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Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-beta in murine brain
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
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, Geriatrics.ORCID iD: 0000-0003-3117-5367
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2012 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 124, no 4, 465-478 p.Article 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.

Place, publisher, year, edition, pages
2012. Vol. 124, no 4, 465-478 p.
Keyword [en]
Neuroinflammation, Heparan sulfate, Heparanase, Amyloid-beta, Clearance, Alzheimer's disease
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-183208DOI: 10.1007/s00401-012-0997-1ISI: 000308962300002PubMedID: 22692572OAI: oai:DiVA.org:uu-183208DiVA: diva2:562829
Available from: 2012-10-26 Created: 2012-10-23 Last updated: 2017-12-07

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Zhang, XiaoO'Callaghan, PaulNilsson, Lars N. G.Lannfelt, LarsLindahl, UlfLi, Jin-Ping

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GeriatricsDepartment of Medical Biochemistry and Microbiology
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