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δ-Secretase-cleaved Tau stimulates Aβ production via upregulating STAT1-BACE1 signaling in Alzheimer’s disease

Molecular Psychiatry volume 26, pages 586–603 (2021)Cite this article

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Abstract

δ-Secretase, an age-dependent asparagine protease, cleaves both amyloid precursor protein (APP) and Tau and is required for amyloid plaque and neurofibrillary tangle pathologies in Alzheimer’s disease (AD). However, whether δ-secretase activation is sufficient to trigger AD pathogenesis remains unknown. Here we show that the fragments of δ-secretase-cleavage, APP (586–695) and Tau(1–368), additively drive AD pathogenesis and cognitive dysfunctions. Tau(1–368) strongly augments BACE1 expression and Aβ generation in the presence of APP. The Tau(1–368) fragment is more robust than full-length Tau in binding active STAT1, a BACE1 transcription factor, and promotes its nuclear translocation, upregulating BACE1 and Aβ production. Notably, Aβ-activated SGK1 or JAK2 kinase phosphorylates STAT1 and induces its association with Tau(1–368). Inhibition of these kinases diminishes stimulatory effect of Tau(1–368). Knockout of STAT1 abolishes AD pathologies induced by δ-secretase-generated APP and Tau fragments. Thus, we show that Tau may not only be a downstream effector of Aβ in the amyloid hypothesis, but also act as a driving force for Aβ, when cleaved by δ-secretase.

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Acknowledgements

This work was supported by grants from M.J. FOX Foundation (Grant ID 11137) and NIH RO1 (AG051538) to K.Y., and grant from National Natural Science Foundation (NSFC) of China (No. 81571249 and 81771382) to ZZ, and NSFC grant (No. 81528007) to KY and JZW. We thank ADRC at Emory University for human AD patients and healthy control samples. HEK293 cells stably transfected with APP were from Dr. Edward Koo, University of California.

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  1. These authors contributed equally: Zhentao Zhang, Xiao-Guang Li

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Zhentao Zhang, Zhi-Hao Wang, Seong Su Kang, Xia Liu, Manling Xie & Keqiang Ye

  2. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Zhentao Zhang & Zhaohui Zhang

  3. Pathophysiology Department, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xiao-Guang Li, Zhi-Hao Wang, Gong-Ping Liu & Jian-Zhi Wang

  4. Department of Aneasthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Mingke Song & Shan Ping Yu

  5. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China

    Gong-Ping Liu & Jian-Zhi Wang

  6. Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China

    Keqiang Ye

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Zhang, Z., Li, XG., Wang, ZH. et al. δ-Secretase-cleaved Tau stimulates Aβ production via upregulating STAT1-BACE1 signaling in Alzheimer’s disease. Mol Psychiatry 26, 586–603 (2021). https://doi.org/10.1038/s41380-018-0286-z

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