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

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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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12974-021-02234-8.

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Most cited references 59

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Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.

Da Huang, Brad T. Sherman, Richard A. Lempicki (2009)

DAVID bioinformatics resources consists of an integrated biological knowledgebase and analytic tools aimed at systematically extracting biological meaning from large gene/protein lists. This protocol explains how to use DAVID, a high-throughput and integrated data-mining environment, to analyze gene lists derived from high-throughput genomic experiments. The procedure first requires uploading a gene list containing any number of common gene identifiers followed by analysis using one or more text and pathway-mining tools such as gene functional classification, functional annotation chart or clustering and functional annotation table. By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.

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Neurotoxic reactive astrocytes are induced by activated microglia

Shane Liddelow, Kevin A. Guttenplan, Laura Clarke … (2017)

A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes.

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Causal analysis approaches in Ingenuity Pathway Analysis

John Osborne, Andreas Kramer, Jeff Green … (2015)

Motivation: Prior biological knowledge greatly facilitates the meaningful interpretation of gene-expression data. Causal networks constructed from individual relationships curated from the literature are particularly suited for this task, since they create mechanistic hypotheses that explain the expression changes observed in datasets. Results: We present and discuss a suite of algorithms and tools for inferring and scoring regulator networks upstream of gene-expression data based on a large-scale causal network derived from the Ingenuity Knowledge Base. We extend the method to predict downstream effects on biological functions and diseases and demonstrate the validity of our approach by applying it to example datasets. Availability: The causal analytics tools ‘Upstream Regulator Analysis', ‘Mechanistic Networks', ‘Causal Network Analysis' and ‘Downstream Effects Analysis' are implemented and available within Ingenuity Pathway Analysis (IPA, http://www.ingenuity.com). Supplementary information: Supplementary material is available at Bioinformatics online.

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Author and article information

Contributors

Li He: heli2003new@126.com

Dandan Sun: sund@upmc.edu

Journal

Journal ID (nlm-ta): J Neuroinflammation

Journal ID (iso-abbrev): J Neuroinflammation

Title: Journal of Neuroinflammation

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-2094

Publication date (Electronic): 28 August 2021

Publication date PMC-release: 28 August 2021

Publication date Collection: 2021

Volume: 18

Electronic Location Identifier: 187

Affiliations

[1 ]GRID grid.13291.38, ISNI 0000 0001 0807 1581, Department of Neurology, West China Hospital, , Sichuan University, ; Chengdu, 610041 Sichuan China

[2 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Department of Neurology, , University of Pittsburgh, ; Pittsburgh, Pennsylvania 15213 USA

[3 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Pittsburgh Institute for Neurodegenerative Disorders, , University of Pittsburgh, ; Pittsburgh, Pennsylvania 15213 USA

[4 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Animal Imaging Center, , University of Pittsburgh, ; Pittsburgh, Pennsylvania 15213 USA

[5 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Department of Neurobiology, , University of Pittsburgh, ; Pittsburgh, Pennsylvania 15213 USA

[6 ]GRID grid.511190.d, ISNI 0000 0004 7648 112X, VA Pittsburgh Healthcare System, , Geriatric Research Education and Clinical Center, ; Pittsburgh, Pennsylvania 15240 USA

[7 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Molecular Biology-Information Service, Health Sciences Library System, , University of Pittsburgh, ; Pittsburgh, Pennsylvania 15261 USA

Article

Publisher ID: 2234

DOI: 10.1186/s12974-021-02234-8

PMC ID: 8403348

PubMed ID: 34454529

SO-VID: fc012235-2a7a-49c7-b9e2-42c205de420e

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 17 June 2021

Date accepted : 4 August 2021

Funding

Funded by: upmc endowed chair professorship for brain disorders research

Funded by: va research career scientist award

Award ID: IK6 BX005647-01

Award Recipient : Dandan Sun

Funded by: FundRef http://dx.doi.org/10.13039/100000002, national institutes of health;

Award ID: R01NS048216

Award ID: RF1NS117509

Award Recipient : Guodong Cao Dandan Sun

Funded by: va merit review grants

Award ID: BX003923

Award ID: BX002346

Award Recipient : Guodong Cao

Funded by: FundRef http://dx.doi.org/10.13039/501100004543, china scholarship council;

Award ID: 201906240207

Award Recipient : Qian Liu

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: hypoperfusion,demyelination,gliosis,na+/h+ exchanger,vascular dementia

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: hypoperfusion, demyelination, gliosis, na+/h+ exchanger, vascular dementia

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

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Abstract

Background

Methods

Results

Conclusion

Supplementary Information

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Most cited references 59

Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.

Neurotoxic reactive astrocytes are induced by activated microglia

Causal analysis approaches in Ingenuity Pathway Analysis

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