Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease

Zhang, Zhentao; Obianyo, Obiamaka; Dall, Elfriede; Du, Yuhong; Fu, Haian; Liu, Xia; Kang, Seong Su; Song, Mingke; Yu, Shan-Ping; Cabrele, Chiara; Schubert, Mario; Li, Xiaoguang; Wang, Jian‐Zhi; Brandstetter, Hans; Ye, Keqiang

doi:10.1038/ncomms14740

Cited by 99 publications

(91 citation statements)

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“…Interestingly, knockdown of AEP in DMSO controls resulted in increased α‐Syn levels, and MAO‐B enzymatic activity tightly associated with α‐Syn N103 fragmentation, but not total α‐Syn levels (Fig D–F), indicating that α‐Syn N103 might be responsible for promoting MAO‐B enzymatic activity. We made similar observations with small molecular AEP inhibitors, compound 11 and MVO (van Kasteren et al , ; Zhang et al , ), which inhibited α‐Syn N103 production triggered by MPP + . As expected, AEP enzymatic activity was inhibited by these two compounds.…”

Section: Resultssupporting

confidence: 82%

α‐Synuclein stimulation of monoamine oxidase‐B and legumain protease mediates the pathology of Parkinson's disease

et al. 2018

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Dopaminergic neurodegeneration in Parkinson's disease (PD) is associated with abnormal dopamine metabolism by MAO-B (monoamine oxidase-B) and intracellular α-Synuclein (α-Syn) aggregates, called the Lewy body. However, the molecular relationship between α-Syn and MAO-B remains unclear. Here, we show that α-Syn directly binds to MAO-B and stimulates its enzymatic activity, which triggers AEP (asparagine endopeptidase; legumain) activation and subsequent α-Syn cleavage at N103, leading to dopaminergic neurodegeneration. Interestingly, the dopamine metabolite, DOPAL, strongly activates AEP, and the N103 fragment of α-Syn binds and activates MAO-B. Accordingly, overexpression of AEP in SNCA transgenic mice elicits α-Syn N103 cleavage and accelerates PD pathogenesis, and inhibition of MAO-B by Rasagiline diminishes α-Syn-mediated PD pathology and motor dysfunction. Moreover, virally mediated expression of α-Syn N103 induces PD pathogenesis in wild-type, but not MAO-B-null mice. Our findings thus support that AEP-mediated cleavage of α-Syn at N103 is required for the association and activation of MAO-B, mediating PD pathogenesis.

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Section: Resultssupporting

confidence: 82%

α‐Synuclein stimulation of monoamine oxidase‐B and legumain protease mediates the pathology of Parkinson's disease

et al. 2018

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“…22 Following confirmatory assays with purified AEP, we identified top hits and subsequent triaging produced a lead compound, termed compound 38 . A kinetic analysis of the small-molecule inhibitor indicated that compound 38 competitively inhibits AEP activity strongly, K I = 105 ± 37 nM (Figure 1A,B).…”

Section: Resultsmentioning

confidence: 99%

“…22 However, its Caco-2 cell permeability was minimal, suggesting that the compound may not be readily absorbed upon oral administration 23 (Table 1). …”

Section: Resultsmentioning

confidence: 99%

Blockade of Asparagine Endopeptidase Inhibits Cancer Metastasis

Obianyo

et al. 2017

J. Med. Chem.

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Asparagine endopeptidase (AEP), also called legumain, is highly expressed in various solid tumors, promoting cancer cell invasion, migration, and metastasis. It has been proposed to be a prognostic marker and therapeutic target for cancer treatment. However, an effective nonpeptide, smallmolecule inhibitor against this protease has not yet been identified. Here we show that a family of xanthine derivatives selectively inhibit AEP and suppress matrix metalloproteinase (MMP) cleavage, leading to the inhibition of cancer metastasis. Through structure–activity relationship (SAR) analysis, we obtained an optimized lead compound (38u) that represses breast cancer invasion and migration. Chronic treatment of nude mice, which had been inoculated with MDA-MB-231 cells, with inhibitor 38u via oral administration robustly inhibits breast cancer lung metastasis in a dose-dependent manner, associated with blockade of MMP-2 by AEP. Therefore, our study supports that 38u might act as a potent and specific AEP inhibitor useful for cancer treatment.

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“…Sheddases and the relevant substrates are consequently considered as drug targets. A key example is an excessive level of shed TNFa, Zhang et al (2017Zhang et al ( , 2015 The table lists selected examples where the pathological role of a sheddase or its substrate to a disease has been established in animal models and through human genetics. The many instances where altered sheddase expression only correlates with disease are not listed.…”

Section: Disease Association and Shedding-based Drugsmentioning

confidence: 99%

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

2018

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Proteolytic removal of membrane protein ectodomains (ectodomain shedding) is a post-translational modification that controls levels and function of hundreds of membrane proteins. The contributing proteases, referred to as sheddases, act as important molecular switches in processes ranging from signaling to cell adhesion. When deregulated, ectodomain shedding is linked to pathologies such as inflammation and Alzheimer's disease. While proteases of the "a disintegrin and metalloprotease" (ADAM) and "beta-site APP cleaving enzyme" (BACE) families are widely considered as sheddases, in recent years a much broader range of proteases, including intramembrane and soluble proteases, were shown to catalyze similar cleavage reactions. This review demonstrates that shedding is a fundamental process in cell biology and discusses the current understanding of sheddases and their substrates, molecular mechanisms and cellular localizations, as well as physiological functions of protein ectodomain shedding. Moreover, we provide an operational definition of shedding and highlight recent conceptual advances in the field. While new developments in proteomics facilitate substrate discovery, we expect that shedding is not a rare exception, but rather the rule for many membrane proteins, and that many more interesting shedding functions await discovery.

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Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease

Cited by 99 publications

References 50 publications

α‐Synuclein stimulation of monoamine oxidase‐B and legumain protease mediates the pathology of Parkinson's disease

α‐Synuclein stimulation of monoamine oxidase‐B and legumain protease mediates the pathology of Parkinson's disease

Blockade of Asparagine Endopeptidase Inhibits Cancer Metastasis

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

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