The pathological hallmark of Alzheimer disease is the senile plaque principally composed of tightly aggregated amyloid-␤ fibrils (fA␤), which are thought to be resistant to degradation and clearance. In this study, we explored whether proteases capable of degrading soluble A␤ (sA␤) could degrade fA␤ as well. We demonstrate that matrix metalloproteinase-9 (MMP-9) can degrade fA␤ and that this ability is not shared by other sA␤-degrading enzymes examined, including endothelinconverting enzyme,

more »

... ulin-degrading enzyme, and neprilysin. fA␤ was decreased in samples incubated with MMP-9 compared with other proteases, assessed using thioflavin-T. Furthermore, fA␤ breakdown with MMP-9 but not with other proteases was demonstrated by transmission electron microscopy. Proteolytic digests of purified fA␤ were analyzed with matrix-assisted laser desorption ionization time-of-flight mass spectrometry to identify sites of A␤ that are cleaved during its degradation. Only MMP-9 digests contained fragments (A␤ 1-20 and A␤ 1-30 ) from fA␤ 1-42 substrate; the corresponding cleavage sites are thought to be important for ␤-pleated sheet formation. To determine whether MMP-9 can degrade plaques formed in vivo, fresh brain slices from aged APP/PS1 mice were incubated with proteases. MMP-9 digestion resulted in a decrease in thioflavin-S (ThS) staining. Consistent with a role for endogenous MMP-9 in this process in vivo, MMP-9 immunoreactivity was detected in astrocytes surrounding amyloid plaques in the brains of aged APP/PS1 and APPsw mice, and increased MMP activity was selectively observed in compact ThS-positive plaques. These findings suggest that MMP-9 can degrade fA␤ and may contribute to ongoing clearance of plaques from amyloid-laden brains.