Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases.
Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases.
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DOI：
10.1080/14728222.2016.1182990
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发表时间：
2016-10
影响因子：
5.8
通讯作者：
Ye K
中科院分区：
文献类型：
--
作者：
Zhang Z;Xie M;Ye K
天冬酰胺内肽酶（AEP）是一种pH依赖性的内溶酶体半胱氨酸蛋白酶，其切割天冬酰胺残基后的底物。我们最近的研究确定它具有δ-分泌酶活性，并且它与许多神经系统疾病如阿尔茨海默病（AD）和中风有关。越来越多的证据支持AEP的抑制对治疗这些毁灭性疾病表现出有益的作用。根据最近的证据，很明显AEP切割其底物，例如淀粉样前体蛋白（APP）、tau和SET，并在各种神经退行性疾病和中风的神经元细胞死亡中发挥关键作用。在这篇文章中，AEP的基本生物学，其在小鼠模型中的敲除表型，其在神经退行性疾病中的底物，以及其小肽基抑制剂和前药进行了讨论。此外，我们还讨论了AEP作为神经退行性疾病新的治疗靶点的潜力。AEP在许多生物过程中发挥着独特的作用，这取决于pH值和环境。最引人注目的是我们最近的发现; AEP以年龄依赖性方式激活，同时切割APP和tau，从而统一AD中的两个主要病理事件。因此，AEP作为神经退行性疾病的创新触发器。AEP的抑制将为包括AD在内的神经退行性疾病提供改善疾病的治疗。
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. 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. 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.