INHIBITORY-ACTION OF AMYLOID PRECURSOR PROTEIN AGAINST HUMAN HAGEMAN-FACTOR (FACTOR-XII)

Amyloid precursor protein forms that contain Kunitz protease inhibitor domains are released from activated platelets, T-lymphocytes,and leuk ocytes and inhibit trypsin, plasmin, and activated factor XI. We inves tigated the effects of amyloid precursor protein isoforms on activated Hageman factor (factor XII), activated factor X (Stuart factor), and thrombin. Recombinant amyloid precursor proteins with or without the K unitz domain, 770 and 695 amino acids, respectively, were produced in insect cells by Baculovirus expression (BAC770 and BAC695). Neither BA C695 nor BAC770 inhibited human alpha-thrombin or activated factor X. The partial thromboplastin time was prolonged by both amyloid precurso r proteins, only one of which, BAC770, contains the Kunitz protease in hibitor domain. Both forms of amyloid precursor proteins inhibited ell agic acid-induced activation of Hageman factor but did not inhibit act ivated Hageman factor. Bismuth subgallate, which is an insoluble analo g of ellagic acid, lost its ability to activate Hageman factor on bein g exposed to BAC770. Inhibition of ellagic acid-induced activation of Hageman factor by both forms of amyloid precursor protein was enhanced by heparin. These findings suggested that the heparin-binding domain of amyloid precursor proteins is not in the Kunitz domain. This hepari n-binding domain may block the activation of Hageman factor by negativ ely charged agents. Thus, amyloid precursor proteins may be involved i n the control of hemostasis, properties not all dependent on the Kunit z domain.