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.

中文翻译：

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基质金属蛋白酶14介导人类神经元细胞中氧化应激诱导的APP蛋白水解和溶酶体改变

淀粉样前体蛋白（APP）蛋白水解的改变是阿尔茨海默氏病（AD）的标志。最近的研究描述了APP处理的非规范途径，似乎部分由溶酶体酶执行。我们实验室的体外人类SK-N-MC模型显示，氧化应激（OS）改变了溶酶体降解途径和APP的加工/代谢。本研究确定了溶酶体蛋白基质金属蛋白酶14（MMP14）作为参与APP非规范加工的蛋白酶。对以上细胞的先前表达分析表明，MMP14在OS下过表达。在目前的工作中，它在OS诱导的APP蛋白水解和溶酶体负荷变化中的作用已得到检验。结果表明，MMP14介导了约85 kDa N端APP片段的积累，并增加了OS诱导的溶酶体负荷。这些结果在散发性AD患者的诱导多能干细胞产生的神经元和神经祖细胞中得到了验证，从而强化了MMP14可以为该疾病提供治疗靶点的想法。