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

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 processing amyloid precursor protein (APP) and fate beta peptide (Aβ) as well its C99, C83. found human embryonic kidney cells (HEK) carrying APP Swedish familial mutation (HEKswe) that deleting C-terminal non-catalytic domains hampered ability to process release soluble 95 kDa form (sAPP95). Catalytically inactive variants increased levels Aβ promoted APP/C99 sorting endolysosomal system, likely through interactions proteinase portion with C99. Most interestingly, deletion domain caused a strong degradation C99 proteasome prevented accumulation. These discoveries reveal control over proteolytic non-proteolytic driven proteinase. The targeting these could, therefore, provide insights into therapeutic regulation APP-related pathology AD.