Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease
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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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AEP cleaves tau without inducing tau accumulation in microglia.
“AEP cleaves tau without inducing tau accumulation in microglia.”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [215]
AEP likely plays a role in regulating tau degradation, rather than enhancing tau aggregation.
“It is therefore likely that AEP plays a role in regulating tau degradation, rather than enhancing tau aggregation [212, 213, 215].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [215]
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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
- ORCID
- Venue
- Nature Communications
- Published
- 2017-03-27
- Volume
- 8
- Issue
- 1
- Pages
- 14740-14740
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5378956
- 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
- gold
- doi.org
- 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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