Degradation of amyloid beta-protein by a serine protease-alpha(2)-macroglobulin complex

Progressive cerebral deposition of the amyloid beta-peptide (A beta) is an early and constant feature of Alzheimer's disease. A beta is derived by proteolysis from the beta-amyloid precursor protein. beta-Amyloid precursor protein processing and the generation of A beta have been extensively characterized, but little is known about the mechanisms of degradation of this potentially neurotoxic peptide. We identified and purified a proteolytic activity in culture medium that can degrade secreted A beta but not larger proteins in the medium. Detection of the activity in conditioned medium required the presence of fetal bovine serum and the passage of the cells with a pancreatic trypsin preparation. Its inhibitor profile showed that the activity was a serine protease other than trypsin or chymotrypsin. The protease occurs as a stable similar to 700-kDa complex with the inhibitor, alpha(2)-macroglobulin (alpha(2)M), that retains activity against small substrates such as A beta. Its NH2-terminal sequence suggests that the protease is previously unidentified. Our results indicate that the A beta-degrading protease we have detected is a non-trypsin component of a pancreatic trypsin preparation or else derives from a zymogen in serum that is activated by a protease in the latter preparation. Because A beta-bearing plaques in Alzheimer's disease brain contain both alpha(2)M and receptors of alpha(2)M-protease complexes, the same or a similar alpha(2)M-protease complex could arise in vivo and play a role in A beta clearance.