Expression of the cysteine protease legumain in vascular lesions and functional implications in atherogenesis

Clerin, Valérie; Shih, Heather H.; Deng, Nanhua; Hebert, Gustave; Resmini, Christine; Shields, Kathleen; Feldman, Jeffrey L.; Winkler, Aaron; Albert, Leo; Maganti, Vasu; Wong, Anthony; Paulsen, Janet; Keith, James C.; Vlasuk, George P.; Pittman, Debra D.

doi:10.1016/j.atherosclerosis.2008.01.016

Cited by 51 publications

(42 citation statements)

References 31 publications

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“…In addition, they show that in the peri-infact area, AEP is processed into its active form. AEP was mainly found in branches of astroglial cells and microglia, suggesting AEP may be secreted 37 and may function as a chemo-attractant for invading inflammatory cells after stroke 35 . However, They found that the infarct volumes between wild-type and AEP knockout mice were similar, suggesting that AEP might be not involved in the acute stage of neurodegeneration but may play a role in neuroinflammation during stroke 35 .…”

Section: Aep Functions In Physiology and Human Brain Diseasesmentioning

confidence: 99%

Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases

Zhang

Xie

2016

Expert Opinion on Therapeutic Targets

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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.

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Section: Aep Functions In Physiology and Human Brain Diseasesmentioning

confidence: 99%

Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases

Zhang

Xie

2016

Expert Opinion on Therapeutic Targets

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“…AEP expression and activity have been linked to a number of pathological conditions including atherosclerosis, cancer, and inflammation (11,12). However, its biological role in these pathologies remains obscure.…”

Section: Cleaves Imentioning

confidence: 99%

“…Processing of AEP requires sequential removal of the C-and N-terminal propeptides at different pH thresholds to generate 46-kDa (active pro-AEP) and 36-kDa (active AEP) active enzymes (8,9). AEP has multiple roles depending on substrate specificity such as initiator of invariant chain processing during MHC class IImediated antigen presentation (10), inducer of cell migration (11,12), and modulator of processes such as proliferation (13) and both pro-death and pro-survival functions using apoptotic mechanisms (14). The variety of roles of AEP is due to its ability to proteolyse multiple substrates, including among others the extracellular matrix protein fibronectin (15), progelatinase (16), and cathepsin H, B, and L (17).…”

mentioning

confidence: 99%

Activation of Asparaginyl Endopeptidase Leads to Tau Hyperphosphorylation in Alzheimer Disease

Basurto-Islas¹,

Grundke‐Iqbal²,

Tung³

et al. 2013

Journal of Biological Chemistry

107

102

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Background: Abnormal hyperphosphorylation of the microtubule-associated protein Tau is a hallmark of Alzheimer disease. Results: Acidosis of the brain activates and translocates asparaginyl endopeptidase from neuronal lysosomes to the cytoplasm where it leads to Tau hyperphosphorylation by inhibition of protein phosphatase 2A through cleavage of its inhibitor 2 into two active fragments. Conclusion: Activated asparaginyl endopeptidase causes Tau pathology. Significance: Brain acidosis can trigger Tau hyperphosphorylation.

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“…It is highly implicated in tumorigenesis [12] and expressed in the majority of human solid tumors, including breast, colon and prostate carcinomas. [12a] Legumain has also been implicated in other diseases, including parasite infection [13] and atherosclerosis, [14] as well as antigen processing [15] and matrix degradation. [16] It is produced as a pro-enzyme with a molecular weight (MW) of approximately 50–60 kDa and undergoes autocleavage at low pH (3.0–6.0) to give the active protease (MW=~30–40 kDa).…”

mentioning

confidence: 99%

The Legumain Protease‐Activated Auristatin Prodrugs Suppress Tumor Growth and Metastasis without Toxicity

Bajjuri

Liu

et al. 2010

ChemMedChem

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Expression of the cysteine protease legumain in vascular lesions and functional implications in atherogenesis

Cited by 51 publications

References 31 publications

Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases

Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases

Activation of Asparaginyl Endopeptidase Leads to Tau Hyperphosphorylation in Alzheimer Disease

The Legumain Protease‐Activated Auristatin Prodrugs Suppress Tumor Growth and Metastasis without Toxicity

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