ORIGINAL PAPER Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-b in murine brain

Abstract Neuroinflammation is typically observed in neurodegenerative diseases such as Alzheimer’s disease, as well as after traumatic injury and pathogen infection. Resi-dent 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 sul-fate proteoglycans in neuroinflammation, we employed a transgenic mouse overexpressing heparanase, an endoglu-curonidase that specifically degrades heparan sulfate side chains. Neuroinflammation was induced by systemic chal-lenge with lipopolysaccharide, or by localized cerebral microinjection of aggregated amyloid-b 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 amy-loid-b 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-over-expressing 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