Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-β 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. 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-β 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-β 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-012-0997-1) contains supplementary material, which is available to authorized users.

Overexpression of Heparanase Lowers the Amyloid Burden in Amyloid-β Precursor Protein Transgenic Mice

“…We regard such experiments to be the subject for separate studies. We do not rule out that additional factors, like differential immune response and HS fragment-mediated A␤ clearance along the perivascular lymphatic drainage pathway (15,34,35), also influence parenchymal and cerebrovascular A␤ deposition in double-transgenic mice.…”

“…However, the cause and effect of this codeposition remains unclear. To understand whether HS and HSPGs are active participators of A␤ pathogenesis or simply adhere to and colocalize with A␤ in amyloid plaques, we generated a double-transgenic mouse model overexpressing both human heparanase and human A␤PP harboring the Swedish mutation (tgHpa*Swe) by crossing the tgHpa (15) and tgSwe (25,26) mice. We found that the double-transgenic mice showed overexpression of heparanase in the brain and produced shorter HS fragments.…”

“…The genotype and phenotypes of a homozygous mouse strain overexpressing human heparanase under a ␤-actin promoter (tgHpa) have been described previously (15). A␤PP-transgenic mice harboring only the Swedish double mutation (K670N/ M671L (27)), the tgSwe model, is a relatively mild model of amyloidosis with onset of plaque deposition at around 12 months of age (25,26).…”

“…Our recent study showed that overexpression of heparanase delayed clearance of A␤ fibrils when these were injected into the brain (15). In this work, we asked whether in vivo overexpression of heparanase affects de novo deposition of A␤.…”

“…HS/HSPGs and heparin have been found to alter amyloid-␤ precursor protein (A␤PP) processing (9 -11) and to increase A␤ aggregation (12,13). Although substantial evidence points to an important role of HS in A␤ deposition in the brain, the majority of the available information has been obtained by invasive in vivo experiments (14,15) or in vitro studies (10 -12). The potential, specific role and effect of HS on A␤ deposition in the brain under native conditions remain to be fully established.…”