Characterization of platelet-releasable forms of beta-amyloid precursor proteins: the effect of thrombin.
Activated platelets release a potent inhibitor of factor XIa previously identified as a Kunitz proteinase inhibitor domain-containing form of the beta-amyloid precursor proteins (beta APP). Two carboxy-terminal truncated forms of the beta APP, beta APP-751 and beta APP-770, are shown to be the predominant isoforms secreted by platelets. The release of beta APP from platelets is responsible for the higher concentration of beta APP in serum compared with plasma, and thrombin dose-response data show that release of beta APP is most consistent with alpha granule localization within the platelet. Thrombin induces a limited and specific proteolysis of platelet-secreted beta APP, 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 thrombin-specific inhibitor hirudin, characteristics that can be duplicated in a mixture of purified recombinant beta APP-751 and thrombin. A similar effect of thrombin on full-length transmembrane forms of beta APP would result in a membrane-bound remnant containing the intact beta-amyloid protein.
Smith
R P
RP
Division of Hematology/Oncology, Jewish Hospital, Washington University Medical Center, St Louis, MO 63110.
Broze
G J
GJ
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000097:blood* / Q000235:genetics / Q000302:isolation & purification; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21; D003594:Cytoplasmic Granules / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005091:Exons; D006801:Humans; D007700:Kinetics; D007962:Leukocytes / Q000502:physiology; D008969:Molecular Sequence Data; D008970:Molecular Weight; D015539:Platelet Activation; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology*
D016564:Amyloid beta-Protein Precursor; D013917:Thrombin