Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 8, Pages 5053-5064Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.600569
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Funding
- University of Oslo
- Anders Jahres Stiftelse
- Helse Sor-Ost
- Civitan Foundation
- Joint Programme Neurodegenerative Disease Research grant
- Swedish Heart and Lung Foundation [20110131]
- Swedish Research Council [K2012-67X-21128-01-4]
- Polysackaridforskning Foundation (Uppsala)
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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.
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