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  • 1. Jendresen, Charlotte B.
    et al.
    Cui, Hao
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Vlodavsky, Israel
    Nilsson, Lars N. G.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Overexpression of Heparanase Lowers the Amyloid Burden in Amyloid-beta Precursor Protein Transgenic Mice2015In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 8, p. 5053-5064Article in journal (Refereed)
    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.

  • 2.
    Jendresen, Charlotte
    et al.
    Univ Oslo, Dept Pharmacol, Postboks 1057, NO-0316 Oslo, Norway;Oslo Univ Hosp, Postboks 1057, NO-0316 Oslo, Norway.
    Digre, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cui, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. College of Life Science, Jiangxi Normal University, Nanchang, 330022, China.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Vlodavsky, Israel
    Technion, Fac Med, Canc & Vasc Biol Res Ctr Rappaport, POB 9649, IL-31096 Haifa, Israel.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Nilsson, Lars N. G.
    Univ Oslo, Dept Pharmacol, Postboks 1057, NO-0316 Oslo, Norway;Oslo Univ Hosp, Postboks 1057, NO-0316 Oslo, Norway.
    Systemic LPS-induced A beta-solubilization and clearance in A beta PP-transgenic mice is diminished by heparanase overexpression2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 4600Article in journal (Refereed)
    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.

  • 3.
    Jia, Juan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Zcharia, Eyal
    Cancer and Vascular Biology Research Center, Technion, Haifa, Israel.
    Vlodavsky, Israel
    Cancer and Vascular Biology Research Center, Technion, Haifa, Israel.
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pejler, Gunnar
    Dept. of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Li, Jin-ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparanase cleavage of heparin modulates protease storage in mast cellsManuscript (preprint) (Other academic)
    Abstract [en]

    Overexpression of heparanase caused extensive degradation of heparan sulfate (HS), and elimination of heparanase resulted in non-degraded HS chains in mice. In this study, we have investigated the impact of heparanase in the processing of heparin and storage of proteases in mast cells. We used fetal skin mast cells (FSMCs) isolated from wild type (WT) embryos and embryos either overexpressing human heparanase (hpa-tg), or lacking heparanase (Hpse-KO). FSMCs from hpa-tg embryos produced substantially shorter heparin chains than did WT counterparts, whereas FSMCs from Hpse-KO embryos expressed longer chains than WT cells. Extensive fragmentation of heparin in hpa-tg FSMC caused losing of proteases in the cells; in contrast, increased storage of proteases was observed in Hpse-KO cells. These results provide the first in vivo evidence demonstrating that heparanase is responsible for processing of mast cell heparin. Control of heparin degradation by heparanase in mast cell may contribute to modulating protease storage in the cells.

  • 4. Li, Jimei
    et al.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lu, Zhongyang
    Yu, Shan Ping
    Wei, Ling
    Expression of heparanase in vascular cells and astrocytes of the mouse brain after focal cerebral ischemia2012In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1433, p. 137-144Article in journal (Refereed)
    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.

  • 5. Li, Lili
    et al.
    Wang, Bo
    Gao, Tianle
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hao, Jing-Xia
    Vlodavsky, Israel
    Wiesenfeld-Hallin, Zsuzsanna
    Xu, Xiao-Jun
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparanase overexpression reduces carrageenan-induced mechanical and cold hypersensitivity in mice2012In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 511, no 1, p. 4-7Article in journal (Refereed)
    Abstract [en]

    Heparanase controls the structure and functions of extracellular matrix (ECM) by degrading heparan sulfate proteoglycans. Heparanase is involved in inflammatory process through modulating the functions of inflammatory cytokines. The present study aimed to find out whether overexpression of heparanase in mice affects carrageenan-induced localized inflammation and inflammatory hyperalgesia. Without challenge, the heparanase overexpression did not significantly affect the mice in response to mechanical, cold and heat stimulation. Unilateral subcutaneous administration of carrageenan produced hypersensitivity to mechanical and cold in both wildtype and the heparanase overexpression (Hpa-tg) mice 24h after treatment. In comparison to wildtype animals, the Hpa-tg mice showed significantly reduced mechanical and cold hypersensitivity. This may, at least partially, due to the reduced mast cell infiltration at the site of inflammation in Hpa-tg mice. These data support a role for heparanase that reduces localized inflammation and inflammatory hyperalgesia in mice.

  • 6.
    Noborn, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    O'Callaghan, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hermansson, Erik
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ancsin, John
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Damas, Ana
    Dacklin, Ingrid
    Presto, Jenny
    Johansson, Jan
    Saraiva, Maria
    Lundgren, Erik
    Kisilevsky, Robert
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Li, Jin-ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparan sulfate/heparin promotes transthyretin fibrillization through selective binding to a basic motif in the protein2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 14, p. 5584-5589Article in journal (Refereed)
    Abstract [en]

    Transthyretin (TTR) is a homotetrameric protein that transports thyroxine and retinol. Tetramer destabilization and misfolding of the released monomers result in TTR aggregation, leading to its deposition as amyloid primarily in the heart and peripheral nervous system. Over 100 mutations of TTR have been linked to familial forms of TTR amyloidosis. Considerable effort has been devoted to the study of TTR aggregation of these mutants, although the majority of TTR-related amyloidosis is represented by sporadic cases due to the aggregation and deposition of the otherwise stable wild-type (WT) protein. Heparan sulfate (HS) has been found as a pertinent component in a number of amyloid deposits, suggesting its participation in amyloidogenesis. This study aimed to investigate possible roles of HS in TTR aggregation. Examination of heart tissue from an elderly cardiomyopathic patient revealed substantial accumulation of HS associated with the TTR amyloid deposits. Studies demonstrated that heparin/HS promoted TTR fibrillization through selective interaction with a basic motif of TTR. The importance of HS for TTR fibrillization was illustrated in a cell model; TTR incubated with WT Chinese hamster ovary cells resulted in fibrillization of the protein, but not with HS-deficient cells (pgsD-677). The effect of heparin on TTR fibril formation was further demonstrated in a Drosophila model that overexpresses TTR. Heparin was colocalized with TTR deposits in the head of the flies reared on heparin-supplemented medium, whereas no heparin was detected in the nontreated flies. Heparin of low molecular weight (Klexane) did not demonstrate this effect.

  • 7.
    O'Callaghan, Paul
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindahl, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Microglial Heparan Sulfate Proteoglycans Facilitate the Cluster-of-Differentiation 14 (CD14)/Toll-like Receptor 4 (TLR4)-Dependent Inflammatory Response2015In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 24, p. 14904-14914Article in journal (Refereed)
    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.

  • 8.
    O'Callaghan, Paul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Noborn, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Li, Jin-ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Apolipoprotein E increases cell association of amyloid-β 40 through heparan sulfate and LRP1 dependent pathways2014In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 21, no 2, p. 76-87Article in journal (Refereed)
  • 9.
    O'Callaghan, Paul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparan Sulfate Proteoglycans as Relays of Neuroinflammation2018In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 66, no 4, p. 305-319Article, review/survey (Refereed)
    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.

  • 10.
    Tan, Ying-Xia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Beijing Inst Transfus Med, Dept Tissue Engn, 27 Taiping Rd, Beijing 100850, Peoples R China.
    Cui, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Jiangxi Normal Univ, Coll Life Sci, 99 Ziyang Rd, Nanchang 330022, Jiangxi, Peoples R China.
    Wan, Lu-Ming
    Beijing Inst Transfus Med, Dept Tissue Engn, 27 Taiping Rd, Beijing 100850, Peoples R China.
    Gong, Feng
    Beijing Inst Transfus Med, Dept Tissue Engn, 27 Taiping Rd, Beijing 100850, Peoples R China.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Vlodavsky, Israel
    Technion, Fac Med, Canc & Vasc Biol Res Ctr Rappaport, Box 9649, IL-31096 Haifa, Israel.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Overexpression of heparanase in mice promoted megakaryopoiesis2018In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 28, no 5, p. 269-275Article in journal (Refereed)
    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.

  • 11. Wang, Bo
    et al.
    Jia, Juan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Zcharia, Eyal
    Vlodavsky, Israel
    Pejler, Gunnar
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparanase affects secretory granule homeostasis of murine mast cells through degrading heparin2011In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 128, no 6, p. 1310-1317.e8Article in journal (Refereed)
    Abstract [en]

    Background: Heparanase degradation of heparan sulfate plays important roles in a number of pathological processes, including inflammation. In vitro experiments show that heparanase is capable of degrading heparin, a polysaccharide present in mast cells (MCs), in which it has a key role in promoting the storage of secretory granule compounds.

    Objective: We sought to investigate the functions of heparanase in MCs.

    Methods: Primarily cultured fetal skin-derived mast cells (FSMCs) isolated from embryos and adult peritoneal MCs were analyzed for storage and release of granule molecules in response to MC activation.

    Results: FSMCs from heparanase-overexpressing mice contained substantially shorter heparin chains and significantly less proteases than control cells. Conversely, FSMCs lacking heparanase contained heparin of larger size and more proteases than control cells. Correspondingly, heparanase-overexpressing adult MCs exhibited reduced release of heparin-bound proteases, a finding that could be attributed to spontaneous release of granular compounds. Heparanase was found to be upregulated in MCs on activation.

    Conclusion: These findings reveal a novel function of heparanase in maintaining MC homeostasis through controlled degradation of heparin present in the MC secretory granules.

  • 12. Zhang, Gan-lin
    et al.
    Zhang, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Wang, Xiao-min
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Towards Understanding the Roles of Heparan Sulfate Proteoglycans in Alzheimer's Disease2014In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, p. 516028-Article, review/survey (Refereed)
    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.

  • 13.
    Zhang, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Wang, Bo
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Implications of heparan sulfate and heparanase in neuroinflammation2014In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 35, p. 174-181Article, review/survey (Refereed)
    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.

  • 14.
    Zhang, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Wang, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    O'Callaghan, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hjertstrom, Elina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jia, Juan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gong, Feng
    Zcharia, Eyal
    Nilsson, Lars N. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Vlodavsky, Israel
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-beta in murine brain2012In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 124, no 4, p. 465-478Article in journal (Refereed)
    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.

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