scholarly journals Air Pollution Particulate Matter Amplifies White Matter Vascular Pathology and Demyelination Caused by Hypoperfusion

2021 ◽  
Vol 12 ◽  
Author(s):  
Mikko T. Huuskonen ◽  
Qinghai Liu ◽  
Krista Lamorie-Foote ◽  
Kristina Shkirkova ◽  
Michelle Connor ◽  
...  
Keyword(s):  
Air Pollution ◽  
White Matter ◽  
Vascular Dysfunction ◽  
Arterial Disease ◽  
Urban Traffic ◽  
Cerebral Hypoperfusion ◽  
Vascular Pathology ◽  
Dsc Mri ◽  
Bilateral Carotid ◽  
Axonal Density

Cerebrovascular pathologies are commonly associated with dementia. Because air pollution increases arterial disease in humans and rodent models, we hypothesized that air pollution would also contribute to brain vascular dysfunction. We examined the effects of exposing mice to nanoparticulate matter (nPM; aerodynamic diameter ≤200 nm) from urban traffic and interactions with cerebral hypoperfusion. C57BL/6 mice were exposed to filtered air or nPM with and without bilateral carotid artery stenosis (BCAS) and analyzed by multiparametric MRI and histochemistry. Exposure to nPM alone did not alter regional cerebral blood flow (CBF) or blood brain barrier (BBB) integrity. However, nPM worsened the white matter hypoperfusion (decreased CBF on DSC-MRI) and exacerbated the BBB permeability (extravascular IgG deposits) resulting from BCAS. White matter MRI diffusion metrics were abnormal in mice subjected to cerebral hypoperfusion and worsened by combined nPM+BCAS. Axonal density was reduced equally in the BCAS cohorts regardless of nPM status, whereas nPM exposure caused demyelination in the white matter with or without cerebral hypoperfusion. In summary, air pollution nPM exacerbates cerebrovascular pathology and demyelination in the setting of cerebral hypoperfusion, suggesting that air pollution exposure can augment underlying cerebrovascular contributions to cognitive loss and dementia in susceptible elderly populations.

Abstract 17112: Transgenic Endothelial-Specific HIV-Nef Expression Induces Pulmonary Hypertension and Systemic Vascular Dysfunction, Which Can Be Reverted by Treatment With Statin

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Natalia Bogatcheva ◽  
Sarvesh Chelvanambi ◽  
Xingjuan Chen ◽  
Alexander Obukhov ◽  
Matthias Clauss
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Dysfunction ◽  
Vascular Diseases ◽  
Arterial Disease ◽  
Statin Treatment ◽  
Systemic Circulation ◽  
Vascular Pathology ◽  
Systemic Hypertension ◽  
Dependent Manner ◽  
Specific Expression

Introduction: HIV patients on ART perplexingly remain at higher risk for developing cardiovascular diseases including acute peripheral arterial disease and pulmonary hypertension. A likely culprit for observed vascular changes is HIV protein Nef, detected both intracellularly and extracellularly in the absence of HIV RNA or DNA. Nef is known to induce endothelial dysfunction through the activation of NADPH; statins are known to inhibit NADPH activation. Hypothesis: Nef expression in endothelial cells will trigger cardiopulmonary and vascular pathology; Nef effects will be reversed by statin. Methods: Endothelial-specific expression of HIV-Nef was achieved by mating the VE-Cadherin-Tet off mice with TRE-Nef mice. The resulting Nef+ double transgenics and their Nef- negative littermates were maintained without doxycycline to induce Nef expression. Changes in pulmonary acceleration and ejection times were analyzed by ultrasound (INVEVO2100). Additionally, we assessed the ability of bradykinin-preconstricted aortic rings to dilate in response to acetylcholine in NO-dependent manner. Results: Between week 10 and week 13 of age, Nef expressing mice displayed gradual reduction of PAT/PET ratio (down to the 75% of the original PAT/PET ratio at week 10), indicative of developing pulmonary hypertension (N=6). PAT/PET ratio in Nef-negative mice did not change significantly between week 10 and 13 of age. Importantly, statin treatment initiated at week 10 completely suppressed PAT/PET changes developing in Nef-expressing mice. Arterial rings from Nef expressing mice (n=4) showed significantly impaired dilatation in response to acetylcholine (10% relaxation in Nef+ mice vs 40% relaxation in Nef-negative littermates, p=0.03), indicative of changes in systemic circulation. This difference was significantly attenuated in Nef+ mice receiving statin treatment. Conclusions: Our data suggests that mice with endothelial expression of HIV-Nef display pathological changes in pulmonary and systemic circulation. Statin treatment significantly attenuates changes in parameters indicative of pulmonary and systemic hypertension, suggesting that statin will be beneficial for patients with HIV-induced cardiopulmonary and vascular diseases.

scholarly journals Attenuating vascular stenosis-induced astrogliosis preserves white matter integrity and cognitive function

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Qian Liu ◽  
Mohammad Iqbal H. Bhuiyan ◽  
Ruijia Liu ◽  
Shanshan Song ◽  
Gulnaz Begum ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Cognitive Impairment ◽  
Cognitive Function ◽  
White Matter ◽  
Spatial Working Memory ◽  
Ex Vivo ◽  
Cerebral Hypoperfusion ◽  
Cellular Mechanisms ◽  
Bilateral Carotid

Abstract Background Chronic cerebral hypoperfusion (CCH) causes white matter damage and cognitive impairment, in which astrogliosis is the major pathology. However, underlying cellular mechanisms are not well defined. Activation of Na+/H+ exchanger-1 (NHE1) in reactive astrocytes causes astrocytic hypertrophy and swelling. In this study, we examined the role of NHE1 protein in astrogliosis, white matter demyelination, and cognitive function in a murine CCH model with bilateral carotid artery stenosis (BCAS). Methods Sham, BCAS, or BCAS mice receiving vehicle or a selective NHE1 inhibitor HOE642 were monitored for changes of the regional cerebral blood flow and behavioral performance for 28 days. Ex vivo MRI-DTI was subsequently conducted to detect brain injury and demyelination. Astrogliosis and demyelination were further examined by immunofluorescence staining. Astrocytic transcriptional profiles were analyzed with bulk RNA-sequencing and RT-qPCR. Results Chronic cerebral blood flow reduction and spatial working memory deficits were detected in the BCAS mice, along with significantly reduced mean fractional anisotropy (FA) values in the corpus callosum, external capsule, and hippocampus in MRI DTI analysis. Compared with the sham control mice, the BCAS mice displayed demyelination and axonal damage and increased GFAP+ astrocytes and Iba1+ microglia. Pharmacological inhibition of NHE1 protein with its inhibitor HOE642 prevented the BCAS-induced gliosis, damage of white matter tracts and hippocampus, and significantly improved cognitive performance. Transcriptome and immunostaining analysis further revealed that NHE1 inhibition specifically attenuated pro-inflammatory pathways and NADPH oxidase activation. Conclusion Our study demonstrates that NHE1 protein is involved in astrogliosis with pro-inflammatory transformation induced by CCH, and its blockade has potentials for reducing astrogliosis, demyelination, and cognitive impairment.

Cerebrovascular Pathology and Responsiveness to Treatment in Alzheimer’s Disease: A Systematic Review

2021 ◽  
Vol 18 ◽  
Author(s):  
Charlotte Bentham ◽  
Matteo De Marco ◽  
Annalena Venneri
Keyword(s):  
White Matter ◽  
Cerebrovascular Disease ◽  
Treatment Response ◽  
Intima Media Thickness ◽  
Cerebral Microbleeds ◽  
Cerebral Hypoperfusion ◽  
Vascular Pathology ◽  
White Matter Changes ◽  
Media Thickness ◽  
Vascular Burden

Introduction: Responsiveness to treatment with cholinesterase inhibitors (ChEIs) is difficult to predict in Alzheimer’s disease (AD). In the current review, vascular burden is considered as a potential moderator of treatment responsiveness. Cerebrovascular burden co-occurs in at least 30% of AD brains, although it is debated if vascular pathology plays a causal or synergistic role in AD pathogenesis. Vascular burden, therefore, could potentially limit response to treatment due to limited brain reserve or augment treatment efficacy as those with vascular pathology may represent a subgroup with comparable clinical expression but less progressed AD neurodegeneration. Methods: A systematic search of Web of Science, Pubmed, Scopus and EthoS identified 32 papers which met the criteria for inclusion. Association of treatment response and vascular burden across five broad markers are discussed: cerebral hypoperfusion, intima-media thickness, white matter changes, cerebral microbleeds and co-existing diagnosis of cerebrovascular disease. Results: Analysis of frontal regional cerebral blood flow and intima-media thickness may have pre- dictive ability to distinguish those with AD who may respond optimally to short-term treatment with ChEIs. The impact of white matter changes is less consistent; the majority of studies demons- trate no association with treatment response and those that do implicate changes in executive func- tioning. There is preliminary evidence that deep cerebral microbleeds limit treatment response in subcortical cognitive domains, but this requires replication. The use of diagnosis of co-occurring cerebrovascular disease yields no robust variability in response to ChEIs in AD. Conclusion: There is limited evidence that markers of cerebral hypoperfusion, intima-media thick- ness and cerebral microbleeds moderate response to ChEIs. Findings for other markers of vascular burden are less consistent and do not support any moderating effect.

Axon–glial disruption: the link between vascular disease and Alzheimer's disease?

2011 ◽  
Vol 39 (4) ◽  
pp. 881-885 ◽  
Author(s):  
Karen Horsburgh ◽  
Michell M. Reimer ◽  
Philip Holland ◽  
Guiquan Chen ◽  
Gillian Scullion ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Cognitive Decline ◽  
Vascular Dysfunction ◽  
Critical Role ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Early Event ◽  
Published Data

Vascular risk factors play a critical role in the development of cognitive decline and AD (Alzheimer's disease), during aging, and often result in chronic cerebral hypoperfusion. The neurobiological link between hypoperfusion and cognitive decline is not yet defined, but is proposed to involve damage to the brain's white matter. In a newly developed mouse model, hypoperfusion, in isolation, produces a slowly developing and diffuse damage to myelinated axons, which is widespread in the brain, and is associated with a selective impairment in working memory. Cerebral hypoperfusion, an early event in AD, has also been shown to be associated with white matter damage and notably an accumulation of amyloid. The present review highlights some of the published data linking white matter disruption to aging and AD as a result of vascular dysfunction. A model is proposed by which chronic cerebral hypoperfusion, as a result of vascular factors, results in both the generation and accumulation of amyloid and injury to white matter integrity, resulting in cognitive impairment. The generation of amyloid and accumulation in the vasculature may act to perpetuate further vascular dysfunction and accelerate white matter pathology, and as a consequence grey matter pathology and cognitive decline.

scholarly journals Inhibition of the Immunoproteasome Subunit LMP7 Ameliorates Cerebral White Matter Demyelination Possibly via TGFβ/Smad Signaling

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Xingyong Chen ◽  
Nannan Yao ◽  
Zejing Lin ◽  
Yinzhou Wang
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Function ◽  
White Matter ◽  
Growth Factor ◽  
Ischemic Injury ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Cerebral White Matter ◽  
Smad Signaling ◽  
Bilateral Carotid

Objectives. Chronic cerebral hypoperfusion induces white matter ischemic injury and cognitive impairment, whereas the mechanism remains unclear. Immunoproteasomes have been implicated in the pathogenesis of acute ischemia stroke and multiple sclerosis. However, the expression and role of immunoproteasomes in the brain of chronic cerebral hypoperfusion remain to be clarified. Methods. Chronic white matter ischemic injury mice models were induced by bilateral carotid artery stenosis (BCAS). A selective immunoproteasome subunit low-molecular-mass peptide-7 (LMP7) inhibitor PR957 was administered to mice. Cognitive function, white matter integrity, and potential pathways were assessed after BCAS. Results. The present study found that chronic cerebral hypoperfusion following BCAS induced cerebral white matter demyelination and cognitive impairment, accompanied with elevated expression of the immunoproteasomes LMP2 and LMP7, activation of astrocytes and microglia, and increased production of inflammatory cytokines (e.g., interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-10, transforming growth factor-β1 (TGFβ1), and insulin-like growth factor-1 (IGF-1)). However, inhibition of LMP7 with the specific proteasome inhibitor PR957 significantly mitigated the histological damage of the white matter, suppressed inflammatory response, and paralleled by an improvement of cognitive function. Furthermore, treatment of PR957 significantly upregulated the level of TGFβ1, the total expression level, and the phosphorylation level of Smad2/3 and promoted brain remyelination. Surprisingly, PR957 alone had no effects on the neuroinflammation response and the activation of TGFβ/Smad signaling in the sham-operated (BCAS-nonoperated) mice. Conclusions. The possible mechanism underlying this was attributed to that the immunoproteasome regulates TGFβ/Smad signaling-mediated neuroinflammation and oligodendrocyte remyelination.

scholarly journals Air Pollution Particulate Matter Exposure and Chronic Cerebral Hypoperfusion and Measures of White Matter Injury in a Murine Model

2021 ◽  
Vol 129 (8) ◽  
pp. 087006
Author(s):  
Qinghai Liu ◽  
Kristina Shkirkova ◽  
Krista Lamorie-Foote ◽  
Michelle Connor ◽  
Arati Patel ◽  
...  
Keyword(s):  
Air Pollution ◽  
Particulate Matter ◽  
White Matter ◽  
Murine Model ◽  
Chronic Cerebral Hypoperfusion ◽  
White Matter Injury ◽  
Cerebral Hypoperfusion ◽  
Particulate Matter Exposure

Abstract 119: Apoe-ɛ4 Is Associated With Cerebrovascular Insufficiency, Increased Susceptibility to White Matter Injury and Cognitive Dysfunction

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Kenzo Koizumi ◽  
Laibaik Park ◽  
Lingzhi Zhao ◽  
Wenjie Luo ◽  
Steven M Paul ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
White Matter Injury ◽  
Cerebral Hypoperfusion ◽  
Doppler Flowmetry ◽  
Nodal Structure ◽  
Apoe4 Allele ◽  
Bilateral Carotid ◽  
Underlying Mechanisms

ApoE-ɛ4 (apoE4) is a risk factor for white matter ischemic lesions (Neurology 81:292, 2013) and Alzheimer’s disease (Neuron 63:287, 2009). However, the underlying mechanisms remain to be defined. We tested the hypothesis that the apoE4 allele is associated with alterations in the regulation of the cerebral circulation and increased white matter susceptibility to ischemic injury. To this end, we used human ApoE targeted replacement mice (Sullivan et al., JBC, 272:17972, 1997) in which cerebral blood flow (CBF) was measured by laser-Doppler flowmetry in the somatosensory cortex under anesthesia (n=5/group; age 4 mo.). In apoE4 mice, the increase in CBF produced by whisker stimulation (WS) or by topical application of the endothelium-dependent vasodilator acetylcholine (ACh) was attenuated (WS, -48%; ACh, -39%; p<0.05; mean±SE). Next, we asked if this neurovascular dysfunction increases the propensity of apoE4 mice to develop white matter ischemic lesions. White matter hypoperfusion was induced in the corpus callosum by bilateral carotid artery stenosis (BCAS) with microcoils for 4 weeks. BCAS led to more severe white matter injury in apoE4 than in apoE3 mice. Thus, BCAS reduced myelin density more in apoE4 (10±1 relative fluorescence units) than in apoE3 mice (15±1), a reduction of 33% (p<0.05). Furthermore, the axonal nodal structure, assessed by the NaV1.6/caspr index, was disrupted in apoE4 mice (normal index 0.5; BCAS apoE3: 0.58±0.13; BCAS apoE4: 1.05±0.13; p<0.05 from apoE3). BCAS induced impairments in spatial memory in the Y-maze test (arm alternation rate), an effect worse in apoE4 (43±3%) than apoE3 mice (52±3) (p<0.05). These findings suggest that the apoE4 allele is associated with cerebrovascular dysfunction, which leads to more severe white matter damage and cognitive deficits following exposure to chronic cerebral hypoperfusion. Cerebrovascular alterations in apoE4 carriers may play a role in the cognitive impairment associated with vascular risk factors and in the ischemic pathology associated with Alzheimer's disease.

Chronic cerebral hypoperfusion induces white matter lesions and cognitive abnormalities; a comparison between mouse and rat models for vascular dementia

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S263-S263
Author(s):  
Hidekazu Tomimoto ◽  
Masunari Shibata ◽  
Kayoko Nakaji ◽  
Masafumi Ihara ◽  
Makoto Noda ◽  
...  
Keyword(s):  
White Matter ◽  
Vascular Dementia ◽  
White Matter Lesions ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Rat Models

Comprehensive Pricing Model of Urban Traffic Air Pollution Based on Bi-Level Programming

2012 ◽  
Vol 253-255 ◽  
pp. 1913-1917
Author(s):  
Ze Bin Zhao
Keyword(s):  
Air Pollution ◽  
Negative Impact ◽  
Urban Traffic ◽  
Vehicle Speed ◽  
Pricing Model ◽  
The Sustainable Development ◽  
Transport Services ◽  
Relationship Model ◽  
The Relationship

In order to reduce the negative impact of urban traffic air pollution, this paper firstly analyzes the relationship between urban traffic air pollution and vehicle speed, after providing the relationship model, the paper establishes a comprehensive pricing model of urban traffic air pollution based on bi-level programming, the model considers the traffic air pollution pricing, and includes the factors of congestion pricing, bus fee, pricing revenue redistribution on improvement of public transport services and the expansion of road capacity. The case study shows that the implementation of comprehensive pricing of urban traffic air pollution can reduce traffic pollution and unreasonable traffic flow, which is conducive to the sustainable development of the city.

Ginkgolide B promotes oligodendrocyte precursor cell differentiation and survival via Akt/CREB/bcl-2 signaling pathway after white matter lesion

2021 ◽  
pp. 153537022198995
Author(s):  
Jian Huang ◽  
Jun Yang ◽  
Xingju Zou ◽  
Shilun Zuo ◽  
Jing Wang ◽  
...  
Keyword(s):  
White Matter ◽  
White Matter Lesion ◽  
Neuroprotective Effect ◽  
Precursor Cell ◽  
Cerebral Hypoperfusion ◽  
Ginkgolide B ◽  
Oligodendrocyte Precursor Cell ◽  
Learning Abilities ◽  
Phosphorylated Akt ◽  
Oligodendrocyte Precursor

White matter lesion (WML) is caused by chronic cerebral hypoperfusion, which are usually associated with cognitive impairment. Evidence from recent studies has shown that ginkgolide B has a neuroprotective effect that could be beneficial for the treatment of ischemia; however, it is not clear whether ginkgolide B has a protective effect on WML. Our data show that ginkgolide B can promote the differentiation of oligodendrocyte precursor cell (OPC) into oligodendrocytes and promote oligodendrocyte survival following a WML. Ginkgolide B (5, 10, 20 mg/kg) or saline is administered intraperitoneally every day after WML. After 4 weeks, the data of Morris water maze suggested that rats’ memory and learning abilities were impaired, and the administration of ginkgolide B enhanced behavioral achievement. Also, treatment with ginkgolide B significantly attenuated this loss of myelin. Our result suggests that ginkgolide B promotes the differentiation of OPC into oligodendrocytes. We also found that ginkgolide B ameliorates oligodendrocytes apoptosis. Furthermore, ginkgolide B enhanced the expression of phosphorylated Akt and CREB. In conclusion, our data firstly show that ginkgolide B promotes oligodendrocyte genesis and oligodendrocyte myelin following a WML, possibly involving the Akt and CREB pathways.

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