Jendresen Charlotte B, Cui Hao, Zhang Xiao, Vlodavsky Israel, Nilsson Lars N G, Li Jin-Ping
From the Department of Pharmacology, University of Oslo and Oslo University Hospital, Postboks 1057 Blindern, 0316 Oslo, Norway.
the Department of Medical Biochemistry and Microbiology, SciLifeLab Uppsala, The Biomedical Center, University of Uppsala, Box 582, Husargatan 3, 75123 Uppsala, Sweden.
J Biol Chem. 2015 Feb 20;290(8):5053-5064. doi: 10.1074/jbc.M114.600569. Epub 2014 Dec 29.
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 (tgHpaSwe). 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 tgHpaSwe and single-transgenic tgSwe mice. In contrast, the Congo red-positive amyloid burden was significantly lower in 15-month-old tgHpaSwe brain than in tgSwe brain. Likewise, the Aβ burden, measured by Aβx-40 and Aβx-42 immunohistochemistry, was reduced significantly in tgHpaSwe 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.
硫酸乙酰肝素（HS）和HS蛋白聚糖（HSPG）与阿尔茨海默病大脑及β淀粉样前体蛋白（AβPP）转基因小鼠模型中的β淀粉样蛋白（Aβ）沉积物共定位。乙酰肝素酶是一种内切糖苷酶，可特异性降解HSPG的无分支糖胺聚糖侧链。本研究的目的是检验HS和HSPG在体内是Aβ发病机制的积极参与者这一假说。因此，我们构建了一种双转基因小鼠模型，该模型同时过表达人乙酰肝素酶和携带瑞典突变的人AβPP（tgHpaSwe）。乙酰肝素酶的过表达并不影响AβPP的加工处理，因为在2至3月龄的双转基因tgHpaSwe小鼠和单转基因tgSwe小鼠中，Aβ1-40、Aβ1-42和可溶性AβPPβ的稳态水平相同。相比之下，15月龄tgHpaSwe小鼠大脑中刚果红阳性淀粉样蛋白负荷明显低于tgSwe小鼠大脑。同样，通过Aβx-40和Aβx-42免疫组化测量的Aβ负荷在tgHpaSwe小鼠大脑中也显著降低。HS染色斑块的强度与Aβx-42负荷相关，并且在tgHpa*Swe小鼠中降低。此外，在体外硫黄素T试验中，HS样分子肝素促进了Aβ1-42的聚集。这些发现表明，HSPG通过增加Aβ纤维形成促进tgSwe小鼠中的淀粉样蛋白沉积，因为乙酰肝素酶诱导的HS片段化导致淀粉样蛋白负荷降低。因此，干扰Aβ-HSPG相互作用的药物可能是治疗阿尔茨海默病的一种潜在策略。
