Possible role of calpain in normal processing of β-amyloid precursor protein in human platelets
Possible role of calpain in normal processing of β-amyloid precursor protein in human platelets
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DOI：
10.1006/bbrc.2000.2919
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发表时间：
2000-06-24
影响因子：
3.1
通讯作者：
Fernandez, HL
中科院分区：
文献类型：
--
作者：
Chen, M;Durr, J;Fernandez, HL
在衰老和阿尔茨海默病中，β-淀粉样前体蛋白(APP)的异常蛋白分解过程是形成淀粉样斑块的基础。参与这一过程的蛋白酶尚未确定。在这里，我们发现，在洗涤剂裂解的人血小板中，完整的APP自发的蛋白分解产生了一个N-末端片段，在免疫学上与分泌的APP没有区别，这让人想起可能的α-分泌酶的作用。APP的这种蛋白分解被EDTA抑制，这表明它参与了一种金属依赖的蛋白水解酶。在被测试的几种金属中，钙是唯一能促进APP蛋白分解的金属，该反应可被EGTA和几种钙蛋白酶抑制剂阻断。在血小板裂解产物中自发蛋白分解产生的APP片段与部分纯化的APP暴露于外源钙蛋白酶产生的APP片段相同。最后，完整的血小板分泌APP被细胞通透性的钙蛋白酶抑制剂抑制，这些结果表明，人血小板中APP的正常加工是由一种钙依赖的蛋白水解酶介导的，该酶具有钙蛋白酶样的特性。(C)2000年学术出版社。
Abnormal proteolytic processing of beta-amyloid precursor protein (APP) underlies the formation of amyloid plaques in aging and Alzheimer's disease. The proteases involved in the process have not been identified. Here we found that spontaneous proteolysis of intact APP in detergent-lysed human platelets generated a N-terminal fragment that was immunologically indistinguishable from secreted APP, reminiscent of the action of a putative alpha-secretase. This proteolysis of APP was inhibited by EDTA, suggesting that a metal-dependent protease was involved. Among the several metals tested, calcium was the only one that enhanced APP proteolysis and the reaction was blocked by EGTA as well as by several calpain inhibitors. The APP fragments generated by spontaneous proteolysis in platelet lysates were identical to those produced by exposure of partially purified APP to exogenous calpain. Finally, the secretion of APP from intact platelets was inhibited by cell-permeable calpain inhibitors, Taken together, these results suggest that normal processing of APP in human platelets is mediated by a calcium dependent protease that exhibits calpain-like properties. (C) 2000 Academic Press.