Chronic stepwise cerebral hypoperfusion differentially induces synaptic proteome changes in the frontal cortex, occipital cortex, and hippocampus in rats

Abstract

During chronic cerebral hypoperfusion (CCH), the cerebral blood flow gradually decreases, leading to cognitive impairments and neurodegenerative disorders, such as vascular dementia. The reduced oxygenation, energy supply induced metabolic changes, and insufficient neuroplasticity could be reflected in the synaptic proteome. We performed stepwise bilateral common carotid occlusions on rats and studied the synaptic proteome changes of the hippocampus, occipital and frontal cortices. Samples were prepared and separated by 2-D DIGE and significantly altered protein spots were identified by HPLC–MS/MS. We revealed an outstanding amount of protein changes in the occipital cortex compared to the frontal cortex and the hippocampus with 94, 33, and 17 proteins, respectively. The high alterations in the occipital cortex are probably due to the hypoxia-induced retrograde degeneration of the primary visual cortex, which was demonstrated by electrophysiological experiments. Altered proteins have functions related to cytoskeletal organization and energy metabolism. As CCH could also be an important risk factor for Alzheimer’s disease (AD), we investigated whether our altered proteins overlap with AD protein databases. We revealed a significant amount of altered proteins associated with AD in the two neocortical areas, suggesting a prominent overlap with the AD pathomechanism.

Cortex-specific transcriptome profiling reveals upregulation of interferon-regulated genes after deeper cerebral hypoperfusion in mice

“…Long-term cerebral hypoperfusion could lead to vascular cognitive impairment, and even stroke. Currently, in preclinical experimental studies, many researchers have explored various animal models to mimic patients’ cerebral hypoperfusion status, including mice, rats and non-human primates’ animal models ( Woodruff et al, 2011 ; Tukacs et al, 2020 ). These models include BCAS model, bilateral common carotid artery occlusion (BCCAO) model, left vertebral artery and bilateral internal carotid artery occlusion (three-vessel occlusion; 3VO) model and others.…”

“…Long-term cerebral hypoperfusion could lead to vascular cognitive impairment, and even stroke. Currently, in preclinical experimental studies, many researchers have explored various animal models to mimic patients' cerebral hypoperfusion status, including mice, rats and non-human primates' animal models (Woodruff et al, 2011;Tukacs et al, 2020).…”

Chronic Cerebral Hypoperfusion-Induced Disturbed Proteostasis of Mitochondria and MAM Is Reflected in the CSF of Rats by Proteomic Analysis

“…Stepwise bilateral common carotid artery occlusion was performed on rats as previously described [ 7 , 23 , 24 ]. Briefly, rats were anesthetized with isoflurane (1.5–2% in air), and a ventral midline incision was placed on the neck.…”

Identification of Molecular Signatures and Candidate Drugs in Vascular Dementia by Bioinformatics Analyses

“…A recent study found that the incidence of post-event dementia at 1 year was 34•4% in patients with severe stroke, 8•2% in patients with minor stroke, and 5•2% in patients with transient ischemic attack (Pendlebury and Rothwell, 2019). The underlying mechanism of VaD is still largely unknown but may be associated with pathological processes including chronic hypoperfusion and hypoxia (Tukacs et al, 2020), vascular endothelial dysfunction and damage (Wang et al, 2018), increased blood-brain barrier permeability (Ueno et al, 2019), and oxidative stress and inflammation (Guo et al, 2020;Wang et al, 2020). Therefore, there is a need to elucidate the detailed molecular mechanisms of VaD and explore potential drugs for VaD treatment.…”