Heparan Sulfate Subdomains that are Degraded by Sulf Accumulate in Cerebral Amyloid β Plaques of Alzheimer's Disease Evidence from Mouse Models and Patients
Heparan Sulfate Subdomains that are Degraded by Sulf Accumulate in Cerebral Amyloid β Plaques of Alzheimer's Disease Evidence from Mouse Models and Patients
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DOI：
10.1016/j.ajpath.2012.01.015
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发表时间：
2012-05-01
影响因子：
6
通讯作者：
Uchimura, Kenji
中科院分区：
文献类型：
--
作者：
Hosono-Fukao, Tomomi;Ohtake-Niimi, Shiori;Uchimura, Kenji
阿尔茨海默病（AD）的特征在于淀粉样蛋白P肽（All）的细胞外脑积聚。硫酸乙酰肝素（HS）是一种糖胺聚糖，在细胞外空间中含量丰富。HS链内的硫酸化状态影响其与各种蛋白质相互作用的能力。ITS内的高度硫酸化结构域对于All体外聚集至关重要。在这里，我们研究了Tg 2576，J20和T41转基因AD小鼠模型和AD患者脑中硫酸化结构域和ITS二糖组成的表达。噬菌体展示抗体RB 4CD 12识别HS的高度硫酸化结构域。在生理条件下，RB 4 CD 12表位在脑血管基底膜中丰富。在小鼠和AD患者的皮质和海马中，RB 4CD 12强烈染色弥漫性和神经炎性淀粉样斑块。有趣的是，RB 4CD 12还染色AD脑中某些海马神经元的细胞内颗粒。在血管富集和非血管馏分的Tg 2576小鼠和AD患者的二糖组合物被发现是可比的非转基因和非痴呆对照，分别。淀粉样蛋白斑块中的RB 4CD 12表位被细胞外HS内切硫酸酯酶Sulf-1和Sulf-2离体降解。这些结果表明，高度硫酸化的HS结构域的形成可能与AD发病机制一起上调，并且这些结构域可以在AD脑中酶促重塑。(Am J Pathol 2012，180：2056-2067; DOI：10.1016/j.ajpath.2012.01.015）
Alzheimer's disease (AD) is characterized by extracellular cerebral accumulation of amyloid p peptide (All). Heparan sulfate (HS) is a glycosaminoglycan that is abundant in the extracelhilar space. The state of sulfation within the HS chain influences its ability to interact with a variety of proteins. Highly sulfated domains within ITS are crucial for All aggregation in vitro. Here, we investigated the expression of the sulfated domains and ITS disaccharide composition in the brains of Tg2576, J20, and T41 transgenic AD mouse models, and patients with AD. RB4CD12, a phage display antibody, recognizes highly sulfated domains of HS. The RB4CD12 epitope is abundant in the basement membrane of brain vessels under physiological conditions. In the cortex and hippocampus of the mice and patients with AD, RB4CD12 strongly stained both diffuse and neuritic amyloid plaques. Interestingly, RB4CD12 also stained the intracellular granules of certain hippocampal neurons in AD brains. Disaccharide compositions in vessel-enriched and nonvasculature fractions of Tg2576 mice and AD patients were found to be comparable to those of non-transgenic and non-demented controls, respectively. The RB4CD12 epitope in amyloid plaques was substantially degraded ex vivo by Sulf-1 and Sulf-2, extracellular HS endosulfatases. These results indicate that formation of highly sulfated HS domains may be upregulated in conjunction with AD pathogenesis, and that these domains can be enzymatically remodeled in AD brains. (Am J Pathol 2012, 180: 2056-2067; DOI: 10.1016/j.ajpath.2012.01.015)