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The ProNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau

Molecular Psychiatry volume 23, pages 1813–1824 (2018)Cite this article

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Abstract

Tau pathology is characterized as a form of frontotemporal lobar degeneration (FTLD) known as FTLD-tau. The underlying pathogenic mechanisms are not known and no therapeutic interventions are currently available. Here, we report that the neurotrophin receptor p75NTR plays a critical role in the pathogenesis of FTLD-tau. The expression of p75NTR and the precursor of nerve growth factor (proNGF) were increased in the brains of FTLD-tau patients and mice (P301L transgenic). ProNGF-induced tau phosphorylation via p75NTR in vitro, which was associated with the AKT/glycogen synthase kinase (GSK)3β pathway. Genetic reduction of p75NTR in P301L mice rescued the memory deficits, alleviated tau hyperphosphorylation and restored the activity of the AKT/GSK3β pathway. Treatment of the P301L mice with the soluble p75NTR extracellular domain (p75ECD-Fc), which can antagonize neurotoxic ligands of p75NTR, effectively improved memory behavior and suppressed tau pathology. This suggests that p75NTR plays a crucial role in tau paGSKthology and represents a potential druggable target for FTLD-tau and related tauopathies.

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References

  1. Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology. 2002;58:1615–21.

    Article  CAS  Google Scholar 

  2. Vieira RT, Caixeta L, Machado S, Silva AC, Nardi AE, Arias-Carrion O, et al. Epidemiology of early-onset dementia: a review of the literature. Clin Pract Epidemiol Ment Health. 2013;9:88–95.

    Article  Google Scholar 

  3. Bang J, Spina S, Miller BL. Frontotemporal dementia. Lancet. 2015;386:1672–82.

    Article  Google Scholar 

  4. Wang QH, Wang X, Bu XL, Lian Y, Xiang Y, Luo HB, et al. Comorbidity burden of dementia: a hospital-based retrospective study from 2003 to 2012 in seven cities in China. Neurosci Bull. 2017;33:703–10.

    Article  Google Scholar 

  5. Li YQ, Tan MS, Yu JT, Tan L. Frontotemporal lobar degeneration: mechanisms and therapeutic strategies. Mol Neurobiol. 2016;53:6091–105.

    Article  CAS  Google Scholar 

  6. Tsai RM, Boxer AL. Therapy and clinical trials in frontotemporal dementia: past, present, and future. J Neurochem. 2016;138(Suppl 1):211–21.

    Article  CAS  Google Scholar 

  7. Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol. 2010;119:1–4.

    Article  Google Scholar 

  8. Josephs KA, Hodges JR, Snowden JS, Mackenzie IR, Neumann M, Mann DM, et al. Neuropathological background of phenotypical variability in frontotemporal dementia. Acta Neuropathol. 2011;122:137–53.

    Article  Google Scholar 

  9. Baborie A, Griffiths TD, Jaros E, McKeith IG, Burn DJ, Richardson A, et al. Pathological correlates of frontotemporal lobar degeneration in the elderly. Acta Neuropathol. 2011;121:365–71.

    Article  Google Scholar 

  10. Hanger DP, Anderton BH, Noble W. Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med. 2009;15:112–9.

    Article  CAS  Google Scholar 

  11. Yoshiyama Y, Lee VM, Trojanowski JQ. Therapeutic strategies for tau mediated neurodegeneration. J Neurol Neurosurg Psychiatry. 2013;84:784–95.

    Article  Google Scholar 

  12. Bodea LG, Eckert A, Ittner LM, Piguet O, Gotz J. Tau physiology and pathomechanisms in frontotemporal lobar degeneration. J Neurochem. 2016;138(Suppl 1):71–94.

    Article  CAS  Google Scholar 

  13. Zuo YC, Li HL, Xiong NX, Shen JY, Huang YZ, Fu P, et al. Overexpression of Tau rescues Nogo-66-induced neurite outgrowth inhibition in vitro. Neurosci Bull. 2016;32:577–84.

    Article  CAS  Google Scholar 

  14. Brito V, Giralt A, Enriquez-Barreto L, Puigdellivol M, Suelves N, Zamora-Moratalla A, et al. Neurotrophin receptor p75(NTR) mediates Huntington’s disease-associated synaptic and memory dysfunction. J Clin Invest. 2014;124:4411–28.

    Article  CAS  Google Scholar 

  15. Plotkin JL, Day M, Peterson JD, Xie Z, Kress GJ, Rafalovich I, et al. Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington’s disease. Neuron. 2014;83:178–88.

    Article  CAS  Google Scholar 

  16. Capsoni S, Giannotta S, Cattaneo A. Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice. Proc Natl Acad Sci USA. 2002;99:12432–7.

    Article  CAS  Google Scholar 

  17. Cattaneo A, Calissano P. Nerve growth factor and Alzheimer’s disease: new facts for an old hypothesis. Mol Neurobiol. 2012;46:588–604.

    Article  CAS  Google Scholar 

  18. Ibanez CF, Simi A. p75 neurotrophin receptor signaling in nervous system injury and degeneration: paradox and opportunity. Trends Neurosci. 2012;35:431–40.

    Article  CAS  Google Scholar 

  19. Sakuragi S, Tominaga-Yoshino K, Ogura A. Involvement of TrkB- andp75(NTR)-signaling pathways in two contrasting forms of long-lasting synaptic plasticity. Sci Rep. 2013;3:3185.

  20. Dechant G, Barde YA. The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system. Nat Neurosci. 2002;5:1131–6.

    Article  CAS  Google Scholar 

  21. Yamashita T, Higuchi H, Tohyama M. The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. J Cell Biol. 2002;157:565–70.

    Article  CAS  Google Scholar 

  22. Walsh GS, Krol KM, Crutcher KA, Kawaja MD. Enhanced neurotrophin-induced axon growth in myelinated portions of the CNS in mice lacking the p75 neurotrophin receptor. J Neurosci. 1999;19:4155–68.

    Article  CAS  Google Scholar 

  23. Kraemer BR, Snow JP, Vollbrecht P, Pathak A, Valentine WM, Deutch AY, et al. A role for the p75 neurotrophin receptor in axonal degeneration and apoptosis induced by oxidative stress. J Biol Chem. 2014;289:21205–16.

    Article  Google Scholar 

  24. Zhou XF, Li HY. Roles of glial p75NTR in axonal regeneration. J Neurosci Res. 2007;85:1601–5.

    Article  CAS  Google Scholar 

  25. Roux PP, Barker PA. Neurotrophin signaling through the p75 neurotrophin receptor. Prog Neurobiol. 2002;67:203–33.

    Article  CAS  Google Scholar 

  26. Nykjaer A, Willnow TE, Petersen CM. p75NTR--live or let die. Curr Opin Neurobiol. 2005;15:49–57.

    Article  CAS  Google Scholar 

  27. Tanaka K, Kelly CE, Goh KY, Lim KB, Ibanez CF. Death domain signaling by disulfide-linked dimers of the p75 neurotrophin receptor mediates neuronal death in the CNS. J Neurosci. 2016;36:5587–95.

    Article  CAS  Google Scholar 

  28. Yao XQ, Jiao SS, Saadipour K, Zeng F, Wang QH, Zhu C, et al. p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer’s disease. Mol Psychiatry. 2015;20:1301–10.

    Article  CAS  Google Scholar 

  29. Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, et al. Sortilin is essential for proNGF-induced neuronal cell death. Nature. 2004;427:843–8.

    Article  CAS  Google Scholar 

  30. Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, et al. Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci. 2005;8:1069–77.

    Article  CAS  Google Scholar 

  31. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 2006;112:389–404.

    Article  Google Scholar 

  32. Augustinack JC, Schneider A, Mandelkow EM, Hyman BT. Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol. 2002;103:26–35.

    Article  CAS  Google Scholar 

  33. Kohler C, Dinekov M, Gotz J. Active glycogen synthase kinase-3 and tau pathology-related tyrosine phosphorylation in pR5 human tau transgenic mice. Neurobiol Aging. 2013;34:1369–79.

    Article  Google Scholar 

  34. Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer’s disease. J Neurochem. 2008;104:1433–9.

    Article  CAS  Google Scholar 

  35. Pennanen L, Wolfer DP, Nitsch RM, Gotz J. Impaired spatial reference memory and increased exploratory behavior in P301L tau transgenic mice. Genes Brain Behav. 2006;5:369–79.

    Article  CAS  Google Scholar 

  36. Pennanen L, Welzl H, D’Adamo P, Nitsch RM, Gotz J. Accelerated extinction of conditioned taste aversion in P301L tau transgenic mice. Neurobiol Dis. 2004;15:500–9.

    Article  CAS  Google Scholar 

  37. Bodea LG, Evans HT, Van der Jeugd A, Ittner LM, Delerue F, Kril J, et al. Accelerated aging exacerbates a pre-existing pathology in a tau transgenic mouse model. Aging Cell. 2017;16:377–86.

    Article  CAS  Google Scholar 

  38. Deters N, Ittner LM, Gotz J. Divergent phosphorylation pattern of tau in P301L tau transgenic mice. Eur J Neurosci. 2008;28:137–47.

    Article  Google Scholar 

  39. Wang YJ, Wang X, Lu JJ, Li QX, Gao CY, Liu XH, et al. p75NTR regulates Abeta deposition by increasing Abeta production but inhibiting Abeta aggregation with its extracellular domain. J Neurosci. 2011;31:2292–304.

    Article  CAS  Google Scholar 

  40. Wang YJ, Valadares D, Sun Y, Wang X, Zhong JH, Liu XH, et al. Effects of proNGF on neuronal viability, neurite growth and amyloid-beta metabolism. Neurotox Res. 2010;17:257–67.

    Article  Google Scholar 

  41. Jiao SS, Bu XL, Liu YH, Wang QH, Liu CH, Yao XQ, et al. Differential levels of p75NTR ectodomain in CSF and blood in patients with Alzheimer’s disease: a novel diagnostic marker. Transl Psychiatry. 2015;5:e650.

    Article  CAS  Google Scholar 

  42. Jiao SS, Shen LL, Zhu C, Bu XL, Liu YH, Liu CH, et al. Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer’s disease. Transl Psychiatry. 2016;6:e907.

    Article  CAS  Google Scholar 

  43. Zhang F, Kang Z, Li W, Xiao Z, Zhou X. Roles of brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) signalling in Alzheimer’s disease. J Clin Neurosci. 2012;19:946–9.

    Article  CAS  Google Scholar 

  44. Gomez-Isla T, Hollister R, West H, Mui S, Growdon JH, Petersen RC, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol. 1997;41:17–24.

    Article  CAS  Google Scholar 

  45. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology. 1992;42(3 Pt1):631–9.

    Article  CAS  Google Scholar 

  46. Feng D, Kim T, Ozkan E, Light M, Torkin R, Teng KK, et al. Molecular and structural insight into proNGF engagement of p75NTR and sortilin. J Mol Biol. 2010;396:967–84.

    Article  CAS  Google Scholar 

  47. Belrose JC, Masoudi R, Michalski B, Fahnestock M. Increased pro-nerve growth factor and decreased brain-derived neurotrophic factor in non-Alzheimer’s disease tauopathies. Neurobiol Aging. 2014;35:926–33.

    Article  CAS  Google Scholar 

  48. Matrone C, Marolda R, Ciafre S, Ciotti MT, Mercanti D, Calissano P. Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation. Proc Natl Acad Sci USA. 2009;106:11358–63.

    Article  CAS  Google Scholar 

  49. Costantini C, Scrable H, Puglielli L. An aging pathway controls the TrkA to p75NTR receptor switch and amyloid beta-peptide generation. EMBO J. 2006;25:1997–2006.

    Article  CAS  Google Scholar 

  50. Gotz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science. 2001;293:1491–5.

    Article  CAS  Google Scholar 

  51. Hu XY, Zhang HY, Qin S, Xu H, Swaab DF, Zhou JN. Increasedp75(NTR) expression in hippocampal neurons containing hyperphosphorylated tau in Alzheimer patients. Exp Neurol. 2002;178:104–11.

    Article  CAS  Google Scholar 

  52. Song W, Volosin M, Cragnolini AB, Hempstead BL, Friedman WJ. ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons. J Neurosci. 2010;30:15608–15.

    Article  CAS  Google Scholar 

  53. Cho JH, Johnson GV. Glycogen synthase kinase 3beta phosphorylates tau at both primed and unprimed sites. Differential impact on microtubule binding. J Biol Chem. 2003;278:187–93.

    Article  CAS  Google Scholar 

  54. Pei JJ, Khatoon S, An WL, Nordlinder M, Tanaka T, Braak H, et al. Role of protein kinase B in Alzheimer’s neurofibrillary pathology. Acta Neuropathol. 2003;105:381–92.

    CAS  PubMed  Google Scholar 

  55. Capsoni S, Ugolini G, Comparini A, Ruberti F, Berardi N, Cattaneo A. Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice. Proc Natl Acad Sci USA. 2000;97:6826–31.

    Article  CAS  Google Scholar 

  56. Nuydens R, Dispersyn G, de Jong M, van den Kieboom G, Borgers M, Geerts H. Aberrant tau phosphorylation and neurite retraction during NGF deprivation in PC12 cells. Biochem Biophys Res Commun. 1997;240:687–91.

    Article  CAS  Google Scholar 

  57. Terry AV Jr, Kutiyanawalla A, Pillai A. Age-dependent alterations in nerve growth factor (NGF)-related proteins, sortilin, and learning and memory in rats. Physiol Behav. 2011;10:149–57.

    Article  Google Scholar 

  58. Boxer AL, Yu J-T, Golbe LI, Litvan I, Lang AE, Höglinger GU. Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. Lancet Neurol. 2017;16:552–63.

    Article  Google Scholar 

  59. Spillantini MG, Goedert M. Tau pathology and neurodegeneration. Lancet Neurol. 2013;12:609–22.

    Article  CAS  Google Scholar 

  60. Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci. 2016;17:5–21.

    Article  Google Scholar 

  61. Holtzman DM, Carrillo MC, Hendrix JA, Bain LJ, Catafau AM, Gault LM, et al. Tau: from research to clinical development. Alzheimers Dement. 2016;12:1033–39.

    Article  Google Scholar 

  62. Chao MV. Cleavage of p75 neurotrophin receptor is linked to Alzheimer’s disease. Mol Psychiatry. 2016;21:300–1.

    Article  CAS  Google Scholar 

  63. Zeng F, Lu JJ, Zhou XF, Wang YJ. Roles of p75NTR in the pathogenesis of Alzheimer’s disease: a novel therapeutic target. Biochem Pharmacol. 2011;82:1500–9.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant no. 81625007, 91749206 and 81571239), National Health and Medical Research Council (APP1021409 to X-FZ and Y-JW and APP1020567 fellowship grant to X-FZ). NBM-T was supported by UniSA President Scholarship and Overseas Student Scholarship. We wish to thank Professor Juergen Gotz from Queensland Brain Institute, Queensland University (Australia) for sharing the P301L transgenic mice with us. We also thank Professors  Jianzhi Wang and Rong Liu at Huazhong University of Science and Technology (China) for pEGFP-tau2N4R plasmid.

Author contributions

Y-JW, X-FZ and X-QY conceived and designed the project, L-LS, NBM-T, S-HG, CZ, JW, FZ, X-LB, Y-HL, C-YG and Z-QX performed animal and in vitro experiments, W-WL and L-LS performed human sample experiments, LB, WS, H-DZ, J-TY, PL, X-QY, X-FZ and Y-JW analyzed data. L-LS, X-FZ and Y-JW wrote the manuscript.

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  1. These authors contributed equally: Lin-Lin Shen, Noralyn B. Mañucat-Tan.

Authors and Affiliations

  1. Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China

    Lin-Lin Shen, Wei-Wei Li, Fan Zeng, Chi Zhu, Jun Wang, Xian-Le Bu, Yu-Hui Liu, Chang-Yue Gao, Zhi-Qiang Xu, Hua-Dong Zhou, Xiu-Qing Yao & Yan-Jiang Wang

  2. School of Pharmacy and Medical Sciences and Sansom Institute, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia

    Noralyn B. Mañucat-Tan, Larisa Bobrovskaya & Xin-Fu Zhou

  3. Department of Neurobiology, College of Basic Medical Science, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, 400038, Chongqing, China

    Shi-Hao Gao

  4. West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China

    Peng Lei

  5. Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China

    Jin-Tai Yu

  6. Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada

    Weihong Song

  7. State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University, Chongqing, China

    Yan-Jiang Wang

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Shen, LL., Mañucat-Tan, N.B., Gao, SH. et al. The ProNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau. Mol Psychiatry 23, 1813–1824 (2018). https://doi.org/10.1038/s41380-018-0071-z

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