title: Overexpression of heparanase lowers the amyloid burden in amyloid-β precursor protein transgenic mice.
abstract: Heparan sulfate (HS) and HS proteoglycans (HSPGs) colocalize with amyloid-β (Aβ) deposits in Alzheimer disease brain and in Aβ precursor protein (AβPP) 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 Aβ pathogenesis in vivo. We therefore generated a double-transgenic mouse model overexpressing both human heparanase and human AβPP harboring the Swedish mutation (tgHpa*Swe). Overexpression of heparanase did not affect AβPP processing because the steady-state levels of Aβ1-40, Aβ1-42, and soluble AβPP β 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 Aβ burden, measured by Aβx-40 and Aβx-42 immunohistochemistry, was reduced significantly in tgHpa*Swe brain. The intensity of HS-stained plaques correlated with the Aβx-42 burden and was reduced in tgHpa*Swe mice. Moreover, the HS-like molecule heparin facilitated Aβ1-42-aggregation in an in vitro Thioflavin T assay. The findings suggest that HSPGs contribute to amyloid deposition in tgSwe mice by increasing Aβ fibril formation because heparanase-induced fragmentation of HS led to a reduced amyloid burden. Therefore, drugs interfering with Aβ-HSPG interactions might be a potential strategy for Alzheimer disease treatment.
authors.affiliation: From the Department of Pharmacology, University of Oslo and Oslo University Hospital, Postboks 1057 Blindern, 0316 Oslo, Norway.
authors.forename: Charlotte B
authors.initials: CB
authors.lastname: Jendresen
authors.affiliation: the Department of Medical Biochemistry and Microbiology, SciLifeLab Uppsala, The Biomedical Center, University of Uppsala, Box 582, Husargatan 3, 75123 Uppsala, Sweden.
authors.forename: Hao
authors.initials: H
authors.lastname: Cui
authors.affiliation: the Department of Neuroscience and Pharmacology, University of Uppsala, Box 593, Husargatan 3, 75124 Uppsala, Sweden, and.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: the Cancer and Vascular Biology Research Center Rappaport, Faculty of Medicine, Technion, P.O. Box 9649, 31096 Haifa, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: From the Department of Pharmacology, University of Oslo and Oslo University Hospital, Postboks 1057 Blindern, 0316 Oslo, Norway,. Electronic address: lars.nilsson@medisin.uio.no.
authors.forename: Lars N G
authors.initials: LNG
authors.lastname: Nilsson
authors.affiliation: the Department of Medical Biochemistry and Microbiology, SciLifeLab Uppsala, The Biomedical Center, University of Uppsala, Box 582, Husargatan 3, 75123 Uppsala, Sweden,. Electronic address: jin-ping.li@imbim.uu.se.
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005966:Glucuronidase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D000099175:Heparanase
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D005966:Glucuronidase; D010446:Peptide Fragments; D000099175:Heparanase; C545487:APP protein, human; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Alzheimer Disease; Amyloid; Amyloid-β (AB); Glycosaminoglycan; Heparan Sulfate; Heparanase; Neuroscience; Proteoglycan; Transgenic Mice