Possible role of calpain in normal processing of beta-amyloid precursor protein in human platelets

Abnormal proteolytic processing of beta-amyloid precursor protein (APP) und erlies the formation of amyloid plaques in aging and Alzheimer's disease. T he proteases involved in the process have not been identified. Here we foun d that spontaneous proteolysis of intact APP in detergent-lysed human plate lets generated a N-terminal fragment that was immunologically indistinguish able from secreted APP, reminiscent of the action of a putative alpha-secre tase. This proteolysis of APP was inhibited by EDTA, suggesting that a meta l-dependent protease was involved. Among the several metals tested, calcium was the only one that enhanced APP proteolysis and the reaction was blocke d by EGTA as well as by several calpain inhibitors. The APP fragments gener ated by spontaneous proteolysis in platelet lysates were identical to those produced by exposure of partially purified APP to exogenous calpain. Final ly, the secretion of APP from intact platelets was inhibited by cell-permea ble calpain inhibitors, Taken together, these results suggest that normal p rocessing of APP in human platelets is mediated by a calcium dependent prot ease that exhibits calpain-like properties. (C) 2000 Academic Press.