Matrix Metalloproteinase 14 Mediates APP Proteolysis and Lysosomal Alterations Induced by Oxidative Stress in Human Neuronal Cells

Oxid Med Cell Longev. 2020 Nov 16;2020:5917187. doi: 10.1155/2020/5917187. eCollection 2020.

Abstract

The alteration of amyloid precursor protein (APP) proteolysis is a hallmark of Alzheimer's disease (AD). Recent studies have described noncanonical pathways of APP processing that seem partly executed by lysosomal enzymes. Our laboratory's in vitro human SK-N-MC model has shown that oxidative stress (OS) alters the lysosomal degradation pathway and the processing/metabolism of APP. The present study identifies the lysosomal protein matrix metalloproteinase 14 (MMP14) as a protease involved in the APP noncanonical processing. Previous expression analyses of the above cells showed MMP14 to be overexpressed under OS. In the present work, its role in changes in OS-induced APP proteolysis and lysosomal load was examined. The results show that MMP14 mediates the accumulation of an ≈85 kDa N-terminal APP fragment and increases the lysosome load induced by OS. These results were validated in neurons and neural progenitor cells generated from the induced pluripotent stem cells of patients with sporadic AD, reinforcing the idea that MMP14 may offer a therapeutic target in this disease.

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / metabolism*
  • Humans
  • Lysosomes / metabolism*
  • Matrix Metalloproteinase 14 / metabolism*
  • Neurons / metabolism*
  • Oxidative Stress / physiology*
  • Proteolysis

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Amyloid Precursor Protein Secretases
  • MMP14 protein, human
  • Matrix Metalloproteinase 14