scholarly journals AIM2 Inflammasome Mediates Hallmark Neuropathological Alterations and Cognitive Impairment in a Mouse Model of Vascular Dementia

2020 ◽  
Author(s):  
Luting Poh ◽  
David Y. Fann ◽  
Peiyan Wong ◽  
Hong Meng Lim ◽  
Sok Lin Foo ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mouse Model ◽  
Vascular Dementia ◽  
Cell Activation ◽  
Memory Loss ◽  
Neuronal Loss ◽  
Brain Regions ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Glial Cell Activation

AbstractChronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long-term cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response – particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their downstream products (IL-1β and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Polarized glial cell activation, white matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioural and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.

scholarly journals NXP031 Improves Cognitive Impairment in a Chronic Cerebral Hypoperfusion-Induced Vascular Dementia Rat Model through Nrf2 Signaling

2021 ◽  
Vol 22 (12) ◽  
pp. 6285
Author(s):  
Jae-Min Lee ◽  
Joo-Hee Lee ◽  
Min-Kyung Song ◽  
Youn-Jung Kim
Keyword(s):  
Oxidative Stress ◽  
Cognitive Impairment ◽  
Vitamin C ◽  
Vascular Dementia ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Vital Role ◽  
Chronic Cerebral Hypoperfusion ◽  
Dna Aptamer ◽  
Cerebral Hypoperfusion

Vascular dementia (VaD) is a progressive cognitive impairment caused by a reduced blood supply to the brain. Chronic cerebral hypoperfusion (CCH) is one cause of VaD; it induces oxidative stress, neuroinflammation, and blood-brain barrier (BBB) disruption, damaging several brain regions. Vitamin C plays a vital role in preventing oxidative stress-related diseases induced by reactive oxygen species, but it is easily oxidized and loses its antioxidant activity. To overcome this weakness, we have developed a vitamin C/DNA aptamer complex (NXP031) that increases vitamin C’s antioxidant efficacy. Aptamers are short single-stranded nucleic acid polymers (DNA or RNA) that can interact with their corresponding target with high affinity. We established an animal model of VaD by permanent bilateral common carotid artery occlusion (BCCAO) in 12 week old Wistar rats. Twelve weeks after BCCAO, we injected NXP031 into the rats intraperitoneally for two weeks at moderate (200 mg/4 mg/kg) and high concentrations (200 mg/20 mg/kg). NXP031 administration alleviates cognitive impairment, microglial activity, and oxidative stress after CCH. NXP031 increased the expression of basal lamina (laminin), endothelial cell (RECA-1, PECAM-1), and pericyte (PDGFRβ); these markers maintain the BBB integrity. We found that NXP031 administration activated the Nrf2-ARE pathway and increased the expression of SOD-1 and GSTO1/2. These results suggest that this new aptamer complex, NXP031, could be a therapeutic intervention in CCH-induced VaD.

scholarly journals Chronic Cerebral Hypoperfusion Induces Vascular Plasticity and Hemodynamics but Also Neuronal Degeneration and Cognitive Impairment

2015 ◽  
Vol 35 (8) ◽  
pp. 1249-1259 ◽  
Author(s):  
Zhen Jing ◽  
Changzheng Shi ◽  
Lihui Zhu ◽  
Yonghui Xiang ◽  
Peihao Chen ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Carotid Artery ◽  
Common Carotid Artery ◽  
Neuronal Degeneration ◽  
Neuronal Loss ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Common Carotid Artery Occlusion

Chronic cerebral hypoperfusion (CCH) induces cognitive impairment, but the compensative mechanism of cerebral blood flow (CBF) is not fully understood. The present study mainly investigated dynamic changes in CBF, angiogenesis, and cellular pathology in the cortex, the striatum, and the cerebellum, and also studied cognitive impairment of rats induced by bilateral common carotid artery occlusion (BCCAO). Magnetic resonance imaging (MRI) techniques, immunochemistry, and Morris water maze were employed to the study. The CBF of the cortex, striatum, and cerebellum dramatically decreased after right common carotid artery occlusion (RCCAO), and remained lower level at 2 weeks after BCCAO. It returned to the sham level from 3 to 6 weeks companied by the dilation of vertebral arteries after BCCAO. The number of microvessels declined at 2, 3, and 4 weeks but increased at 6 weeks after BCCAO. Neuronal degeneration occurred in the cortex and striatum from 2 to 6 weeks, but the number of glial cells dramatically increased at 4 weeks after BCCAO. Cognitive impairment of ischemic rats was directly related to ischemic duration. Our results suggest that CCH induces a compensative mechanism attempting to maintain optimal CBF to the brain. However, this limited compensation cannot prevent neuronal loss and cognitive impairment after permanent ischemia.

scholarly journals Lessons from a Mouse Model Characterizing Features of Vascular Cognitive Impairment with White Matter Changes

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Masafumi Ihara ◽  
Hidekazu Tomimoto
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Mouse Model ◽  
The Elderly ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Demographic Shift ◽  
White Matter Changes ◽  
Blood Brain Barrier Disruption

With the demographic shift in age in advanced countries inexorably set to progress in the 21st century, dementia will become one of the most important health problems worldwide. Vascular cognitive impairment is the second most common type of dementia after Alzheimer's disease and is frequently responsible for the cognitive decline of the elderly. It is characterized by cerebrovascular white matter changes; thus, in order to investigate the underlying mechanisms involved in white matter changes, a mouse model of chronic cerebral hypoperfusion has been developed, which involves the narrowing of the bilateral common carotid arteries with newly designed microcoils. The purpose of this paper is to provide a comprehensive summary of the achievements made with the model that shows good reproducibility of the white matter changes characterized by blood-brain barrier disruption, glial activation, oxidative stress, and oligodendrocyte loss following chronic cerebral hypoperfusion. Detailed characterization of this model may help to decipher the substrates associated with impaired memory and move toward a more integrated therapy of vascular cognitive impairment.

The Effect of Long-Term Environmental Enrichment in Chronic Cerebral Hypoperfusion-Induced Memory Impairment in Rats

2016 ◽  
Vol 19 (3) ◽  
pp. 278-286 ◽  
Author(s):  
Jong-Min Park ◽  
Ho-Hyun Seong ◽  
Han-Byeol Jin ◽  
Youn-Jung Kim
Keyword(s):  
Cognitive Impairment ◽  
Vascular Dementia ◽  
Cognitive Functions ◽  
Environmental Enrichment ◽  
Nursing Intervention ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Vegf Expression ◽  
Y Maze

Vascular dementia (VaD) is the second most common cause of dementia. It occurs when the cerebral blood supply is reduced by disarrangement of the circulatory system. Environmental enrichment (EE) has been associated with cognitive improvement, motor function recovery, and anxiety relief with respect to various neurodegenerative diseases and emotional stress models. The purpose of this study was to determine whether long-term EE influenced cognitive impairment in a rat model of chronic hypoperfusion induced by permanent occlusion of bilateral common carotid arteries (BCCAo). The Y-maze and Morris water maze tests were performed to evaluate the rats’ cognitive functions. Also, the protein expression of brain-derived neurotrophic factor (BDNF), phosphorylated cAMP-calcium response element binding protein (pCREB), and vascular endothelial growth factor (VEGF) were confirmed by Western blot. The microvessels and angiogenesis-associated proteins in the hippocampal region were investigated using immunohistochemistry. The VaD + EE group showed significantly better cognitive functions than the VaD group in both the Y-maze and MWM tests. In addition, the VaD + EE group showed significantly increased expression of BDNF, pCREB, and VEGF in the hippocampus compared to the VaD group. Rats in the VaD + EE group also had increased length of microvessels and VEGF expression in the hippocampus. These results suggest that long-term EE exerts neuroprotective effects against cognitive impairment induced by chronic cerebral hypoperfusion through the enhancement of BDNF, pCREB, and VEGF expression and indicate that EE may be a good nursing intervention in vascular dementia patients.

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