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Zhang, Xiao
Publications (10 of 14) Show all publications
Jendresen, C., Digre, A., Cui, H., Zhang, X., Vlodavsky, I., Li, J.-P. & Nilsson, L. N. G. (2019). Systemic LPS-induced A beta-solubilization and clearance in A beta PP-transgenic mice is diminished by heparanase overexpression. Scientific Reports, 9, Article ID 4600.
Open this publication in new window or tab >>Systemic LPS-induced A beta-solubilization and clearance in A beta PP-transgenic mice is diminished by heparanase overexpression
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 4600Article in journal (Refereed) Published
Abstract [en]

Amyloid-beta (A(beta) is the main constituent of amyloid deposits in Alzheimer's disease (AD). The neuropathology is associated with neuroinflammation. Here, we investigated effects of systemic lipopolysaccharide (LPS)-treatment on neuroinflammation and A beta deposition in A beta PP-mice and doubletransgenic mice with brain expression of A beta PP and heparanase, an enzyme that degrades HS and generates an attenuated LPS-response. At 13 months of age, the mice received a single intraperitoneal injection of 50 mu g LPS or vehicle, and were sacrificed 1.5 months thereafter. A beta in the brain was analyzed histologically and biochemically after sequential detergent extraction. Neuroinflammation was assessed by CD45 immunostaining and mesoscale cytokine/chemokine ELISA. In single-transgenic mice, LPS-treatment reduced total A beta deposition and increased Tween-soluble A beta. This was associated with a reduced CXCL1, IL-1 beta, TNF-alpha-level and microgliosis, which correlated with amyloid deposition and total A beta. In contrast, LPS did not change A beta accumulation or inflammation marker in the doubletransgenic mice. Our findings suggest that a single pro-inflammatory LPS-stimulus, if given sufficient time to act, triggers A beta-clearance in A beta PP-transgenic mouse brain. The effects depend on HS and heparanase.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-380445 (URN)10.1038/s41598-019-40999-4 (DOI)000461159600077 ()30872722 (PubMedID)
Funder
Swedish Research Council, K2012-67X-21128-01-4
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-03-28Bibliographically approved
O'Callaghan, P., Zhang, X. & Li, J.-P. (2018). Heparan Sulfate Proteoglycans as Relays of Neuroinflammation. Journal of Histochemistry and Cytochemistry, 66(4), 305-319
Open this publication in new window or tab >>Heparan Sulfate Proteoglycans as Relays of Neuroinflammation
2018 (English)In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 66, no 4, p. 305-319Article, review/survey (Refereed) Published
Abstract [en]

Heparan sulfate proteoglycans (HSPGs) are implicated as inflammatory mediators in a variety of settings, including chemokine activation, which is required to recruit circulating leukocytes to infection sites. Heparan sulfate (HS) polysaccharide chains are highly interactive and serve co-receptor roles in multiple ligand:receptor interactions. HS may also serve as a storage depot, sequestering ligands such as cytokines and restricting their access to binding partners. Heparanase, through its ability to fragment HS chains, is a key regulator of HS function and has featured prominently in studies of HS's involvement in inflammatory processes. This review focuses on recent discoveries regarding the role of HSPGs, HS, and heparanase during inflammation, with particular focus on the brain. HS chains emerge as critical go-betweens in multiple aspects of the inflammatory responserelaying signals between receptors and cells. The molecular interactions proposed to occur between HSPGs and the pathogen receptor toll-like receptor 4 (TLR4) are discussed, and we summarize some of the contrasting roles that HS and heparanase have been assigned in diseases associated with chronic inflammatory states, including Alzheimer's disease (AD). We conclude by briefly discussing how current knowledge could potentially be applied to augment HS-mediated events during sustained neuroinflammation, which contributes to neurodegeneration in AD.

Place, publisher, year, edition, pages
SAGE PUBLICATIONS LTD, 2018
Keywords
Alzheimer's disease (AD), extracellular matrix (ECM), heparan sulfate (HS), heparan sulfate proteoglycans (HSPGs), heparanase, inflammation, innate immunity, microglia, neuroinflammation, toll-like receptor 4 (TLR4)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-357172 (URN)10.1369/0022155417742147 (DOI)000429872800008 ()29290138 (PubMedID)
Funder
Swedish Research Council, 2015-02595
Available from: 2018-08-14 Created: 2018-08-14 Last updated: 2018-08-14Bibliographically approved
Tan, Y.-X., Cui, H., Wan, L.-M., Gong, F., Zhang, X., Vlodavsky, I. & Li, J.-P. (2018). Overexpression of heparanase in mice promoted megakaryopoiesis. Glycobiology, 28(5), 269-275
Open this publication in new window or tab >>Overexpression of heparanase in mice promoted megakaryopoiesis
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2018 (English)In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 28, no 5, p. 269-275Article in journal (Refereed) Published
Abstract [en]

Heparanase, an endo-glucuronidase that specifically cleaves heparan sulfate (HS), is upregulated in several pathological conditions. In this study, we aimed to find a correlation of heparanase expression and platelets production. In the transgenic mice overexpressing human heparanase (Hpa-tg), hematological analysis of blood samples revealed a significantly higher number of platelets in comparison with wild-type (Ctr) mice, while no significant difference was found in leukocytes and red blood cell number between the two groups. Total number of thiazole orange positive platelets was increased in Hpa-tg vs. Ctr blood, reflecting a higher rate of platelets production. Concomitantly, megakaryocytes from Hpa-tg mice produced more and shorter HS fragments that were shed into the medium. Further, thrombopoietin (TPO) level was elevated in the liver and plasma of Hpa-tg mice. Together, the data indicate that heparanase expression promoted megakaryopoiesis, which may be through upregulated expression of TPO and direct effect of released HS fragments expressed in the megakaryocytes.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2018
Keywords
heparan sulfate, heparanase, megakaryopoiesis, platelets
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-352573 (URN)10.1093/glycob/cwy011 (DOI)000429486500003 ()
Funder
Swedish Research Council, 2015-02595
Available from: 2018-08-07 Created: 2018-08-07 Last updated: 2018-08-07Bibliographically approved
O'Callaghan, P., Li, J.-P., Lannfelt, L., Lindahl, U. & Zhang, X. (2015). Microglial Heparan Sulfate Proteoglycans Facilitate the Cluster-of-Differentiation 14 (CD14)/Toll-like Receptor 4 (TLR4)-Dependent Inflammatory Response. Journal of Biological Chemistry, 290(24), 14904-14914
Open this publication in new window or tab >>Microglial Heparan Sulfate Proteoglycans Facilitate the Cluster-of-Differentiation 14 (CD14)/Toll-like Receptor 4 (TLR4)-Dependent Inflammatory Response
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2015 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 24, p. 14904-14914Article in journal (Refereed) Published
Abstract [en]

Microglia rapidly mount an inflammatory response to pathogens in the central nervous system (CNS). Heparan sulfate proteoglycans (HSPGs) have been attributed various roles in inflammation. To elucidate the relevance of microglial HSPGs in a pro-inflammatory response we isolated microglia from mice overexpressing heparanase (Hpa-tg), the HS-degrading endoglucuronidase, and challenged them with lipopolysaccharide (LPS), a bacterial endotoxin. Prior to LPS-stimulation, the LPS-receptor cluster-of-differentiation 14 (CD14) and Toll-like receptor 4 (TLR4; essential for the LPS response) were similarly expressed in Ctrl and Hpa-tg microglia. However, compared with Ctrl microglia, Hpa-tg cells released significantly less tumor necrosis factor-α (TNFα), essentially failed to up-regulate interleukin-1β (IL1β) and did not initiate synthesis of proCD14. Isolated primary astroyctes expressed TLR4, but notably lacked CD14 and in contrast to microglia, LPS challenge induced a similar TNFα response in Ctrl and Hpa-tg astrocytes, while neither released IL1β. The astrocyte TNFα-induction was thus attributed to CD14-independent TLR4 activation and was unaffected by the cells HS status. Equally, the suppressed LPS-response in Hpa-tg microglia indicated a loss of CD14-dependent TLR4 activation, suggesting that microglial HSPGs facilitate this process. Indeed, confocal microscopy confirmed interactions between microglial HS and CD14 in LPS-stimulated microglia and a potential HS-binding motif in CD14 was identified. We conclude that microglial HSPGs facilitate CD14-dependent TLR4 activation and that heparanase can modulate this mechanism.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-257815 (URN)10.1074/jbc.M114.634337 (DOI)000356177300010 ()25869127 (PubMedID)
Funder
Swedish Research Council, 2003-5546
Available from: 2015-07-09 Created: 2015-07-09 Last updated: 2017-12-04Bibliographically approved
Jendresen, C. B., Cui, H., Zhang, X., Vlodavsky, I., Nilsson, L. N. G. & Li, J.-P. (2015). Overexpression of Heparanase Lowers the Amyloid Burden in Amyloid-beta Precursor Protein Transgenic Mice. Journal of Biological Chemistry, 290(8), 5053-5064
Open this publication in new window or tab >>Overexpression of Heparanase Lowers the Amyloid Burden in Amyloid-beta Precursor Protein Transgenic Mice
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2015 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 8, p. 5053-5064Article in journal (Refereed) Published
Abstract [en]

Heparan sulfate (HS) and HS proteoglycans (HSPGs) colocalize with amyloid-beta (A beta) deposits in Alzheimer disease brain and in A beta precursor protein (A beta PP) transgenic mouse models. Heparanase is an endoglycosidase that specifically degrades the unbranched glycosaminoglycan side chains of HSPGs. The aim of this study was to test the hypothesis that HS and HSPGs are active participators of A beta pathogenesis in vivo. We therefore generated a double-transgenic mouse model overexpressing both human heparanase and human A beta PP harboring the Swedish mutation (tgHpa*Swe). Overexpression of heparanase did not affect A beta PP processing because the steady-state levels of A beta(1-40), A beta(1-42), and soluble A beta PP beta were the same in 2- to 3-month-old double-transgenic tgHpa*Swe and single-transgenic tgSwe mice. In contrast, the Congo red-positive amyloid burden was significantly lower in 15-month-old tgHpa*Swe brain than in tgSwe brain. Likewise, the A beta burden, measured by A beta(x-40) and A beta(x-42) immunohistochemistry, was reduced significantly in tgHpa*Swe brain. The intensity of HS-stained plaques correlated with the A beta(x-42) burden and was reduced in tgHpa*Swe mice. Moreover, the HS-like molecule heparin facilitated A beta(1-42)-aggregation in an in vitro Thioflavin T assay. The findings suggest that HSPGs contribute to amyloid deposition in tgSwe mice by increasing A beta fibril formation because heparanase-induced fragmentation of HS led to a reduced amyloid burden. Therefore, drugs interfering with A beta-HSPG interactions might be a potential strategy for Alzheimer disease treatment.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-248835 (URN)10.1074/jbc.M114.600569 (DOI)000350042000046 ()25548284 (PubMedID)
Available from: 2015-04-08 Created: 2015-04-08 Last updated: 2017-12-04Bibliographically approved
O'Callaghan, P., Noborn, F., Sehlin, D., Li, J.-p., Lannfelt, L., Lindahl, U. & Zhang, X. (2014). Apolipoprotein E increases cell association of amyloid-β 40 through heparan sulfate and LRP1 dependent pathways. Amyloid: Journal of Protein Folding Disorders, 21(2), 76-87
Open this publication in new window or tab >>Apolipoprotein E increases cell association of amyloid-β 40 through heparan sulfate and LRP1 dependent pathways
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2014 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 21, no 2, p. 76-87Article in journal (Refereed) Published
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-168315 (URN)10.3109/13506129.2013.879643 (DOI)000336146700002 ()
Available from: 2012-02-08 Created: 2012-02-08 Last updated: 2017-12-08
Zhang, X., Wang, B. & Li, J.-P. (2014). Implications of heparan sulfate and heparanase in neuroinflammation. Matrix Biology, 35, 174-181
Open this publication in new window or tab >>Implications of heparan sulfate and heparanase in neuroinflammation
2014 (English)In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 35, p. 174-181Article, review/survey (Refereed) Published
Abstract [en]

Heparan sulfate proteoglycans (HSPGs), expressed on the cell surface and in the extracellular matrix of most animal tissues, have essential functions in development and homeostasis, and have been implicated in several pathological conditions. The functions of HSPGs are mainly mediated through interactions of the heparan sulfate (HS) polysaccharide side chains with different protein ligands. The molecular structure of HS is highly diverse, expressed in a cell-type specific manner. The flexible yet controlled structure of HS is primarily generated through a strictly regulated biosynthesis process and is further modified post-synthetically, such as desulfation by endosulfatases and fragmentation by heparanase. Heparanase is an endo-glucuronidase expressed in all tissues. The enzyme has been found up-regulated in a number of pathological conditions, implying a role in diseases mainly through degradation of HS. Emerging evidence demonstrates important roles of HS and heparanase in inflammatory reactions, particularly in the regulation of leukocyte activation and extravasation. Neuroinflammation is a common feature of various central nervous system disorders, thus it is a great interest to understand the implications of HS and heparanase in neuroinflammation.

Keywords
Heparan sulfate proteoglycan, Heparanase, Neuroinflammation, Brain, Alzheimer's disease
National Category
Microbiology in the medical area Neurosciences
Identifiers
urn:nbn:se:uu:diva-228913 (URN)10.1016/j.matbio.2013.12.009 (DOI)000337556500022 ()
Available from: 2014-07-22 Created: 2014-07-22 Last updated: 2018-01-11Bibliographically approved
Zhang, G.-l., Zhang, X., Wang, X.-m. & Li, J.-P. (2014). Towards Understanding the Roles of Heparan Sulfate Proteoglycans in Alzheimer's Disease. BioMed Research International, 516028
Open this publication in new window or tab >>Towards Understanding the Roles of Heparan Sulfate Proteoglycans in Alzheimer's Disease
2014 (English)In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, p. 516028-Article, review/survey (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive loss of memory and cognitive dysfunctions. A central pathological event of AD is accumulation and deposition of cytotoxic amyloid-beta peptide (A beta) in the brain parenchyma. Heparan sulfate proteoglycans (HSPGs) and the side chains heparan sulfate (HS) are found associated with A beta deposits in the brains of AD patients and transgenic animal models of AD. A growing body of evidence from in vitro and in vivo studies suggests functional roles of HSPG/HS in A beta pathogenesis. Although the question of "how and why HSPG/HS is codeposited with A beta?" still remains, it is within reach to understand the mechanisms of the events. Recent progress by immunohistochemical examination with advanced antibodies shed light on molecular structures of HS codeposited with A beta Several recent reports have provided important new insights into the roles of HSPG in A beta pathogenesis. Particularly, experiments on mouse models revealed indispensible functions of HSPG in modulating A beta-associated neuroinflammation and clearance of A beta from the brain. Application of molecules to interfere with the interaction between HS and A beta peptides has demonstrated beneficial effects on AD mouse models. Elucidating the functions of HSPG/HS in A beta deposition and toxicity is leading to further understanding of the complex pathology of AD. The progress is encouraging development of new treatments for AD by targeting HS-A beta interactions.

National Category
Medical Biotechnology
Identifiers
urn:nbn:se:uu:diva-231495 (URN)10.1155/2014/516028 (DOI)000340142600001 ()
Available from: 2014-09-08 Created: 2014-09-08 Last updated: 2017-12-05Bibliographically approved
Li, J., Li, J.-P., Zhang, X., Lu, Z., Yu, S. P. & Wei, L. (2012). Expression of heparanase in vascular cells and astrocytes of the mouse brain after focal cerebral ischemia. Brain Research, 1433, 137-144
Open this publication in new window or tab >>Expression of heparanase in vascular cells and astrocytes of the mouse brain after focal cerebral ischemia
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2012 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1433, p. 137-144Article in journal (Refereed) Published
Abstract [en]

Heparanase is a heparan sulfate degrading endoglycosidase. Previous work has demonstrated that heparanase plays important roles in various biological processes including angiogenesis, wound healing and metastasis. However, the role of heparanase in the post-ischemic brain is not well defined. Transient focal cerebral ischemia in adult mice was induced by ligations of the right middle cerebral artery (MCA) and both common carotid arteries (CCAs). All mice were subjected to bromodeoxyuridine (BrdU) injection and sacrificed at different time points after stroke for immunohistochemical and Western blot analyses. Heparanase expression increased after ischemia in both cell-specific and time-dependent manners. Three to 7 days after stroke, levels of the 50-kD heparanase, basic fibroblast growth factor (FGF-2), and angiopoietin-2 (Ang-2) increased in the peri-infarct region. At early time points, heparanase expression was largely confined to proliferating vascular endothelial cells. At 14 days after ischemia, this expression had shifted to astrocytes in the same region. These data show that cerebral ischemia markedly increases heparanase levels in endothelial cells and then in astrocytes. The unique features of the heparanase upregulation imply that heparanase may play specific roles in the pathological and regenerative processes during the acute and sub-acute/chronic phases in the post-stroke brain.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-169158 (URN)10.1016/j.brainres.2011.11.032 (DOI)000300534100016 ()22169133 (PubMedID)
Available from: 2012-02-23 Created: 2012-02-23 Last updated: 2017-12-07Bibliographically approved
Zhang, X., Wang, B., O'Callaghan, P., Hjertstrom, E., Jia, J., Gong, F., . . . Li, J.-P. (2012). Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-beta in murine brain. Acta Neuropathologica, 124(4), 465-478
Open this publication in new window or tab >>Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-beta in murine brain
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2012 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 124, no 4, p. 465-478Article in journal (Refereed) Published
Abstract [en]

Neuroinflammation is typically observed in neurodegenerative diseases such as Alzheimer's disease, as well as after traumatic injury and pathogen infection. Resident immune cells, microglia and astrocytes, are activated and joined by blood-borne monocytes that traverse the blood-brain barrier and convert into activated macrophages. The activated cells express various cytokines, chemokines and proteolytic enzymes. To study the role of heparan sulfate proteoglycans in neuroinflammation, we employed a transgenic mouse overexpressing heparanase, an endoglucuronidase that specifically degrades heparan sulfate side chains. Neuroinflammation was induced by systemic challenge with lipopolysaccharide, or by localized cerebral microinjection of aggregated amyloid-beta peptide, implicated in Alzheimer's disease. Lipopolysaccharide-treated control mice showed massive activation of resident microglia as well as recruitment of monocyte-derived macrophages into the brain parenchyma. Microinjection of aggregated amyloid-beta elicited a similar inflammatory response, albeit restricted to the injection site, which led to dispersion and clearance of the amyloid. In the heparanase-overexpressing mice, all aspects of immune cell recruitment and activation were significantly attenuated in both inflammation models, as was amyloid dispersion. Accordingly, an in vitro blood-brain barrier model constructed from heparanase-overexpressing cerebral vascular cells showed impaired transmigration of monocytes compared to a corresponding assembly of control cells. Our data indicate that intact heparan sulfate chains are required at multiple sites to mediate neuroinflammatory responses, and further point to heparanase as a modulator of this process, with potential implications for Alzheimer's disease.

Keywords
Neuroinflammation, Heparan sulfate, Heparanase, Amyloid-beta, Clearance, Alzheimer's disease
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-183208 (URN)10.1007/s00401-012-0997-1 (DOI)000308962300002 ()22692572 (PubMedID)
Available from: 2012-10-26 Created: 2012-10-23 Last updated: 2017-12-07
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