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TrkB receptor cleavage by delta-secretase abolishes its phosphorylation of APP, aggravating Alzheimer’s disease pathologies

Molecular Psychiatry volume 26, pages 2943–2963 (2021)Cite this article

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Abstract

Neurotrophins promote neuronal survival and synaptic plasticity via activating the tropomyosin receptor kinases. BDNF and its high-affinity receptor TrkB are reduced in Alzheimer’s disease (AD), contributing to progressive cognitive decline. However, how the signaling mediates AD pathologies remains incompletely understood. Here we show that the TrkB receptor binds and phosphorylates APP, reducing amyloid-β production, which are abrogated by δ-secretase cleavage of TrkB in AD. Remarkably, BDNF stimulates TrkB to phosphorylate APP Y687 residue that accumulates APP in the TGN (Trans-Golgi Network) and diminishes its amyloidogenic cleavage. Delta-secretase cleaves TrkB at N365 and N486/489 residues and abolishes its neurotrophic activity, decreasing p-APP Y687 and altering its subcellular trafficking. Notably, both TrkB and APP are robustly cleaved by δ-secretase in AD brains, accompanied by mitigated TrkB signaling and reduced p-Y687. Blockade of TrkB cleavage attenuates AD pathologies in 5xFAD mice, rescuing the learning and memory. Viral expression of TrkB 1-486 fragment in the hippocampus of APP/PS1 mice facilitates amyloid pathology and mitigates cognitive functions. Hence, δ-secretase cleaves TrkB and blunts its phosphorylation of APP, facilitating AD pathogenesis.

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Fig. 1: TrkB receptors strongly bind to APP.
Fig. 2: TrkB phosphorylates APP on Y687 residue.
Fig. 3: APP Y687 phosphorylation by TrkB receptor regulates APP TGN residency.
Fig. 4: TrkB is truncated by δ-secretase at N365 and N486/489 sites.
Fig. 5: TrkB receptors are cleaved by δ-secretase in AD brains, abolishing APP Y687 phosphorylation.
Fig. 6: δ-secretase-resistant TrkB N486/489 A mutant attenuates AD pathologies in 5xFAD mice.
Fig. 7: TrkB 1-486 fragment from δ-secretase cleavage accelerates AD pathologies in APP/PS1 mice.

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Acknowledgements

This work was supported by grants from NIH grant (RF1, AG051538) to KY, and the National Natural Science Foundation (NSFC) of China (No. 31771114) to XCW. We thank ADRC at Emory University for human AD patients and healthy control samples. This study was supported by the Viral Vector Core of the Emory Neuroscience NINDS Core Facilities (P30NS055077). Additional support by the Rodent Behavioral Core (RBC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Further support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378.

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  1. These authors contributed equally: Yiyuan Xia, Zhi-Hao Wang

Authors and Affiliations

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

    Yiyuan Xia, Zhi-Hao Wang, Pai Liu, Xia Liu & Keqiang Ye

  2. Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Yiyuan Xia & Xiao-Chuan Wang

  3. Neuroscience Program, Laney Graduate School, Emory University School of Medicine, Atlanta, GA, USA

    Pai Liu

  4. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, The University of Melbourne, Melbourne, VIC, 3010, Australia

    Laura Edgington-Mitchell

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

    Xiao-Chuan Wang

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Contributions

KY conceived the project, designed the experiments, analyzed the data and wrote the manuscript. YX, ZHW, PL designed and performed most of the experiments. XL prepared primary neurons and bred the animal models. LEM contributed LE-28. LEM and XCW assisted with data analysis and interpretation and critically read the manuscript.

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Correspondence to Xiao-Chuan Wang or Keqiang Ye.

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Xia, Y., Wang, ZH., Liu, P. et al. TrkB receptor cleavage by delta-secretase abolishes its phosphorylation of APP, aggravating Alzheimer’s disease pathologies. Mol Psychiatry 26, 2943–2963 (2021). https://doi.org/10.1038/s41380-020-00863-8

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