MT5-MMP controls APP metabolism and the fate of beta-CTF/C99 and Abeta through proteolytic-dependent and -independent mechanisms relevant for Alzheimer's disease

We have previously discovered the implication of membrane-type 5-matrix metalloproteinase (MT5-MMP) in AD pathogenesis. Here we shed new light on pathogenic mechanisms by which MT5-MMP controls APP processing and the fate of amyloid beta peptide (Aβ) and its precursor C99. We found that MT5-MMP in HEK carrying the APP Swedish familial mutation (HEKswe) processed APP to release a soluble form of 95 kDa (sAPP95). This process was hampered by the removal of the C-terminal non-catalytic domains of MT5-MMP. Catalytically inactive MT5-MMP variants increased the levels of Aβ and promoted APP/C99 sorting in the endolysosomal system. We found interaction of C99 with the C-terminal portion of MT5-MMP, de deletion of which caused a strong degradation of C99 by the proteasome, preventing Aβ accumulation. These findings reveal novel mechanisms for MT5-MMP control of APP metabolism and C99 fate involving proteolytic and non-proteolytic actions mainly mediated by the C-terminal part of the proteinase.