callosum and caudoputamen within 30 days. The extent of hippocampal and cortical pathology remains unclear, as investigators have either not observed change in these regions and do not report it or few studies have examined regions outside of the white matter
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