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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