Journal of Molecular Neuroscience

, Volume 25, Issue 2, pp 141–156

Characterization of the signaling pathway downstream p75 neurotrophin receptor involved in β-amyloid peptide-dependent cell death

  • Claudio Costantini
  • Filippo Rossi
  • Elena Formaggio
  • Roberto Bernardoni
  • Daniela Cecconi
  • Vittorina Della-Bianca
Original Article


The accumulation of β-amyloid (Aβ) peptide is a key pathogenic event in Alzheimer’s disease. Previous studies have shown that Aβ peptide can damage neurons by activating the p75 neurotrophin receptor (p75NTR). However, the signaling pathway leading to neuronal cell death is not completely understood. By using a neuroblastoma cell line devoid of neurotrophin receptors and engineered to express either a full-length or a death domain (DD)-truncated form of p75NTR, we demonstrated that Aβ peptide activates the mitogen-activated protein kinases (MAPKs) p38 and c-Jun N-terminal kinase (JNK). We also found that Aβ peptide induces the translocation of nuclear factor-κB (NF-κB). These events depend on the DD of p75NTR. β-Amyloid (Aβ) peptide was found not to be toxic when the above interactors were inhibited, indicating that they are required for Aβ-induced neuronal cell death. p75 neurotrophin receptor (p75NTR)-expressing cells became resistant to Aβ toxicity when transfected with dominant-negative mutants of MAPK kinases 3, 4, or 6 (MKK3, MKK4, or MKK6), the inhibitor of κBα, or when treated with chemical inhibitors of p38 and JNK. Furthermore, p75NTR-expressing cells became resistant to Aβ peptide upon transfection with a dominant-negative mutant of p53. These results were obtained in the presence of normal p38 and JNK activation, indicating that p53 acts downstream of p38 and JNK. Finally, we demonstrated that NF-κB activation is dependent on p38 and JNK activation. Therefore, our data suggest a signaling pathway in which Aβ peptide binds to p75NTR and activates p38 and JNK in a DD-dependent manner, followed by NF-κB translocation and p53 activation.

Index Entries

Aβ p75NTR p38 JNK NF-κB p53 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aloyz R. S., Bamji S. X., Pozniak C. D., Toma J. G., Atwal J., Kaplan D. R., and Miller F. D. (1998) p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors. J. Cell. Biol. 143, 1691–1703.PubMedCrossRefGoogle Scholar
  2. Behrens M. M., Strasser U., Koh J. Y., Gwag B. J., and Choi D. W. (1999) Prevention of neuronal apoptosis by phorbol ester-induced activation of protein kinase C: blockade of p38 mitogen-activated protein kinase. Neuroscience 94, 917–927.PubMedCrossRefGoogle Scholar
  3. Boland K., Behrens M., Choi D., Manias K., and Perlmutter D. H. (1996) The serpin-enzyme complex receptor recognizes soluble, nontoxic amyloid-beta peptide but not aggregated, cytotoxic amyloid-beta peptide. J. Biol. Chem. 271, 18,032–18,044.Google Scholar
  4. Bozyczko-Coyne D., O’Kane T. M., Wu Z. L., Dobrzanski P., Murthy S., Vaught J. L., and Scott R. W. (2001) CEP-1347/KT-7515, an inhibitor of SAPK/JNK pathway activation, promotes survival and blocks multiple events associated with Abeta-induced cortical neuron apoptosis. J. Neurochem. 77, 849–863.PubMedCrossRefGoogle Scholar
  5. Brann A. B., Tcherpakov M., Williams I. M., Futerman A. H., and Fainzilber M. (2002) Nerve growth factor-induced p75-mediated death of cultured hippocampal neurons is age-dependent and transduced through ceramide generated by neutral sphingomyelinase. J. Biol. Chem. 277, 9812–9818.PubMedCrossRefGoogle Scholar
  6. Bui N. T., Konig H. G., Culmsee C., Bauerbach E., Poppe M., Krieglstein J., and Prehn J. H. (2002) p75 neurotrophin receptor is required for constitutive and NGF-induced survival signalling in PC12 cells and rat hippocampal neurones. J. Neurochem. 81, 594–605.PubMedCrossRefGoogle Scholar
  7. Carter B. D., Kaltschmidt C., Kaltschmidt B., Offenhauser N., Bohm-Matthaei R., Baeuerle P. A., and Barde Y. A. (1996) Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75. Science 272, 542–545.PubMedCrossRefGoogle Scholar
  8. Casaccia-Bonnefil P., Carter B. D., Dobrowsky R. T., and Chao M. V. (1996) Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 383, 716–719.PubMedCrossRefGoogle Scholar
  9. Daniels W. M., Hendricks J., Salie R., and Taljaard J. J. (2001) The role of the MAP-kinase superfamily in beta-amyloid toxicity. Metab. Brain. Dis. 16, 175–185.PubMedCrossRefGoogle Scholar
  10. Dawbarn D. and Allen S. J. (2001) Neurobiology of Alzheimer’s Disease, 2nd ed., Oxford University Press, New York.Google Scholar
  11. Dechant G. and Barde Y. A. (2002) The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system. Nat. Neurosci. 5, 1131–1136.PubMedCrossRefGoogle Scholar
  12. El Khoury J., Hickman S. E., Thomas C. A., Cao L., Silverstein S. C., and Loike J. D. (1996) Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382, 716–719.PubMedCrossRefGoogle Scholar
  13. Foehr E. D., Lin X., O’Mahony A., Geleziunas R., Bradshaw R. A., and Greene W. C. (2000) NF-kappa B signaling promotes both cell survival and neurite process formation in nerve growth factor-stimulated PC12 cells. J. Neurosci. 20, 7556–7563.PubMedGoogle Scholar
  14. Fogarty M. P., Downer E. J., and Campbell V. (2003) A role for c-Jun N-terminal kinase 1 (JNK1), but not JNK2, in the beta-amyloid-mediated stabilization of protein p53 and induction of the apoptotic cascade in cultured cortical neurons. Biochem. J. 371, 789–798.PubMedCrossRefGoogle Scholar
  15. Friedman W. J. (2000) Neurotrophins induce death of hippocampal neurons via the p75 receptor. J. Neurosci. 20, 6340–6346.PubMedGoogle Scholar
  16. Gentry J. J., Casaccia-Bonnefil P., and Carter B. D. (2000) Nerve growth factor activation of nuclear factor kappaB through its p75 receptor is an anti-apoptotic signal in RN22 schwannoma cells. J. Biol. Chem. 275, 7558–7565.PubMedCrossRefGoogle Scholar
  17. Hamanoue M., Middleton G., Wyatt S., Jaffray E., Hay R. T., and Davies A. M. (1999) p75-mediated NF-kappaB activation enhances the survival response of developing sensory neurons to nerve growth factor. Mol. Cell. Neurosci. 14, 28–40.PubMedCrossRefGoogle Scholar
  18. Hardy J. and Selkoe D. J. (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353–356.PubMedCrossRefGoogle Scholar
  19. Harrington A. W., Kim J. Y., and Yoon S. O. (2002) Activation of Rac GTPase by p75 is necessary for c-jun N-terminal kinase-mediated apoptosis. J. Neurosci. 22, 156–166.PubMedGoogle Scholar
  20. Iversen L. L., Mortishire-Smith R. J., Pollack S. J., and Shearman M. S. (1995) The toxicity in vitro of beta-amyloid protein. Biochem. J. 311(Pt. 1), 1–16.PubMedGoogle Scholar
  21. Jang J. H. and Surh Y. J. (2002) beta-Amyloid induces oxidative DNA damage and cell death through activation of c-Jun N terminal kinase. Ann. N. Y. Acad. Sci. 973, 228–236.PubMedCrossRefGoogle Scholar
  22. Johnson G. L. and Lapadat R. (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 1911,1912.PubMedCrossRefGoogle Scholar
  23. Kajkowski E. M., Lo C. F., Ning X., Walker S., Sofia H. J., Wang W., et al. (2001) Beta -Amyloid peptide-induced apoptosis regulated by a novel protein containing a g protein activation module. J. Biol. Chem. 276, 18,748–18756.CrossRefGoogle Scholar
  24. Khursigara G., Bertin J., Yano H., Moffett H., DiStefano P. S., and Chao M. V. (2001) A prosurvival function for the p75 receptor death domain mediated via the caspase recruitment domain receptor-interacting protein 2. J. Neurosci. 21, 5854–5863.PubMedGoogle Scholar
  25. Khursigara G., Orlinick J. R., and Chao M. V. (1999) Association of the p75 neurotrophin receptor with TRAF6. J. Biol. Chem. 274, 2597–2600.PubMedCrossRefGoogle Scholar
  26. Kim S. J., Hwang S. G., Shin D. Y., Kang S. S., and Chun J. S. (2002) p38 kinase regulates nitric oxide-induced apoptosis of articular chondrocytes by accumulating p53 via NF-kappa B-dependent transcription and stabilization by serine 15 phosphorylation. J. Biol. Chem. 277, 33501–33508.PubMedCrossRefGoogle Scholar
  27. Kuner P., Schubenel R., and Hertel C. (1998) Beta-amyloid binds to p57NTR and activates NF-kappaB in human neuroblastoma cells. J. Neurosci. Res. 54, 798–804.PubMedCrossRefGoogle Scholar
  28. Ladiwala U., Lachance C., Simoneau S. J., Bhakar A., Barker P. A., and Antel J. P. (1998) p75 neurotrophin receptor expression on adult human oligodendrocytes: signaling without cell death in response to NGF. J. Neurosci. 18, 1297–1304.PubMedGoogle Scholar
  29. Lorenzo A., Yuan M., Zhang Z., Paganetti P. A., Sturchler-Pierrat C., Staufenbiel M., et al. (2000) Amyloid beta interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer’s disease. Nat. Neurosci. 3, 460–464.PubMedCrossRefGoogle Scholar
  30. McLaurin J. and Chakrabartty A. (1996) Membrane disruption by Alzheimer beta-amyloid peptides mediated through specific binding to either phospholipids or gangliosides. Implications for neurotoxicity. J. Biol. Chem. 271, 26482–26489.PubMedCrossRefGoogle Scholar
  31. Minogue A. M., Schmid A. W., Fogarty M. P., Moore A. C., Campbell V. A., Herron C. E., and Lynch M. A. (2003) Activation of the c-Jun N-terminal kinase signaling cascade mediates the effect of amyloid-beta on long term potentiation and cell death in hippocampus: a role for interleukin-1 beta? J. Biol. Chem. 278, 27,971–27,980.CrossRefGoogle Scholar
  32. Morishima Y., Gotoh Y., Zieg J., Barrett T., Takano H., Flavell R., et al. (2001) Beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand. J. Neurosci. 21, 7551–7560.PubMedGoogle Scholar
  33. Morrison R. S., Kinoshita Y., Johnson M. D., Guo W., and Garden G. A. (2003) p53-dependent cell death signaling in neurons. Neurochem. Res. 28, 15–27.PubMedCrossRefGoogle Scholar
  34. Pei J. J., Braak E., Braak H., Grundke-Iqbal I., Iqbal K., Winblad B., and Cowburn R. F. (2001) Localization of active forms of C-jun kinase (JNK) and p38 kinase in Alzheimer’s disease brains at different stages of neurofibrillary degeneration. J. Alzheimers Dis. 3, 41–48.PubMedGoogle Scholar
  35. Perfettini J. L., Roumier T., Castedo M., Larochette N., Boya P., Raynal B., et al. (2004) NF-kappa B and p53 are the dominant apoptosis-inducing transcription factors elicited by the HIV-1 envelope. J. Exp. Med. 199, 629–640.PubMedCrossRefGoogle Scholar
  36. Perini G., Della-Bianca V., Politi V., Della Valle G., Dal-Pra I., et al. (2002) Role of p75 neurotrophin receptor in the neurotoxicity by beta-amyloid peptides and synergistic effect of inflammatory cytokines. J. Exp. Med. 195, 907–918.PubMedCrossRefGoogle Scholar
  37. Rabizadeh S. and Bredesen D. E. (2003) Ten years on: mediation of cell death by the common neurotrophin receptor p75(NTR). Cytokine Growth Factor Rev. 14, 225–239.PubMedCrossRefGoogle Scholar
  38. Ryan K. M., Ernst M. K., Rice N. R., and Vousden K. H. (2000) Role of NF-kappaB in p53-mediated programmed cell death. Nature 404, 892–897.PubMedCrossRefGoogle Scholar
  39. Salehi A. H., Xanthoudakis S., and Barker P. A. (2002) NRAGE, a p75 neurotrophin receptor-interacting protein, induces caspase activation and cell death through a JNK-dependent mitochondrial pathway. J. Biol. Chem. 277, 48043–48050.PubMedCrossRefGoogle Scholar
  40. Santoro M. G., Rossi A., and Amici C. (2003) NF-kappaB and virus infection: who controls whom. EMBO J. 22, 2552–2560.PubMedCrossRefGoogle Scholar
  41. Savage M. J., Lin Y. G., Ciallella J. R., Flood D. G., and Scott R. W. (2002) Activation of c-Jun N-terminal kinase and p38 in an Alzheimer’s disease model is associated with amyloid deposition. J. Neurosci. 22, 3376–3385.PubMedGoogle Scholar
  42. Shimada K., Nakamura M., Ishida E., Kishi M., and Konishi N. (2003) Roles of p38- and c-jun NH2-terminal kinase-mediated pathways in 2-methoxyestradiol-induced p53 induction and apoptosis. Carcinogenesis 24, 1067–1075.PubMedCrossRefGoogle Scholar
  43. Takuma H., Tomiyama T., Kuida K., and Mori H. (2004) Amyloid beta peptide-induced cerebral neuronal loss is mediated by caspase-3 in vivo. J. Neuropathol. Exp. Neurol. 63, 255–261.PubMedGoogle Scholar
  44. Tamagno E., Robino G., Obbili A., Bardini P., Aragno M., Parola M., and Danni O. (2003a) H2O2 and 4-hydroxynonenal mediate amyloid beta-induced neuronal apoptosis by activating JNKs and p38MAPK. Exp. Neurol. 180, 144–155.PubMedCrossRefGoogle Scholar
  45. Tamagno E., Parola M., Guglielmotto M., Santoro G., Bardini P., Marra L., et al. (2003b) Multiple signaling events in amyloid beta-induced, oxidative stress-dependent neuronal apoptosis. Free Radic. Biol. Med. 35, 45–58.PubMedCrossRefGoogle Scholar
  46. Tiffany H. L., Lavigne M. C., Cui Y. H., Wang J. M., Leto T. L., Gao J. L., and Murphy P. M. (2001) Amyloid-beta induces chemotaxis and oxidant stress by acting at formylpeptide receptor 2, a G protein-coupled receptor expressed in phagocytes and brain. J. Biol. Chem. 276, 23,645–23,652.CrossRefGoogle Scholar
  47. Troy C. M., Rabacchi S. A., Xu Z., Maroney A. C., Connors T. J., Shelanski M. L., and Greene L. A. (2001) Beta-Amyloid-induced neuronal apoptosis requires c-Jun N-terminal kinase activation. J. Neurochem. 77, 157–164.PubMedCrossRefGoogle Scholar
  48. Tsukamoto E., Hashimoto Y., Kanekura K., Niikura T., Aiso S., and Nishimoto I. (2003) Characterization of the toxic mechanism triggered by Alzheimer’s amyloid-beta peptides via p75 neurotrophin receptor in neuronal hybrid cells. J. Neurosci. Res. 73, 627–636.PubMedCrossRefGoogle Scholar
  49. Wang H. Y., Lee D. H., D’Andrea M. R., Peterson P. A., Shank R. P., and Reitz A. B. (2000) Beta-Amyloid (1–42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer’s disease pathology. J. Biol. Chem. 275, 5626–5632.PubMedCrossRefGoogle Scholar
  50. Wei W., Wang X., and Kusiak J. W. (2002) Signaling events in amyloid beta-peptide-induced neuronal death and insulin-like growth factor I protection. J. Biol. Chem. 277, 17649–17656.PubMedCrossRefGoogle Scholar
  51. Willaime-Morawek S., Brami-Cherrier K., Mariani J., Caboche J., and Brugg B. (2003) C-Jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis. Neuroscience 119, 387–397.PubMedCrossRefGoogle Scholar
  52. Yaar M., Zhai S., Fine R. E., Eisenhauer P. B., Arble B. L., Stewart K. B., and Gilchrest B. A. (2002) Amyloid beta binds trimers as well as monomers of the 75-kDa neurotrophin receptor and activates receptor signaling. J. Biol. Chem. 277, 7720–7725.PubMedCrossRefGoogle Scholar
  53. Yaar M., Zhai S., Pilch P. F., Doyle S. M., Eisenhauer P. B., Fine R. E., and Gilchrest B. A. (1997) Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer’s disease. J. Clin. Invest. 100, 2333–2340.PubMedCrossRefGoogle Scholar
  54. Yan S. D., Chen X., Fu J., Chen M., Zhu H., Roher A., et al. (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382, 685–691.PubMedCrossRefGoogle Scholar
  55. Yoon S. O., Casaccia-Bonnefil P., Carter B., and Chao M. V. (1998) Competitive signaling between TrkA and p75 nerve growth factor receptors determines cell survival. J. Neurosci. 18, 3273–3281.PubMedGoogle Scholar
  56. Zhang Y., Hong Y., Bounhar Y., Blacker M., Roucou X., Tounekti O., et al. (2003) p75 neurotrophin receptor protects primary cultures of human neurons against extracellular amyloid beta peptide cytotoxicity. J. Neurosci. 23, 7385–7394.PubMedGoogle Scholar
  57. Zhu Y., Mao X. O., Sun Y., Xia Z., and Greenberg D. A. (2002) p38 Mitogen-activated protein kinase mediates hypoxic regulation of Mdm2 and p53 in neurons. J. Biol. Chem. 277, 22,909–22,914.Google Scholar
  58. Zhu X., Ogawa O., Wang Y., Perry G., and Smith M. A. (2003) JKK1, an upstream activator of JNK/SAPK, is activated in Alzheimer’s disease. J. Neurochem. 85, 87–93.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  • Claudio Costantini
    • 1
  • Filippo Rossi
    • 1
  • Elena Formaggio
    • 2
  • Roberto Bernardoni
    • 3
  • Daniela Cecconi
    • 4
  • Vittorina Della-Bianca
    • 1
  1. 1.Department of Pathology Section of General PathologyUniversity of VeronaVeronaItaly
  2. 2.Department of Medicine and Public Health, Section of PharmacologyUniversity of VeronaVeronaItaly
  3. 3.Department of BiologyUniversity of BolognaBolognaItaly
  4. 4.Department of Agricultural and Industrial BiotechnologiesUniversity of VeronaVeronaItaly

Personalised recommendations