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

Zhentao Zhang, Obiamaka Obianyo, Elfriede Dall, Yuhong Du, Haian Fu, Xia Liu, Seong Su Kang, Mingke Song, Shan-Ping Yu, Chiara Cabrele, Mario Schubert, Xiaoguang Li, Jian-Zhi Wang (), Hans Brandstetter () and Keqiang Ye ()
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Zhentao Zhang: Emory University School of Medicine
Obiamaka Obianyo: Emory University School of Medicine
Elfriede Dall: University of Salzburg
Yuhong Du: Emory Chemical Biology Discovery Center, Emory University School of Medicine
Haian Fu: Emory Chemical Biology Discovery Center, Emory University School of Medicine
Xia Liu: Emory University School of Medicine
Seong Su Kang: Emory University School of Medicine
Mingke Song: Department of Anesthesiology Emory University School of Medicine
Shan-Ping Yu: Department of Anesthesiology Emory University School of Medicine
Chiara Cabrele: University of Salzburg
Mario Schubert: University of Salzburg
Xiaoguang Li: School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology
Jian-Zhi Wang: School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology
Hans Brandstetter: University of Salzburg
Keqiang Ye: Emory University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14740

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