Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.01.258665v1?rss=1 Authors: Garcia-Gonzalez, L., Paumier, J.-M., Louis, L., Pilat, D., Bernard, A., Stephan, D., Jullien, N., Checler, F., Nivet, E., KHRESTCHATISKY, M., Baranger, K., Rivera, S. Abstract: 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 (A{beta}) 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 A{beta} 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 A{beta} 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. Copy rights belong to original authors. Visit the link for more info