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

• Type of Material: Article
• Authors: Zhentao Zhang, Emory University; Obiamaka Obianyo, Emory University; Elfriede Dall, University of Salzburg; Yuhong Du, Emory University; Haian Fu, Emory University; Xia Liu, Emory University; Seong Su Kang, Emory University; Mingke Song, Emory University; Shan Yu, Emory University; Chiara Cabrele, Salzburg University; Mario Schubert, Salzburg University; Xiaoguang Li, Huazhong University of Science and Technology; Jian-Zhi Wang, Huazhong University of Science and Technology; Hans Brandstetter, Salzburg University; Keqiang Ye, Emory University
• Language: English
• Date: 2017-03-27
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Final Published Version
• Copyright Statement: © 2017, The Author(s)
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/ncomms14740
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 8
• Start Page: 14740
• End Page: 14740
• Grant/Funding Information: This work is supported by a grant from National Institute of Health (RO1, NS060680) to K.Y., a collaborative grant from the National Natural Science Foundation of China (No. 81528007) to K.Y. and J.-Z.W., a grant from the National Natural Science Foundation of China (No. 81571249) to Z.Z. and the Austrian Science Fund (project P23454-B11).
• Keywords: Science & Technology; PROTEIN; Science & Technology - Other Topics; ELECTROSTATICS; Multidisciplinary Sciences; MAMMALIAN LEGUMAIN; ASPARAGINYL ENDOPEPTIDASE; MICE; METASTASIS; SYNAPTIC LOSS; ACTIVATION; SUPPRESS TUMOR-GROWTH; ASSAY INTERFERENCE
• Research Categories: Health Sciences, Pathology

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.