Dataset Information

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

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.

SUBMITTER: Llorente P

PROVIDER: S-EPMC7685830 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Llorente Patricia P Martins Soraia S Sastre Isabel I Aldudo Jesús J Recuero María M Adjaye James J Bullido Maria J MJ

Oxidative medicine and cellular longevity 20201116

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 <i>in vitro</i> 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 involve ...[more]

PMID: 33282112

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Project description:RationaleInduced mainly by cigarette smoking, chronic obstructive pulmonary disease (COPD) is a global public health problem characterized by progressive difficulty in breathing and increased mucin production. Previously, we reported that acrolein levels found in COPD sputum could activate matrix metalloproteinase-9 (MMP9).ObjectivesTo determine whether acrolein increases expression and activity of MMP14, a critical membrane-bound endopeptidase that can initial a MMP-activation cascade.MethodsMMP14 activity and adduct formation were measured following direct acrolein treatment. MMP14 expression and activity was measured in human airway epithelial cells. MMP14 immunohistochemistry was performed with COPD tissue, and in acrolein- or tobacco-exposed mice.Measurements and main resultsIn a cell-free system, acrolein, in concentrations equal to those found in COPD sputum, directly adducted cysteine 319 in the MMP14 hemopexin-like domain and activated MMP14. In cells, acrolein increased MMP14 activity, which was inhibited by a proprotein convertase inhibitor, hexa-d-arginine. In the airway epithelium of COPD subjects, immunoreactive MMP14 protein increased. In mouse lung, acrolein or tobacco smoke increased lung MMP14 activity and protein. In cells, acrolein-induced MMP14 transcripts were inhibited by an epidermal growth factor receptor (EGFR) neutralizing antibody, EGFR kinase inhibitor, metalloproteinase inhibitor, or mitogen-activated protein kinase (MAPK) 3/2 or MAPK8 inhibitors, but not a MAPK14 inhibitor. Decreasing the MMP14 protein and activity in vitro by small interfering (si)RNA to MMP14 diminished the acrolein-induced MUC5AC transcripts. In acrolein-exposed mice or transgenic mice with lung-specific transforming growth factor-alpha (an EGFR ligand) expression, lung MMP14 and MUC5AC levels increased and these effects were inhibited by a EGFR inhibitor, erlotinib.ConclusionsTaken together, these findings implicate acrolein-induced MMP14 expression and activity in mucin production in COPD.

Dataset Information

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

Publications

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

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