scholarly journals Mfsd2a Reverses Spatial Learning and Memory Impairment Caused by Chronic Cerebral Hypoperfusion via Protection of the Blood–Brain Barrier

2020 ◽  
Vol 14 ◽  
Author(s):  
Changhua Qu ◽  
Hao Song ◽  
Jun Shen ◽  
Linling Xu ◽  
Yaqing Li ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Blood Brain Barrier ◽  
Spatial Learning ◽  
Memory Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Brain Barrier ◽  
Cerebral Hypoperfusion ◽  
Spatial Learning And Memory ◽  
Blood Brain

scholarly journals Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Zhao-Hui Yao ◽  
Xiao-li Yao ◽  
Shao-feng Zhang ◽  
Ji-chang Hu ◽  
Yong Zhang
Keyword(s):  
Cognitive Impairment ◽  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Long Term Potentiation ◽  
Chronic Cerebral Hypoperfusion ◽  
Synaptic Proteins ◽  
Cerebral Hypoperfusion ◽  
Spatial Learning And Memory ◽  
Pathophysiological Mechanism

Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism that underlies cognitive decline and degenerative processes in dementia and other neurodegenerative diseases. Low cerebral blood flow (CBF) during CCH leads to disturbances in the homeostasis of hemodynamics and energy metabolism, which in turn results in oxidative stress, astroglia overactivation, and synaptic protein downregulation. These events contribute to synaptic plasticity and cognitive dysfunction after CCH. Tripchlorolide (TRC) is an herbal compound with potent neuroprotective effects. The potential of TRC to improve CCH-induced cognitive impairment has not yet been determined. In the current study, we employed behavioral techniques, electrophysiology, Western blotting, immunofluorescence, and Golgi staining to investigate the effect of TRC on spatial learning and memory impairment and on synaptic plasticity changes in rats after CCH. Our findings showed that TRC could rescue CCH-induced spatial learning and memory dysfunction and improve long-term potentiation (LTP) disorders. We also found that TRC could prevent CCH-induced reductions in N-methyl-D-aspartic acid receptor 2B, synapsin I, and postsynaptic density protein 95 levels. Moreover, TRC upregulated cAMP-response element binding protein, which is an important transcription factor for synaptic proteins. TRC also prevented the reduction in dendritic spine density that is caused by CCH. However, sham rats treated with TRC did not show any improvement in cognition. Because CCH causes disturbances in brain energy homeostasis, TRC therapy may resolve this instability by correcting a variety of cognitive-related signaling pathways. However, for the normal brain, TRC treatment led to neither disturbance nor improvement in neural plasticity. Additionally, this treatment neither impaired nor further improved cognition. In conclusion, we found that TRC can improve spatial learning and memory, enhance synaptic plasticity, upregulate the expression of some synaptic proteins, and increase the density of dendritic spines. Our findings suggest that TRC may be beneficial in the treatment of cognitive impairment induced by CCH.

scholarly journals Deficiency of Nrf2 exacerbates white matter damage and microglia/macrophage levels in a mouse model of vascular cognitive impairment

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Emma Sigfridsson ◽  
Martina Marangoni ◽  
Giles E. Hardingham ◽  
Karen Horsburgh ◽  
Jill H. Fowler
Keyword(s):  
White Matter ◽  
Blood Brain Barrier ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Brain Barrier ◽  
Cerebral Hypoperfusion ◽  
Blood Brain ◽  
Barrier Breakdown ◽  
White Matter Pathology ◽  
Blood Brain Barrier Breakdown

Abstract Background Chronic cerebral hypoperfusion causes damage to the brain’s white matter underpinning vascular cognitive impairment. Inflammation and oxidative stress have been proposed as key pathophysiological mechanisms of which the transcription factor Nrf2 is a master regulator. We hypothesised that white matter pathology, microgliosis, blood-brain barrier breakdown and behavioural deficits induced by chronic hypoperfusion would be exacerbated in mice deficient in the transcription factor Nrf2. Methods Mice deficient in Nrf2 (male heterozygote or homozygous for Nrf2 knockout) or wild-type littermates on a C57Bl6/J background underwent bilateral carotid artery stenosis (BCAS) to induce chronic cerebral hypoperfusion or sham surgery and survived for a further 6 weeks. White matter pathology was assessed with MAG immunohistochemistry as a marker of altered axon-glial integrity; alterations to astrocytes and microglia/macrophages were assessed with GFAP and Iba1 immunohistochemistry, and blood-brain barrier breakdown was assessed with IgG immunohistochemistry. Behavioural alterations were assessed using 8-arm radial arm maze, and alterations to Nrf2-related and inflammatory-related genes were assessed with qRT-PCR. Results Chronic cerebral hypoperfusion induced white matter pathology, elevated microglial/macrophage levels and blood-brain barrier breakdown in white matter tracts that were increased in Nrf2+/− mice and further exacerbated by the complete absence of Nrf2. Chronic hypoperfusion induced white matter astrogliosis and induced an impairment in behaviour assessed with radial arm maze; however, these measures were not affected by Nrf2 deficiency. Although Nrf2-related antioxidant gene expression was not altered by chronic cerebral hypoperfusion, there was evidence for elevated pro-inflammatory related gene expression following chronic hypoperfusion that was not affected by Nrf2 deficiency. Conclusions The results demonstrate that the absence of Nrf2 exacerbates white matter pathology and microgliosis following cerebral hypoperfusion but does not affect behavioural impairment.

scholarly journals Ultrasound-mediated blood-brain barrier disruption improves anti-pyroglutamate3 Aβ antibody efficacy and enhances phagocyte infiltration into brain in aged Alzheimer’s disease-like mice

2021 ◽  
Author(s):  
Qiaoqiao Shi ◽  
Tao Sun ◽  
Yongzhi Zhang ◽  
Chanikarn Power ◽  
Camilla Hoesch ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Learning And Memory ◽  
Blood Brain Barrier ◽  
Combination Treatment ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Plaque Burden ◽  
Spatial Learning And Memory ◽  
Blood Brain

AbstractPyroglutamate-3 amyloid-β (pGlu3 Aβ) is an N-terminally modified, toxic form of amyloid-β that is present in cerebral amyloid plaques and vascular deposits. Using the Fc-competent murine anti-pGlu3 Aβ monoclonal antibody (mAb), 07/2a, we present here a nonpharmacological approach using focused ultrasound (FUS) with intravenous (i.v.) injection of microbubbles (MB) to facilitate i.v. delivery of the 07/2a mAb across the blood brain barrier (BBB) in order to improve Aβ removal and restore memory in aged APP/PS1 mice, an Alzheimer’s disease (AD)-like model of amyloidogenesis.Compared to sham-treated controls, aged APP/PS1 mice treated with 07/2a immediately prior to FUS-mediated BBB disruption (mAb + FUS-BBBD combination treatment) showed significantly better spatial learning and memory in the Water T Maze. FUS-BBBD treatment alone improved contextual fear learning and memory in aged WT and APP/PS1 mice, respectively. APP/PS1 mice given the combination treatment had reduced Aβ42 and pGlu3 Aβ hippocampal plaque burden compared to PBS-treated APP/PS1 mice.Hippocampal synaptic puncta density and synaptosomal synaptic protein levels were also higher in APP/PS1 mice treated with 07/2a just prior to BBB disruption. Increased Iba-1+ microglia were observed in the hippocampi of AD mice treated with 07/2a with and without FUS-BBBD, and APP/PS1 mice that received hippocampal BBB disruption and 07/2a showed increased Ly6G+ monocytes in hippocampal CA3. FUS-induced BBB disruption did not increase the incidence of microhemorrhage in mice with or without 07/2a mAb treatment.Our findings suggest that FUS is useful tool that may enhance delivery of an anti-pGlu3 Aβ mAb for immunotherapy. FUS-mediated BBB disruption in combination with the 07/2a mAb also appears to facilitate monocyte infiltration in this AD model. Overall, these effects resulted in greater sparing of synapses and improved cognitive function without causing overt damage, suggesting the possibility of FUS as a noninvasive method to increase the therapeutic efficacy in AD patients.

scholarly journals Reduction of Pericyte Coverage Leads to Blood-Brain Barrier Dysfunction Via Endothelial Transcytosis Following Chronic Cerebral Hypoperfusion

2021 ◽  
Author(s):  
Zhengyu Sun ◽  
Chenhao Gao ◽  
Dandan Gao ◽  
Ruihua Sun ◽  
Wei Li ◽  
...  
Keyword(s):  
Brain Damage ◽  
Blood Brain Barrier ◽  
Serum Proteins ◽  
Chronic Cerebral Hypoperfusion ◽  
Brain Barrier ◽  
Cerebral Hypoperfusion ◽  
Transmission Electron Microscopy Data ◽  
Pericyte Coverage ◽  
Blood Brain ◽  
Post Operation

Abstract Background: Chronic cerebral hypoperfusion (CCH) is the leading cause for cerebral small vessel disease (CSVD). CCH is strongly associated with blood–brain barrier (BBB) dysfunction and white matter lesions (WML) in CSVD. But the effects of CCH on BBB integrity and constituents as well as the cellular and molecular mechanisms about the consequences of BBB dysfunction remain elusive. Whether maintaining BBB integrity can reverse CCH induced brain damage has also not been explored. Methods: In this study, we used a rat model of CSVD, established via permanent bilateral common carotid artery occlusion (2VO) to mimic the chronic hypoperfusive state of CSVD. The progression of BBB dysfunction and components of the BBB was assessed using immunostaining, western blotting and transmission electron microscopy. Data were analyzed using the one-way ANOVA test or two-tailed unpaired Student’s t tests.Results: We noted a transient yet severe breakdown of the BBB in the CC following CCH. The BBB was severely impaired as early as 1 day post operation and most severely impaired 3 days post operation. BBB breakdown preceded WML and neuroinflammatory responses. Moreover, pericyte loss was associated with BBB impairment and accumulation of serum proteins was mediated by increased endothelial transcytosis in the CC. BBB dysfunction led to brain damage by regulating TGF-β/Smad2 signaling. Further, protection of the BBB via inhibition of endothelial transcytosis ameliorated serum proteins leakage, microglial activation, oligodendrocyte progenitor cells (OPCs) activation and inappropriate TGF-β/Smad2 signaling activation. Conclusions: Our results indicate that reduced pericyte coverage leads to increased BBB permeability via endothelial transcytosis and protection of the BBB integrity ameliorates brain damage by regulating TGF-β/Smad2 signaling following CCH, therefore reversal of BBB dysfunction may be a promising strategy to treat CSVD.

scholarly journals Experimental chronic cerebral hypoperfusion results in decreased pericyte coverage and increased blood–brain barrier permeability in the corpus callosum

2017 ◽  
Vol 39 (2) ◽  
pp. 240-250 ◽  
Author(s):  
Qinghai Liu ◽  
Ryan Radwanski ◽  
Robin Babadjouni ◽  
Arati Patel ◽  
Drew M Hodis ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Blood Brain Barrier ◽  
Chronic Cerebral Hypoperfusion ◽  
Brain Barrier ◽  
Cerebral Hypoperfusion ◽  
Behavioral Deficits ◽  
Pericyte Coverage ◽  
Blood Brain ◽  
Bilateral Carotid ◽  
Bbb Permeability

Murine chronic cerebral hypoperfusion (CCH) results in white matter (WM) injury and behavioral deficits. Pericytes influence blood–brain barrier (BBB) integrity and cerebral blood flow. Under hypoxic conditions, pericytes detach from perivascular locations increasing vessel permeability and neuronal injury. This study characterizes the time course of BBB dysfunction and pericyte coverage following murine experimental CCH secondary to bilateral carotid artery stenosis (BCAS). Mice underwent BCAS or sham operation. On post-procedure days 1, 3, 7 and 30, corpus callosum BBB permeability was characterized using Evans blue (EB) extravasation and IgG staining and pericyte coverage/count was calculated. The BCAS cohort demonstrated increased EB extravasation on postoperative days 1 ( p = 0.003) 3 ( p = 0.002), and 7 ( p = 0.001) when compared to sham mice. Further, EB extravasation was significantly greater ( p = 0.05) at day 3 than at day 30 in BCAS mice. BCAS mice demonstrated a nadir in pericyte coverage and count on post-operative day 3 ( p < 0.05, compared to day 7, day 30 and sham). Decreased pericyte coverage/count and increased BBB permeability are most pronounced on postoperative day 3 following murine CCH. This precedes any notable WM injury or behavioral deficits.

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