A beta(1-40) prevents heparanase-catalyzed degradation of heparan sulfate glycosaminoglycans and proteoglycans in vitro - A role for heparan sulfate proteoglycan turnover in Alzheimer's disease
A beta(1-40) prevents heparanase-catalyzed degradation of heparan sulfate glycosaminoglycans and proteoglycans in vitro - A role for heparan sulfate proteoglycan turnover in Alzheimer's disease
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DOI：
10.1074/jbc.272.27.17005
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发表时间：
1997-07-04
影响因子：
4.8
通讯作者：
Tumova, S
中科院分区：
文献类型：
--
作者：
Bame, KJ;Danda, J;Tumova, S
阿尔茨海默氏病的特征是由 β 淀粉样蛋白 (Aβ) 聚合原纤维组成的老年斑，β 淀粉样蛋白是淀粉样蛋白前体蛋白 (β APP) 蛋白水解加工后形成的 39-42 个氨基酸肽。硫酸乙酰肝素蛋白聚糖已被证明与阿尔茨海默病大脑中的 Aβ 共定位，并且实验证据表明蛋白聚糖和肽之间的相互作用对于老年斑的促进、沉积和/或持续很重要。大鼠脑研究表明，核心蛋白和硫酸乙酰肝素糖胺聚糖链都是体内淀粉样纤维形成和沉积所必需的（Snow, A. D.、Sekiguchi, R.、Nochlin, D.、Fraser, P.、Kimata, K.、Mizutani, A.、Arai, Ra.、Schreier, W. A. 和 Morgan, D. G. (1994) Neuron 12, 219-234），表明防止导致淀粉样蛋白沉积的 A β-乙酰肝素硫酸盐蛋白聚糖复合物形成的一种机制是降解蛋白聚糖。通常，硫酸乙酰肝素蛋白聚糖被细胞内乙酰肝素酶内化并降解为短糖胺聚糖。这些反应发生在内体-溶酶体途径中，该途径与 β APP 被加工成 A β 的细胞内位置相同。利用中国仓鼠卵巢细胞部分纯化的乙酰肝素酶活性，我们在体外检测了 A beta(1-40) 是否影响中国仓鼠卵巢硫酸乙酰肝素糖胺聚糖和蛋白聚糖的分解代谢。 A beta(1-40) 以浓度依赖性和 pH 依赖性方式与附着在核心蛋白上的长硫酸乙酰肝素糖胺聚糖和乙酰肝素酶衍生的短链结合。当 A beta(1-40) 添加到乙酰肝素酶测定中时，它可以防止部分纯化的活性从核心蛋白中释放硫酸乙酰肝素链并将其降解为短糖胺聚糖；然而，需要相对于硫酸乙酰肝素大量过量的肽才能看到效果。我们的结果表明，通常内体途径中的 Aβ 水平不足以干扰体内乙酰肝素酶活性。然而，一旦 A β 肽的水平升高（如阿尔茨海默病中的情况），它们就可以与硫酸乙酰肝素蛋白聚糖相互作用并阻止其分解代谢。这可以促进淀粉样蛋白的形成和沉积，因为 Aβ 与蛋白多糖的结合将占主导地位。
Alzheimer's disease is characterized by senile plaques composed of polymeric fibrils of beta amyloid (A beta), a 39-42-amino acid peptide formed after proteolytic processing of the amyloid precursor protein (beta APP). Heparan sulfate proteoglycans have been shown to colocalize with A beta in Alzheimer's disease brain, and experimental evidence indicates that the interactions between the proteoglycan and the peptide are important for the promotion, deposition, and/or persistence of the senile plaques. Studies in rat brain indicated that both the core protein and the heparan sulfate glycosaminoglycan chains are required for amyloid fiber formation and deposition in vivo (Snow, A. D., Sekiguchi, R., Nochlin, D., Fraser, P., Kimata, K., Mizutani, A., Arai, Ra., Schreier, W. A., and Morgan, D. G. (1994) Neuron 12, 219-234), suggesting that one mechanism to prevent the formation of A beta-heparan sulfate proteoglycan complexes that lead to deposition of amyloid would be to degrade the proteoglycan. Normally, heparan sulfate proteoglycans are internalized and degraded to short glycosaminoglycans by intracellular heparanases. These reactions occur in the endosomal-lysosomal pathway, which is the same intracellular location where beta APP is processed to A beta. Using partially purified heparanase activities from Chinese hamster ovary cells we examined whether A beta(1-40) affects the catabolism of Chinese hamster ovary heparan sulfate glycosaminoglycans and proteoglycans in vitro. A beta(1-40) binds to both the long heparan sulfate glycosaminoglycans attached to core proteins and the short, heparanase-derived chains in a concentration-dependent and pH-dependent manner. When A beta(1-40) is added to heparanase assays, it prevents the partially purified activities from releasing heparan sulfate chains from core proteins and degrading them to short glycosaminoglycans; however, a large molar excess of the peptide to heparan sulfate is required to see the effect. Our results suggest that normally the levels of A beta in the endosomal pathway are not sufficient to interfere with heparanase activity in vivo. However, once the level of A beta-peptides are elevated, as they are in Alzheimer's disease, they could interact with heparan sulfate proteoglycans and prevent their catabolism. This could promote the formation and deposition of amyloid, since the binding of A beta to the proteoglycan species will predominate.