Original magnification: 63x. from the induced pluripotent stem cells of patients with sporadic AD, reinforcing the idea that MMP14 may offer a therapeutic target in this disease. 1. Introduction Alzheimer’s disease (AD) is characterized by massive ORY-1001(trans) neuronal damage leading to cerebral atrophy and the loss of cognitive function. Sporadic AD, which accounts for more than 95% of all cases, ORY-1001(trans) is a highly complex disease for which neither the causal agents nor the molecular mechanisms involved are well known. It is widely accepted, however, that oxidative stress (OS), which is intimately linked to aging, is crucial in the onset and development of the disease. Using an ORY-1001(trans) 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  and that the lysosome Rabbit Polyclonal to MAGE-1 axis is part of the mechanism linking OS with neurodegeneration, APP metabolism, and amyloidogenesis [2, 3]. APP processing is central to the pathophysiological mechanism of AD . It is therefore of great interest to identify the proteases that might account for the APP proteolytic pattern seen in neurodegeneration modelsnot least because they might offer therapeutic targets. APP proteolysis, which is intimately linked with its intracellular trafficking, generates Apeptides plus multiple fragments with either neuroprotective or neurotoxic capacity . Recent studies have revealed the proteolytic processing of APP to be more complex than just the canonical amyloidogenic and nonamyloidogenic pathways, with routes involving new secretases and their corresponding APP proteolytic fragments. The latter may accumulate in the brain of patients with AD, contributing to the synaptic dysfunction observed in the disease [6C8]. Remarkably, many of these noncanonical proteases act in the endolysosomal system, where endogenous APP seems to be mostly processed , highlighting the importance of the relationships between APP proteolysis and alterations in the above system. In previous work, whole transcriptome analysis of SK-N-MC cells under OS induced by the xanthine-xanthine oxidase (X-XOD) system [2, 10] revealed the upregulation of MMP14 (also known as MT1-MMP and a member of the matrix metalloproteinase [MMP] family). This enzyme might therefore be part of the mechanism mediating the alterations in APP proteolysis induced by OS. The MMPs belong to the metzincin group of proteases, which share a conserved zinc-binding motif in their active site. MMPs have been classically divided into six groups according to their known substrates in the extracellular matrix: collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and other nonclassified MMPs . More recent data illustrate an extremely wide range of substrates and interconnections for these enzymes, locating them at the crossroads of many biological processes [12, 13]. Soluble and membrane-bound MMPs are attracting increasing interest in neurodegenerative disease research, particularly AD, since they can cleave APP and Aand [14, 15]. MMP14 is phylogenetically close to MMP24, the APP in endosomes, where Aproduction mainly occurs . MMP14 is highly expressed in brain regions that show amyloid pathology and neuroinflammation. The upregulation of the active form of MMP14 has also been described in the hippocampus in 5xFAD model ORY-1001(trans) mice, and it is strongly associated with the accumulation of the trimers . When amyloid deposition and neuroinflammation occur, as in AD, reactive astrocytes and vascular smooth muscle cells markedly increase their expression of MMP14 which may then play a significant ORY-1001(trans) role in degrading soluble and deposited Apeptides . Further, the abolishment of basal Aproduction by BACE-1 inhibition is rescued by MMP14, indicating that the latter might also mimic modelling of AD [21, 22]. Their use helps overcome the problem of the species gap between initial discoveries in rodent models and human studies and our inadequate understanding of the biology of AD.