Related Experiment Video

Updated: Nov 2, 2025

Quantitative Analysis of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Stabilization in a Neural Model of Alzheimer's Disease (AD)
06:41

Quantitative Analysis of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Stabilization in a Neural Model of Alzheimer's Disease (AD)

Published on: January 10, 2025

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

Laura García-González1, Jean-Michel Paumier1, Laurence Louis1

  • 1Aix-Marseille Univ, CNRS, INP, Inst Neurophysiopathol, Marseille, France.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|June 12, 2021
PubMed

Insights

Membrane-type 5-matrix metalloproteinase (MT5-MMP) influences Alzheimer's disease (AD) by controlling amyloid precursor protein (APP) processing. Targeting MT5-MMP's non-catalytic domains offers new therapeutic strategies for AD.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Alzheimer's disease (AD) pathogenesis involves amyloid precursor protein (APP) processing.
  • Membrane-type 5-matrix metalloproteinase (MT5-MMP) has been implicated in AD.
  • The precise role of MT5-MMP in APP processing and amyloid beta (Aβ) formation remains unclear.

Purpose of the Study:

  • To elucidate the mechanisms by which MT5-MMP regulates APP processing.
  • To investigate the role of MT5-MMP's C-terminal domains in APP metabolism and Aβ production.
  • To explore MT5-MMP as a potential therapeutic target for AD.

Main Methods:

  • Utilized human embryonic kidney cells (HEK) expressing the Swedish APP mutation (HEKswe).
  • Generated and analyzed MT5-MMP variants with deleted C-terminal non-catalytic domains.
  • Assessed APP processing, Aβ levels, and protein degradation pathways (proteasomal and endolysosomal).

Main Results:

  • Deletion of MT5-MMP's C-terminal domains impaired APP processing and sAPP95 release.
  • Catalytically inactive MT5-MMP increased Aβ levels and promoted APP/C99 endolysosomal sorting.
  • MT5-MMP C-terminal domain deletion led to C99 proteasomal degradation and prevented Aβ accumulation.

Conclusions:

  • MT5-MMP exerts both proteolytic and non-proteolytic control over APP processing via its C-terminal domains.
  • These findings reveal novel regulatory mechanisms of APP metabolism by MT5-MMP.
  • Targeting MT5-MMP's non-catalytic domains presents a potential therapeutic avenue for AD-related APP pathology.
Keywords:
amyloid beta precursor proteinendosomemetalloproteinaseproteasomesecretase

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