Abstract
Vascular cognitive impairment (VCI) encompasses all causes of cerebrovascular disease that lead to cognitive decline, or overt dementia, atherosclerotic disease being the most common contributor. However, few rodent models that mimic the pathology of VCI replicated the clinical cerebrovascular atherosclerosis. Here we aimed to investigate the mechanism underlying VCI in an Apolipoprotein E knockout (ApoE-KO) mouse model fed with western style food with implantation of bilateral shear stress modifiers. We established a cognitive decline in spatial learning and memory developed in the bilateral modifier treated mice. Brain imaging and pathological examinations demonstrated reduced glucose intake and neuronal loss in hippocampus. Although no amyloid plaques or neurofibrillary tangles (NFTs) were observed, tau pathology including hyperphosphorylation, paired helical filament formation and pathologic truncation were found at considerable higher extent in the bilateral modifier group 8 weeks post the procedure. In addition, gliosis and microglia activation were confirmed in corpus callosum (CC) and ventral striatum. Thus, this ApoE-KO mouse model faithfully replicates the stenosis of common carotid artery (CCA) and cognitive impairment following atherosclerotic deposition and global cerebral hypoperfusion. The close correlation of cognitive decline and tau pathology indicates the toxic tau species could be at least partially responsible for the neurodegenerative changes induced by the chronic hypoxia/ischemia.
Highlights
Vascular cognitive impairment (VCI) encompasses all causes of cerebrovascular disease that lead to cognitive decline, from mild cognitive impairment (MCI) to dementia (Iadecola, 2013)
As tau hyperphosphorylation could lead to pathologic accumulation of paired helical filaments (PHF; Sun and Chen, 2015), we further evaluated the alteration of tau phosphorylation at S396 and abnormal conformation conversion in hippocampus
We found that phosphorylated-tau at serine 396 was dramatically increased in BSSM group compared with other groups (p < 0.05, Figures 5C,D) despite the decreased glycogen synthase kinase-3β (GSK-3β) activity, strongly arguing that BSSM treatment increases the enzymatic activities of serine/threonine protein kinases other than GSK-3β
Summary
Vascular cognitive impairment (VCI) encompasses all causes of cerebrovascular disease that lead to cognitive decline, from mild cognitive impairment (MCI) to dementia (Iadecola, 2013). Atherosclerosis of carotid artery or cerebral blood vessels is the major contributor to VCI (Iadecola, 2013; Jellinger, 2013). Previous studies have found that atherosclerosis leads to hemodynamic change and narrowing of carotid artery, Tau Pathology in VCI Model resulting in chronic cerebral hypoperfusion. Considering the fundamental role of the cerebral blood supply for the structural and functional integrity of the brain, it is not surprising that alterations in vascular structure and function have a profound impact on cognitive function (Ruitenberg et al, 2005; Balestrini et al, 2013; Iadecola, 2013). The underlying mechanism connecting cerebral hypoperfusion and cognitive impairment is still elusive
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