Bilateral Implantation of Shear Stress Modifier in ApoE Knockout Mouse Induces Cognitive Impairment and Tau Abnormalities

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.

Atherosclerosis: The Culprit and Co-victim of Vascular Dementia

“…AS alters stable blood flow pattern, which triggers chronic hypoperfusion (Nie et al, 2018). When the brain is under chronic ischemia, the small cerebral arteries expand to the maximum extent due to the compensatory mechanism, resulting in impaired cerebral vascular function (Nagata et al, 2016).…”

“…In the experiment by Nie et al, the loss of neurons in the hippocampus of bilateral implantation of the shear stress modifier mice were observed with a decrease in glucose intake. The evidence demonstrates that a hypoxic environment also causes low sugar level (Nie et al, 2018). Low glucose level rapidly leads to endothelial dysfunction or induces endothelial cell mitochondrial autophagy, which results in nitric oxide (NO) bioavailability decrease, mitochondrial reactive oxygen species (ROS) production increase, and vascular function damage (Tanner et al, 2017).…”

Alterations in brain morphology and functional connectivity mediate cognitive decline in carotid atherosclerotic stenosis

“…VD has become the second most common type of dementia after Alzheimer's disease (AD) (Jia et al, 2014). Increasing evidence suggests that carotid atherosclerotic stenosis (CAS) is an essential cause of vascular cognitive impairment (VCI), which can also lead to VD (Nie et al, 2018;Xu et al, 2022). However, whether and how CAS affects cognition remains indistinct (Paraskevas et al, 2021).…”

Integrated Analysis of Chromatin and Transcriptomic Profiling Identifies PU.1 as a Core Regulatory Factor in Microglial Activation Induced by Chronic Cerebral Hypoperfusion

“…As it is associated with a high rate of disability and mortality, there is an urgent need for effective prevention and treatment methods for this clinical problem [ 3 , 4 ]. Pertinently, chronic cerebral hypoperfusion (CCH) is a significant contributing factor in the development of VCI [ 5 , 6 ]. In addition to causing white matter lesions, decreased cerebral blood flow (CBF) can also cause damage to gray matter, including cortical and subcortical infarction, as well as disseminated lacunar or cerebral watershed infarction [ 7 , 8 ].…”