Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases - PubMed (original) (raw)

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Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases

Zhentao Zhang et al. Expert Opin Ther Targets. 2016 Oct.

Abstract

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.

Keywords: Asparagine endopeptidase; cysteine protease; legumain; neurodegenerative diseases.

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Conflict of interest statement

Declaration of interest

The work was supported by a grant from the National Institute of Health (RO1, NS045627) to K Ye, and a grant from the National Natural Science Foundation of China (No. 81571249) to Z Zhang. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

Figure 1

Figure 1. AEP promotes tau aggregation in AD

  1. AEP might translocate from the endolysosome into the cytoplasmic space, where it cleaves tau. 2) Intracellular AEP cuts SET, leading to PP2A inhibition and consequent tau hyperphosphorylation.

Figure 2

Figure 2. AEP cuts APP and promotes the production of Aβ

AEP cleaves APP extracellularly (1) and/or in the endolysosome (2) and promotes the production of Aβ (3).

References

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