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

Patricia Llorente,Jesús Aldudo,Maria J Bullido,María Recuero,Soraia Martins,Isabel Sastre,James Adjaye,Yolanda De Pablo

doi:10.1155/2020/5917187

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.

Highlights

Alzheimer’s disease (AD) is characterized by massive neuronal damage leading to cerebral atrophy and the loss of cognitive function
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 matrix metalloproteinase 14 (MMP14) may offer a therapeutic target in this disease
These results correlate with those obtained by Western blotting and with the LysoTracker fluorimetric quantifications, indicating that MMP14 inhibition prevents the increase in the lysosome load induced by oxidative stress (OS). These results suggest that MMP14 is part of the mechanism that mediates the connection between OS, lysosomal alterations, and amyloid precursor protein (APP) proteolysis in the SK-N-MC cell model

Summary

Introduction

Alzheimer’s disease (AD) is characterized by massive neuronal damage leading to cerebral atrophy and the loss of cognitive function. Sporadic AD, which accounts for more than 95% of all cases, is a highly complex disease for which neither the causal agents nor the molecular mechanisms involved are well known. It is widely accepted, that oxidative stress (OS), which is intimately linked to aging, is crucial in the onset and development of the disease. Using an in vitro free radical-generating system to simulate the OS associated with sporadic AD, our group has shown that such stress modulates the metabolism and proteolysis of APP [1] and that the lysosome axis is part of the mechanism linking OS with neurodegeneration, APP metabolism, and amyloidogenesis [2, 3].

Methods

Results

Conclusion