title: Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer's disease.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.|Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Zhentao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Obiamaka
authors.initials: O
authors.lastname: Obianyo
authors.affiliation: Department of Molecular Biology, University of Salzburg, Salzburg A-5020, Austria.
authors.forename: Elfriede
authors.initials: E
authors.lastname: Dall
authors.affiliation: Department of Pharmacology, Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Pharmacology, Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Seong Su
authors.initials: SS
authors.lastname: Kang
authors.affiliation: Department of Anesthesiology Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Mingke
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Anesthesiology Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Shan-Ping
authors.initials: SP
authors.lastname: Yu
authors.affiliation: Department of Molecular Biology, University of Salzburg, Salzburg A-5020, Austria.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cabrele
authors.affiliation: Department of Molecular Biology, University of Salzburg, Salzburg A-5020, Austria.
authors.forename: Mario
authors.identifier: 0000-0003-0278-4091
authors.initials: M
authors.lastname: Schubert
authors.affiliation: Pathophysiology Department, 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, Wuhan 430030, China.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Li
authors.affiliation: Pathophysiology Department, 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, Wuhan 430030, China.|Co-innovation Center of Neuroregeneration, Nantong 226001, China.
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology, University of Salzburg, Salzburg A-5020, Austria.
authors.forename: Hans
authors.initials: H
authors.lastname: Brandstetter
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
mesh_terms: D000494:Allosteric Regulation; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology* / Q000523:psychology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D003071:Cognition / Q000187:drug effects*; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D004195:Disease Models, Animal; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016875:tau Proteins / Q000378:metabolism; D000099240:Asparaginyl Endopeptidase
chemical_list: D016564:Amyloid beta-Protein Precursor; D003546:Cysteine Endopeptidases; D011480:Protease Inhibitors; D016875:tau Proteins; D000099240:Asparaginyl Endopeptidase