MT5-MMP controls APP and β-CTF/C99 metabolism through proteolytic-dependent and -independent mechanisms relevant for Alzheimer’s disease

authors

  • García-González Laura
  • Paumier Jean-Michel
  • Louis Laurence
  • Pilat Dominika
  • Bernard Anne
  • Stephan Delphine
  • Jullien Nicolas
  • Checler Frédéric
  • Nivet Emmanuel
  • Khrestchatisky Michel
  • Baranger Kévin
  • Rivera Santiago

keywords

  • Metalloproteinase
  • Secretase
  • Amyloid beta precursor protein
  • Α-CTF/C83
  • Proteasome
  • Endosome
  • Lysosome
  • Scavenger

abstract

We previously discovered the implication of membrane-type 5-matrix metalloproteinase (MT5-MMP) in Alzheimer’s 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 (Aβ), 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 Aβ 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 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.

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