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

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.

doi:10.1101/2020.09.01.258665

bioRxiv · 10.1101/2020.09.01.258665

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

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.

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Abstract

We previously discovered the implication of membrane-type 5-matrix metalloproteinase (MT5-MMP) in Alzheimers disease 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}), its precursor C99 and C83. We found in HEK carrying the APP Swedish familial mutation (HEKswe) that MT5-MMP-mediated processing of APP that releases the soluble 95 kDa form (sAPP95), 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 endo-lysosomal system. We found interaction of C99 with the C-terminal portion of MT5-MMP, the 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.

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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.. 2020-09-01. 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. https://doi.org/10.1101/2020.09.01.258665

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