Cited by 149Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesDementia and Cognitive Impairment Research

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

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Zhang, Zhentao, Obianyo, Obiamaka, Dall, Elfriede, Du, Yuhong, Fu, Haian, Liu, Xia, Kang, Seong Su, Song, Mingke +7 more·2017·Nature Communications

Abstract

δ-secretase, also known as asparagine endopeptidase (AEP) or legumain, is a lysosomal cysteine protease that cleaves both amyloid precursor protein (APP) and tau, mediating the amyloid-β and tau pathology in Alzheimer’s disease (AD). Here we report the therapeutic effect of an orally bioactive and brain permeable δ-secretase inhibitor in mouse models of AD. We performed a high-throughput screen and identified a non-toxic and selective δ-secretase inhibitor, termed compound 11, that specifically blocks δ-secretase but not other related cysteine proteases. Co-crystal structure analysis revealed a dual active site-directed and allosteric inhibition mode of this compound class. Chronic treatment of tau P301S and 5XFAD transgenic mice with this inhibitor reduces tau and APP cleavage, ameliorates synapse loss and augments long-term potentiation, resulting in protection of memory. Therefore, these findings demonstrate that this δ-secretase inhibitor may be an effective clinical therapeutic agent towards AD.

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Authors
Zhang, Z., Obianyo, O., Dall, E., Du, Y., Fu, H., Liu, X., Kang, S. S., Song, M., Yu, S.-P., Cabrele, C., Schubert, M., Li, X., Wang, J.-Z., Brandstetter, H., & Ye, K.
Affiliations
  • Emory University (US)
  • University of Salzburg (AT)
  • Huazhong University of Science and Technology (CN)
Corresponding author
  • Wang, Jian-Zhi
  • Brandstetter, Hans
  • Ye, Keqiang
Venue
Nature Communications
Published
2017-03-27
Volume
8
Issue
1
Pages
14740-14740
ISSN
2041-1723 (ISSN-L)
OpenAlex
W2599676172
Cited by
146
References
53
Citations by year
2026: 11 · 2025: 12 · 2024: 13 · 2023: 26 · 2022: 18 · 2021: 17 · 2020: 16 · 2019: 14 · 2018: 15 · 2017: 4
FWCI
10.12
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81571249, 81528007, No. 81528007)
  • Austrian Science Fund (P23454)
  • National Institute on Aging (RF1AG051538)
  • National Institute of Neurological Disorders and Stroke (R01NS060680)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, amyloid precursor protein cleavage, tau cleavage, amyloid-beta, 5xFAD mice, synaptic loss, long-term potentiation, memory impairment, co-crystal structure, lysosomal cysteine proteases
MeSH terms
Asparaginyl Endopeptidase, Allosteric Regulation, Alzheimer Disease, Animals, Cognition, Cysteine Endopeptidases, Disease Models, Animal, Humans, Mice, Transgenic, Protease Inhibitors, Amyloid beta-Protein Precursor, tau Proteins, Mice, High-Throughput Screening Assays

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