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Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases

机译：天冬酰胺内肽酶是神经退行性疾病的创新治疗靶标

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Introduction: Asparagine endopeptidase (AEP) is a pH-dependent endolysosomal cysteine protease that cleaves its substrates after asparagine residues. Our most recent study identifies that it possesses the delta-secretase activity, and that it is implicated in numerous neurological diseases such as Alzheimer's disease (AD) and stroke. Accumulating evidence supports that the inhibition of AEP exhibits beneficial effects for treating these devastating diseases.Areas covered: Based on recent evidence, it is clear that AEP cleaves its substrate, such as amyloid precursor protein (APP), tau and SET, and plays a critical role in neuronal cell death in various neurodegenerative diseases and stroke. In this article, the basic biology of AEP, its knockout phenotypes in mouse models, its substrates in neurodegenerative diseases, and its small peptidyl inhibitors and prodrugs are discussed. In addition, we discuss the potential of AEP as a novel therapeutic target for neurodegenerative diseases.Expert opinion: AEP plays a unique role in numerous biological processes, depending on both pH and context. Most striking is our most recent finding; that AEP is activated in an age-dependent manner and simultaneously cleaves both APP and tau, thereby unifying both major pathological events in AD. Thus, AEP acts as an innovative trigger for neurodegenerative diseases. Inhibition of AEP will provide a disease-modifying treatment for neurodegenerative diseases including AD.
机译：简介：天冬酰胺内肽酶（AEP）是一种pH依赖性的溶酶体半胱氨酸蛋白酶，可在天冬酰胺残基裂解后切割其底物。我们的最新研究表明，它具有δ-分泌酶活性，并且与多种神经系统疾病有关，例如阿尔茨海默氏病（AD）和中风。越来越多的证据表明，抑制AEP具有治疗这些毁灭性疾病的有益作用。涵盖的领域：根据最近的证据，很明显，AEP会裂解其底物，例如淀粉样蛋白前体蛋白（APP），tau和SET，并发挥作用。在各种神经退行性疾病和中风中神经元细胞死亡中的关键作用。在本文中，讨论了AEP的基本生物学，小鼠模型中的敲除表型，神经退行性疾病中的底物以及小型肽基抑制剂和前药。此外，我们讨论了AEP作为神经退行性疾病的新型治疗靶标的潜力。专家意见：AEP在众多生物学过程中都起着独特的作用，具体取决于pH和环境。最惊人的是我们最近的发现; AEP的激活与年龄有关，并同时切割APP和tau，从而统一了AD中的两个主要病理事件。因此，AEP是神经退行性疾病的创新触发因素。抑制AEP将为神经退行性疾病（包括AD）提供改善疾病的治疗方法。

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