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

APP/PS1 mice facilitates amyloid pathology and mitigates cognitive functions. Hence, δ-secretase cleaves TrkB and blunts its phosphorylation of APP, facilitating AD pathogenesis. Access

through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal

Receive 12 print issues and online access $259.00 per year only $21.58 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices

may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support

SIMILAR CONTENT BEING VIEWED BY OTHERS DELTA-SECRETASE TRIGGERS ALZHEIMER’S DISEASE PATHOLOGIES IN WILD-TYPE HAPP/HMAPT DOUBLE TRANSGENIC MICE Article Open access 12 December 2020 EBP1

POTENTIATES AMYLOID Β PATHOLOGY BY REGULATING Γ-SECRETASE Article 08 January 2025 DELTA-SECRETASE CLEAVAGE OF TAU MEDIATES ITS PATHOLOGY AND PROPAGATION IN ALZHEIMER’S DISEASE Article Open

access 28 August 2020 REFERENCES * Reichardt LF. Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci. 2006;361:1545–64. Article  CAS  PubMed  PubMed Central 

Google Scholar  * Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–6. Article  CAS  PubMed  Google

Scholar  * Elliott E, Ginzburg I. The role of neurotrophins and insulin on tau pathology in Alzheimer’s disease. Rev Neurosci. 2006;17:635–42. Article  CAS  PubMed  Google Scholar  *

Svendsen CN, Cooper JD, Sofroniew MV. Trophic factor effects on septal cholinergic neurons. Ann NY Acad Sci. 1991;640:91–94. Article  CAS  PubMed  Google Scholar  * Crutcher KA, Scott SA,

Liang S, Everson WV, Weingartner J. Detection of NGF-like activity in human brain tissue: increased levels in Alzheimer’s disease. J Neurosci. 1993;13:2540–50. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Hellweg R, Gericke CA, Jendroska K, Hartung HD, Cervos-Navarro J. NGF content in the cerebral cortex of non-demented patients with amyloid-plaques and in

symptomatic Alzheimer’s disease. Int J Dev Neurosci. 1998;16:787–94. Article  CAS  PubMed  Google Scholar  * Peng S, Wuu J, Mufson EJ, Fahnestock M. Increased proNGF levels in subjects with

mild cognitive impairment and mild Alzheimer disease. J Neuropathol Exp Neurol. 2004;63:641–9. Article  CAS  PubMed  Google Scholar  * Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson

SA, Winslow JW. BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron. 1991;7:695–702. Article  CAS  PubMed  Google Scholar  * Connor B, Young D, Yan Q,

Faull RL, Synek B, Dragunow M. Brain-derived neurotrophic factor is reduced in Alzheimer’s disease. Brain Res Mol Brain Res. 1997;49:71–81. Article  CAS  PubMed  Google Scholar  * Ferrer I,

Marin C, Rey MJ, Ribalta T, Goutan E, Blanco R, et al. BDNF and full-length and truncated TrkB expression in Alzheimer disease. Implications in therapeutic strategies. J Neuropathol Exp

Neurol. 1999;58:729–39. Article  CAS  PubMed  Google Scholar  * Rohe M, Synowitz M, Glass R, Paul SM, Nykjaer A, Willnow TE. Brain-derived neurotrophic factor reduces amyloidogenic

processing through control of SORLA gene expression. J Neurosci. 2009;29:15472–8. Article  CAS  PubMed  PubMed Central  Google Scholar  * Matrone C, Ciotti MT, Mercanti D, Marolda R,

Calissano PNGF. and BDNF signaling control amyloidogenic route and Abeta production in hippocampal neurons. Proc Natl Acad Sci USA. 2008;105:13139–44. Article  CAS  PubMed  PubMed Central 

Google Scholar  * Murer MG, Boissiere F, Yan Q, Hunot S, Villares J, Faucheux B, et al. An immunohistochemical study of the distribution of brain-derived neurotrophic factor in the adult

human brain, with particular reference to Alzheimer’s disease. Neuroscience. 1999;88:1015–32. Article  CAS  PubMed  Google Scholar  * Ando S, Kobayashi S, Waki H, Kon K, Fukui F, Tadenuma T,

et al. Animal model of dementia induced by entorhinal synaptic damage and partial restoration of cognitive deficits by BDNF and carnitine. J Neurosci Res. 2002;70:519–27. Article  CAS 

PubMed  Google Scholar  * Kitiyanant N, Kitiyanant Y, Svendsen CN, Thangnipon W. BDNF-, IGF-1- and GDNF-secreting human neural progenitor cells rescue amyloid beta-induced toxicity in

cultured rat septal neurons. Neurochem Res. 2012;37:143–52. Article  CAS  PubMed  Google Scholar  * Arancibia S, Silhol M, Mouliere F, Meffre J, Hollinger I, Maurice T, et al. Protective

effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo in rats. Neurobiol Dis. 2008;31:316–26. Article  CAS  PubMed  Google Scholar  * Wang ZH, Xiang J, Liu X, Yu SP,

Manfredsson FP, Sandoval IM, et al. Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates delta-Secretase by Upregulating C/EBPbeta in Alzheimer’s Disease. Cell Rep. 2019;28:655–669.

e655. Article  CAS  PubMed  PubMed Central  Google Scholar  * Wang ZH, Gong K, Liu X, Zhang Z, Sun X, Wei ZZ, et al. C/EBPbeta regulates delta-secretase expression and mediates pathogenesis

in mouse models of Alzheimer’s disease. Nat Commun. 2018;9:1784. Article  PubMed  PubMed Central  CAS  Google Scholar  * Xiang J, Wang ZH, Ahn EH, Liu X, Yu SP, Manfredsson FP, et al.

Delta-secretase-cleaved Tau antagonizes TrkB neurotrophic signalings, mediating Alzheimer’s disease pathologies. Proc Natl Acad Sci USA. 2019;116:9094–102. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Chen C, Wang Z, Zhang Z, Liu X, Kang SS, Zhang Y, et al. The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer’s disease.

Proc Natl Acad Sci USA. 2018;115:578–83. Article  CAS  PubMed  PubMed Central  Google Scholar  * Zhang Z, Liu X, Schroeder JP, Chan CB, Song M, Yu SP, et al. 7,8-dihydroxyflavone prevents

synaptic loss and memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology. 2014;39:638–50. Article  PubMed  CAS  Google Scholar  * Jang SW, Liu X, Yepes M, Shepherd

KR, Miller GW, Liu Y, et al. A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci USA. 2010;107:2687–92. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Liu Z, Jang SW, Liu X, Cheng D, Peng J, Yepes M, et al. Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase.

Mol Cell. 2008;29:665–78. Article  CAS  PubMed  PubMed Central  Google Scholar  * Zhang Z, Song M, Liu X, Su Kang S, Duong DM, Seyfried NT, et al. Delta-secretase cleaves amyloid precursor

protein and regulates the pathogenesis in Alzheimer’s disease. Nat Commun. 2015;6:8762. Article  CAS  PubMed  Google Scholar  * Zhang Z, Song M, Liu X, Kang SS, Kwon IS, Duong DM, et al.

Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat Med. 2014;20:1254–62. Article  CAS  PubMed  PubMed Central  Google Scholar  *

Bao J, Qin M, Mahaman YAR, Zhang B, Huang F, Zeng K et al. BACE1 SUMOylation increases its stability and escalates the protease activity in Alzheimer’s disease. Proc Natl Acad Sci USA.

2018;115:3954–9. Article  CAS  PubMed  PubMed Central  Google Scholar  * Matrone C, Barbagallo AP, La Rosa LR, Florenzano F, Ciotti MT, Mercanti D, et al. APP is phosphorylated by TrkA and

regulates NGF/TrkA signaling. J Neurosci. 2011;31:11756–61. Article  CAS  PubMed  PubMed Central  Google Scholar  * Canu N, Amadoro G, Triaca V, Latina V, Sposato V, Corsetti V et al. The

intersection of NGF/TrkA signaling and amyloid precursor protein processing in Alzheimer’s disease neuropathology. Int J Mol Sci. 2017;18:1319–35. Article  PubMed Central  CAS  Google

Scholar  * Zhang Z, Kang SS, Liu X, Ahn EH, Zhang Z, He L, et al. Asparagine endopeptidase cleaves alpha-synuclein and mediates pathologic activities in Parkinson’s disease. Nat Struct Mol

Biol. 2017;24:632–42. Article  PubMed  PubMed Central  CAS  Google Scholar  * Wang ZH, Liu P, Liu X, Manfredsson FP, Sandoval IM, Yu SP, et al. Delta-secretase phosphorylation by SRPK2

enhances its enzymatic activity, provoking pathogenesis in Alzheimer’s disease. Mol cell. 2017;67:812–825 e815. Article  CAS  PubMed  PubMed Central  Google Scholar  * Edgington LE, Verdoes

M, Ortega A, Withana NP, Lee J, Syed S, et al. Functional imaging of legumain in cancer using a new quenched activity-based probe. J Am Chem Soc. 2013;135:174–82. Article  CAS  PubMed 

Google Scholar  * Li DN, Matthews SP, Antoniou AN, Mazzeo D, Watts C. Multistep autoactivation of asparaginyl endopeptidase in vitro and in vivo. J Biol Chem. 2003;278:38980–90. Article  CAS

  PubMed  Google Scholar  * Zhang Z, Obianyo O, Dall E, Du Y, Fu H, Liu X, et al. Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease. Nat

Commun. 2017;8:14740. Article  CAS  PubMed  PubMed Central  Google Scholar  * Lunde NN, Haugen MH, Bodin Larsen KB, Damgaard I, Pettersen SJ, Kasem R, et al. Glycosylation is important for

legumain localization and processing to active forms but not for cystatin E/M inhibitory functions. Biochimie. 2017;139:27–37. Article  CAS  PubMed  Google Scholar  * Lee MS, Kao SC, Lemere

CA, Xia W, Tseng HC, Zhou Y, et al. APP processing is regulated by cytoplasmic phosphorylation. J Cell Biol. 2003;163:83–95. Article  CAS  PubMed  PubMed Central  Google Scholar  *

Scheinfeld MH, Ghersi E, Davies P, D’Adamio L. Amyloid beta protein precursor is phosphorylated by JNK-1 independent of, yet facilitated by, JNK-interacting protein (JIP)-1. J Biol Chem.

2003;278:42058–63. Article  CAS  PubMed  Google Scholar  * Barbagallo AP, Wang Z, Zheng H, D’Adamio L. A single tyrosine residue in the amyloid precursor protein intracellular domain is

essential for developmental function. J Biol Chem. 2011;286:8717–21. Article  CAS  PubMed  PubMed Central  Google Scholar  * Barbagallo AP, Weldon R, Tamayev R, Zhou D, Giliberto L, Foreman

O, et al. Tyr(682) in the intracellular domain of APP regulates amyloidogenic APP processing in vivo. PLoS ONE. 2010;5:e15503. Article  PubMed  PubMed Central  CAS  Google Scholar  * Russo

C, Dolcini V, Salis S, Venezia V, Violani E, Carlo P, et al. Signal transduction through tyrosine-phosphorylated carboxy-terminal fragments of APP via an enhanced interaction with Shc/Grb2

adaptor proteins in reactive astrocytes of Alzheimer’s disease brain. Ann NY Acad Sci. 2002;973:323–33. Article  CAS  PubMed  Google Scholar  * Tamayev R, Zhou D, D’Adamio L. The interactome

of the amyloid beta precursor protein family members is shaped by phosphorylation of their intracellular domains. Mol Neurodegener. 2009;4:28. Article  PubMed  PubMed Central  CAS  Google

Scholar  * Tarr PE, Roncarati R, Pelicci G, Pelicci PG, D’Adamio L. Tyrosine phosphorylation of the beta-amyloid precursor protein cytoplasmic tail promotes interaction with Shc. J Biol

Chem. 2002;277:16798–804. Article  CAS  PubMed  Google Scholar  * Alonso M, Medina JH, Pozzo-Miller L. ERK1/2 activation is necessary for BDNF to increase dendritic spine density in

hippocampal CA1 pyramidal neurons. Learn Mem. 2004;11:172–8. Article  PubMed  PubMed Central  Google Scholar  * Amaral MD, Pozzo-Miller L. TRPC3 channels are necessary for brain-derived

neurotrophic factor to activate a nonselective cationic current and to induce dendritic spine formation. J Neurosci. 2007;27:5179–89. Article  CAS  PubMed  PubMed Central  Google Scholar  *

Rex CS, Lin CY, Kramar EA, Chen LY, Gall CM, Lynch G. Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci.

2007;27:3017–29. Article  CAS  PubMed  PubMed Central  Google Scholar  * Triaca V, Sposato V, Bolasco G, Ciotti MT, Pelicci P, Bruni AC, et al. NGF controls APP cleavage by downregulating

APP phosphorylation at Thr668: relevance for Alzheimer’s disease. Aging Cell. 2016;15:661–72. Article  CAS  PubMed  PubMed Central  Google Scholar  * Rebelo S, Vieira SI, Esselmann H,

Wiltfang J, da Cruz e Silva EF, da Cruz e Silva OA. Tyr687 dependent APP endocytosis and Abeta production. J Mol Neurosci. 2007;32:1–8. Article  CAS  PubMed  Google Scholar  * Rebelo S,

Vieira SI, Esselmann H, Wiltfang J, da Cruz e Silva EF, da Cruz e Silva OA. Tyrosine 687 phosphorylated Alzheimer’s amyloid precursor protein is retained intracellularly and exhibits a

decreased turnover rate. Neurodegener Dis. 2007;4:78–87. Article  CAS  PubMed  Google Scholar  * Manucat-Tan NB, Saadipour K, Wang YJ, Bobrovskaya L, Zhou XF. Cellular trafficking of amyloid

precursor protein in amyloidogenesis physiological and pathological significance. Mol Neurobiol. 2019;56:812–30. Article  CAS  PubMed  Google Scholar  Download references 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. AUTHOR INFORMATION Author notes * These authors contributed equally: Yiyuan

Xia, Zhi-Hao Wang AUTHORS AND AFFILIATIONS * 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 * 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 * Neuroscience Program, Laney Graduate School, Emory University School of Medicine, Atlanta, GA, USA Pai Liu * Department of

Biochemistry and Molecular Biology, School of Biomedical Sciences, The University of Melbourne, Melbourne, VIC, 3010, Australia Laura Edgington-Mitchell * Co-innovation Center of

Neuroregeneration, Nantong University, Nantong, Jiangsu, 226001, China Xiao-Chuan Wang Authors * Yiyuan Xia View author publications You can also search for this author inPubMed Google

Scholar * Zhi-Hao Wang View author publications You can also search for this author inPubMed Google Scholar * Pai Liu View author publications You can also search for this author inPubMed 

Google Scholar * Laura Edgington-Mitchell View author publications You can also search for this author inPubMed Google Scholar * Xia Liu View author publications You can also search for this

author inPubMed Google Scholar * Xiao-Chuan Wang View author publications You can also search for this author inPubMed Google Scholar * Keqiang Ye View author publications You can also

search for this author inPubMed Google Scholar 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. CORRESPONDING AUTHORS Correspondence to Xiao-Chuan Wang or Keqiang Ye. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no conflict of

interest. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. SUPPLEMENTARY

INFORMATION SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIGURE 1 SUPPLEMENTARY FIGURE 2 SUPPLEMENTARY FIGURE 3 SUPPLEMENTARY FIGURE 4 SUPPLEMENTARY FIGURE 5 SUPPLEMENTARY FIGURE 6 SUPPLEMENTARY

FIGURE 7 SUPPLEMENTARY FIGURE 8 SUPPLEMENTARY FIGURE 9 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 24 March 2020 * Revised: 27 July 2020 * Accepted: 30 July 2020 * Published: 11 August 2020 * Issue Date: July 2021 *

DOI: https://doi.org/10.1038/s41380-020-00863-8 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is

not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative