Degradation of Amyloid -Protein by a Serine Protease--Macroglobulin Complex

Abstract Progressive cerebral deposition of the amyloid β-peptide (Aβ) is an early and constant feature of Alzheimer's disease. Aβ is derived by proteolysis from the β-amyloid precursor protein. β-Amyloid precursor protein processing and the generation of Aβ 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 Aβ 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 700-kDa complex with the inhibitor, α-macroglobulin (αM), that retains activity against small substrates such as Aβ. Its NH-terminal sequence suggests that the protease is previously unidentified. Our results indicate that the Aβ-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 Aβ-bearing plaques in Alzheimer's disease brain contain both αM and receptors of αM-protease complexes, the same or a similar αM-protease complex could arise in vivo and play a role in Aβ clearance.