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Proamyloidogenic effects of membrane type 1 matrix metalloproteinase involve MMP‐2 and BACE‐1 activities, and the modulation of APP trafficking
Author(s) -
Paumier Jean-Michel,
Py Nathalie A.,
García-González Laura,
Bernard Anne,
Stephan Delphine,
Louis Laurence,
Checler Frédéric,
Khrestchatisky Michel,
Baranger Kévin,
Rivera Santiago
Publication year - 2019
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.201801076r
Subject(s) - amyloid precursor protein , matrix metalloproteinase , chemistry , endosome , presenilin , alpha secretase , amyloid precursor protein secretase , microbiology and biotechnology , hek 293 cells , protein precursor , metalloproteinase , biochemistry , enzyme , cell , alzheimer's disease , biology , receptor , medicine , disease
We previously demonstrated that membrane type 1 (MT1) matrix metalloproteinase (MMP) was up‐regulated in the hippocampus of the model of transgenic mice bearing 5 familial mutations on human amyloid precursor protein (APP) and presenilin 1 of Alzheimer disease (AD), and that the proteinase increased the levels of amyloid β peptide (Aβ) and its APP C‐terminal fragment of 99 aa in a heterologous cell system. Here we provide further evidence that MT1‐MMP interacts with APP and promotes amyloidogenesis in a proteolytic‐dependent manner in Swedish APP‐expressing human embryonic kidney 293 (HEKswe) cells. MT1‐MMP–mediated processing of APP releases a soluble APP fragment, sAPP95. This process partly requires the activation of endogenous MMP‐2 but is independent of β‐site APP cleaving enzyme 1 (BACE‐1) or α‐secretase activities. In contrast, MT1‐MMP–mediated increase of Aβ levels involved BACE‐1 activity and was inhibited by tissue inhibitor of MMP‐2, a natural inhibitor of both MT1‐MMP and MMP‐2. Interestingly, near abolishment of basal Aβ production upon BACE‐1 inhibition was rescued by MT1‐MMP, indicating that the latter could mimic β‐secretase–like activity. Moreover, MT1‐MMP promoted APP/Aβ localization in endosomes, where Aβ production mainly occurs. These data unveil new mechanistic insights to support the proamyloidogenic role of MT1‐MMP based on APP processing and trafficking, and reinforce the idea that this proteinase may become a new potential therapeutic target in AD.—Paumier, J.‐M., Py, N. A., González, L. G., Bernard, A., Stephan, D., Louis, L., Checler, F., Khrestchatisky, M., Baranger, K., Rivera, S. Proamyloidogenic effects of membrane type 1 matrix metalloproteinase involve MMP‐2 and BACE‐1 activities, and the modulation of APP trafficking. FASEB J. 33, 2910–2927 (2019). www.fasebj.org