Characterization of platelet-releasable forms of β-amyloid precursor proteins: The effect of thrombin

Activated platelets release a potent inhibitor of factor XIa previously identified as a Kunitz proteinase inhibitor domaincontaining form of the β-amyloid precursor proteins (βAPP). Two carboxy-terminal truncated forms of the βAPP, βAPP-751 and βAPP-770, are shown to be the predominant isoforms secreted by platelets. The release of βAPP from platelets is responsible for the higher concentration of βAPP in serum compared with plasma, and thrombin doseresponse data show that release of βAPP is most consistent with α granule localization within the platelet. Thrombin induces a limited and specific proteolysis of platelet-secreted βAPP, resulting in loss of a carboxy-terminal fragment. This phenomena is dependent on both thrombin concentration and duration of incubation and is inhibited by the thrombinspecific inhibitor hirudin, characteristics that can be duplicated in a mixture of purified recombinant βAPP-751 and thrombin. A similar effect of thrombin on full-length transmembrane forms of βAPP would result in a membrane-bound remnant containing the intact β-amyloid protein.