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

Author

Listed:
  • Zhentao Zhang

    (Emory University School of Medicine
    Renmin Hospital of Wuhan University)

  • 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
    Co-innovation Center of Neuroregeneration)

  • Hans Brandstetter

    (University of Salzburg)

  • Keqiang Ye

    (Emory University School of Medicine)

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.

Suggested Citation

  • 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 B, 2017. "Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease," Nature Communications, Nature, vol. 8(1), pages 1-17, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14740
    DOI: 10.1038/ncomms14740
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