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MT5‐MMP controls APP and β‐CTF/C99 metabolism through proteolytic‐dependent and ‐independent mechanisms relevant for Alzheimer's disease
Author(s) -
GarcíaGonzález Laura,
Paumier JeanMichel,
Louis Laurence,
Pilat Dominika,
Bernard Anne,
Stephan Delphine,
Jullien Nicolas,
Checler Frédéric,
Nivet Emmanuel,
Khrestchatisky Michel,
Baranger Kévin,
Rivera Santiago
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202100593r
Subject(s) - matrix metalloproteinase , disease , neuroscience , alzheimer's disease , metabolism , chemistry , medicine , biology
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 the processing of amyloid precursor protein (APP) and the fate of amyloid beta peptide (Aβ) as well as its precursor C99, and C83. We found in human embryonic kidney cells (HEK) carrying the APP Swedish familial mutation (HEKswe) that deleting the C‐terminal non‐catalytic domains of MT5‐MMP hampered its ability to process APP and release the soluble 95 kDa form (sAPP95). Catalytically inactive MT5‐MMP variants increased the levels of Aβ and promoted APP/C99 sorting in the endolysosomal system, likely through interactions of the proteinase C‐terminal portion with C99. Most interestingly, the deletion of the C‐terminal domain of MT5‐MMP caused a strong degradation of C99 by the proteasome and prevented Aβ accumulation. These discoveries reveal new control of MT5‐MMP over APP by proteolytic and non‐proteolytic mechanisms driven by the C‐terminal domains of the proteinase. The targeting of these non‐catalytic domains of MT5‐MMP could, therefore, provide new insights into the therapeutic regulation of APP‐related pathology in AD.