In this study we demonstrate by in situ binding that trypsin interacts with the senile plaques found in Alzheimer disease. Characterization of various potential trypsin binding proteins shows that trypsin binding is mediated by beta-protein precursor (beta PP)-the progenitor of amyloid-beta in senile plaques. Using specific antisera against various proteins to sterically block trypsin blocking, we found that only those antibodies raised against proteins or peptides containing the Kunitz protease inhibitor domain were able to abolish binding. By analogy with other protease/inhibitor interactions, we speculate that the binding of trypsin to beta PP could involve concomitant beta PP cleavage. Therefore, beta PP in protecting against potentially damaging proteolysis could simultaneously liberate beta PP fragments or intermediate precursors of amyloid-beta deposits.