Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases.
BACKGROUND
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.


METHODS
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.


CONCLUSIONS
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.
a Department of Neurology , Renmin Hospital of Wuhan University , Wuhan , China.|b Department of Pathology and Laboratory Medicine , Emory University School of Medicine , Atlanta , GA , USA.
Zhentao
Z
Zhang
b Department of Pathology and Laboratory Medicine , Emory University School of Medicine , Atlanta , GA , USA.
Manling
M
Xie
b Department of Pathology and Laboratory Medicine , Emory University School of Medicine , Atlanta , GA , USA.
Keqiang
K
Ye
D000367:Age Factors; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D000818:Animals; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D058990:Molecular Targeted Therapy; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D020521:Stroke / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D000099240:Asparaginyl Endopeptidase
D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors; D000099240:Asparaginyl Endopeptidase
Asparagine endopeptidase; cysteine protease; legumain; neurodegenerative diseases