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RETRACTED ARTICLE: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases

This article was retracted on 18 December 2023

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Abstract

Naturally occurring axonal pruning and neuronal cell death help to sculpt neuronal connections during development, but their mechanistic basis remains poorly understood. Here we report that β-amyloid precursor protein (APP) and death receptor 6 (DR6, also known as TNFRSF21) activate a widespread caspase-dependent self-destruction program. DR6 is broadly expressed by developing neurons, and is required for normal cell body death and axonal pruning both in vivo and after trophic-factor deprivation in vitro. Unlike neuronal cell body apoptosis, which requires caspase 3, we show that axonal degeneration requires caspase 6, which is activated in a punctate pattern that parallels the pattern of axonal fragmentation. DR6 is activated locally by an inactive surface ligand(s) that is released in an active form after trophic-factor deprivation, and we identify APP as a DR6 ligand. Trophic-factor deprivation triggers the shedding of surface APP in a β-secretase (BACE)-dependent manner. Loss- and gain-of-function studies support a model in which a cleaved amino-terminal fragment of APP (N-APP) binds DR6 and triggers degeneration. Genetic support is provided by a common neuromuscular junction phenotype in mutant mice. Our results indicate that APP and DR6 are components of a neuronal self-destruction pathway, and suggest that an extracellular fragment of APP, acting via DR6 and caspase 6, contributes to Alzheimer’s disease.

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Figure 1: DR6 regulates degeneration of several neuronal classes.
Figure 2: DR6 regulates axon pruning in vitro and in vivo.
Figure 3: BAX and caspase 6 regulate axonal degeneration.
Figure 4: The N terminus of APP is a regulated DR6 ligand.
Figure 5: The APP N terminus regulates degeneration.
Figure 6: APP and DR6 signalling: in vivo evidence, and model.

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  • 15 March 2023

    Editor’s Note: Concerns have been raised regarding some of the figures in this paper. Nature is investigating these concerns, and a further editorial response will follow as soon as possible. In the meantime, readers are advised to use caution when using results reported therein.

  • 18 December 2023

    This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1038/s41586-023-06943-3

References

  1. Raff, M. C., Whitmore, A. V. & Finn, J. T. Axonal self-destruction and neurodegeneration. Science 296, 868–871 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  2. Luo, L. & O’Leary, D. D. Axon retraction and degeneration in development and disease. Annu. Rev. Neurosci. 28, 127–156 (2005)

    Article  CAS  PubMed  Google Scholar 

  3. Buss, R. R., Sun, W. & Oppenheim, R. W. Adaptive roles of programmed cell death during nervous system development. Annu. Rev. Neurosci. 29, 1–35 (2006)

    Article  CAS  PubMed  Google Scholar 

  4. Saxena, S. & Caroni, P. Mechanisms of axon degeneration: from development to disease. Prog. Neurobiol. 83, 174–191 (2007)

    Article  CAS  PubMed  Google Scholar 

  5. Haase, G., Pettmann, B., Raoul, C. & Henderson, C. E. Signaling by death receptors in the nervous system. Curr. Opin. Neurobiol. 18, 284–291 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kuida, K. et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384, 368–372 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  7. White, F. A., Keller-Peck, C. R., Knudson, C. M., Korsmeyer, S. J. & Snider, W. D. Widespread elimination of naturally occurring neuronal death in Bax-deficient mice. J. Neurosci. 18, 1428–1439 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Finn, J. T. et al. Evidence that Wallerian degeneration and localized axon degeneration induced by local neurotrophin deprivation do not involve caspases. J. Neurosci. 20, 1333–1341 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kuo, C. T., Zhu, S., Younger, S., Jan, L. Y. & Jan, Y. N. Identification of E2/E3 ubiquitinating enzymes and caspase activity regulating Drosophila sensory neuron dendrite pruning. Neuron 51, 283–290 (2006)

    Article  CAS  PubMed  Google Scholar 

  10. Williams, D. W., Kondo, S., Krzyzanowska, A., Hiromi, Y. & Truman, J. W. Local caspase activity directs engulfment of dendrites during pruning. Nature Neurosci. 9, 1234–1236 (2006)

    Article  CAS  PubMed  Google Scholar 

  11. Plachta, N. et al. Identification of a lectin causing the degeneration of neuronal processes using engineered embryonic stem cells. Nature Neurosci. 10, 712–719 (2007)

    Article  CAS  PubMed  Google Scholar 

  12. Sagot, Y. et al. Bcl-2 overexpression prevents motoneuron cell body loss but not axonal degeneration in a mouse model of a neurodegenerative disease. J. Neurosci. 15, 7727–7733 (1995)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Watts, R. J., Hoopfer, E. D. & Luo, L. Axon pruning during Drosophila metamorphosis: evidence for local degeneration and requirement of the ubiquitin-proteasome system. Neuron 38, 871–885 (2003)

    Article  CAS  PubMed  Google Scholar 

  14. Bodmer, J. L., Schneider, P. & Tschopp, J. The molecular architecture of the TNF superfamily. Trends Biochem. Sci. 27, 19–26 (2002)

    Article  CAS  PubMed  Google Scholar 

  15. Bossen, C. et al. Interactions of tumor necrosis factor (TNF) and TNF receptor family members in the mouse and human. J. Biol. Chem. 281, 13964–13971 (2006)

    Article  CAS  PubMed  Google Scholar 

  16. Pan, G. et al. Identification and functional characterization of DR6, a novel death domain-containing TNF receptor. FEBS Lett. 431, 351–356 (1998)

    Article  CAS  PubMed  Google Scholar 

  17. Zhao, H. et al. Impaired c-Jun amino terminal kinase activity and T cell differentiation in death receptor 6-deficient mice. J. Exp. Med. 194, 1441–1448 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schmidt, C. S. et al. Enhanced B cell expansion, survival, and humoral responses by targeting death receptor 6. J. Exp. Med. 197, 51–62 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Walsh, D. M. et al. The APP family of proteins: similarities and differences. Biochem. Soc. Trans. 35, 416–420 (2007)

    Article  CAS  PubMed  Google Scholar 

  20. Reinhard, C., Hebert, S. S. & De Strooper, B. The amyloid-β precursor protein: integrating structure with biological function. EMBO J. 24, 3996–4006 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Haass, C. & Selkoe, D. J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nature Rev. Mol. Cell Biol. 8, 101–112 (2007)

    Article  CAS  Google Scholar 

  23. Wang, H. & Tessier-Lavigne, M. En passant neurotrophic action of an intermediate axonal target in the developing mammalian CNS. Nature 401, 765–769 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  24. Campenot, R. B., Walji, A. H. & Draker, D. D. Effects of sphingosine, staurosporine, and phorbol ester on neurites of rat sympathetic neurons growing in compartmented cultures. J. Neurosci. 11, 1126–1139 (1991)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cole, S. L. & Vassar, R. BACE1 structure and function in health and Alzheimer’s disease. Curr. Alzheimer Res. 5, 100–120 (2008)

    Article  CAS  PubMed  Google Scholar 

  26. Edwards, P. D. et al. Application of fragment-based lead generation to the discovery of novel, cyclic amidine β-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency. J. Med. Chem. 50, 5912–5925 (2007)

    Article  CAS  PubMed  Google Scholar 

  27. Slunt, H. H. et al. Expression of a ubiquitous, cross-reactive homologue of the mouse β-amyloid precursor protein (APP). J. Biol. Chem. 269, 2637–2644 (1994)

    Article  CAS  PubMed  Google Scholar 

  28. Hilbich, C., Monning, U., Grund, C., Masters, C. L. & Beyreuther, K. Amyloid-like properties of peptides flanking the epitope of amyloid precursor protein-specific monoclonal antibody 22C11. J. Biol. Chem. 268, 26571–26577 (1993)

    Article  CAS  PubMed  Google Scholar 

  29. Wang, P. et al. Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-like protein 2. J. Neurosci. 25, 1219–1225 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Singh, K. K. et al. Developmental axon pruning mediated by BDNF-p75NTR-dependent axon degeneration. Nature Neurosci. 11, 649–658 (2008)

    Article  CAS  PubMed  Google Scholar 

  31. Deppmann, C. D. et al. A model for neuronal competition during development. Science 320, 369–373 (2008)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  32. LeBlanc, A., Liu, H., Goodyer, C., Bergeron, C. & Hammond, J. Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer’s disease. J. Biol. Chem. 274, 23426–23436 (1999)

    Article  CAS  PubMed  Google Scholar 

  33. Horowitz, P. M. et al. Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer’s disease. J. Neurosci. 24, 7895–7902 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Guo, H. et al. Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer’s disease. Am. J. Pathol. 165, 523–531 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Klaiman, G., Petzke, T. L., Hammond, J. & Leblanc, A. C. Targets of caspase-6 activity in human neurons and Alzheimer disease. Mol. Cell. Proteomics 7, 1541–1555 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Young-Pearse, T. L., Chen, A. C., Chang, R., Marquez, C. & Selkoe, D. J. Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin β1. Neural Develop. 3, 15 (2008)

    Article  PubMed Central  Google Scholar 

  37. Heber, S. et al. Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members. J. Neurosci. 20, 7951–7963 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Perez, R. G., Zheng, H., Van der Ploeg, L. H. & Koo, E. H. The β-amyloid precursor protein of Alzheimer’s disease enhances neuron viability and modulates neuronal polarity. J. Neurosci. 17, 9407–9414 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Han, P. et al. Suppression of cyclin-dependent kinase 5 activation by amyloid precursor protein: a novel excitoprotective mechanism involving modulation of Tau phosphorylation. J. Neurosci. 25, 11542–11552 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Matrone, C. et al. Activation of the amyloidogenic route by NGF deprivation induces apoptotic death in PC12 cells. J. Alzheimers Dis. 13, 81–96 (2008)

    Article  CAS  PubMed  Google Scholar 

  41. Matrone, C., Ciotti, M. T., Mercanti, D., Marolda, R. & Calissano, P. NGF and BDNF signaling control amyloidogenic route and Aβ production in hippocampal neurons. Proc. Natl Acad. Sci. USA 105, 13139–13144 (2008)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  42. Medana, I. M. & Esiri, M. M. Axonal damage: a key predictor of outcome in human CNS diseases. Brain 126, 515–530 (2003)

    Article  CAS  PubMed  Google Scholar 

  43. Chiang, L. W. et al. An orchestrated gene expression component of neuronal programmed cell death revealed by cDNA array analysis. Proc. Natl Acad. Sci. USA 98, 2814–2819 (2001)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  44. Muller, T., Meyer, H. E., Egensperger, R. & Marcus, K. The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics-relevance for Alzheimer’s disease. Prog. Neurobiol. 85, 393–406 (2008)

    Article  PubMed  Google Scholar 

  45. Van Gool, D., De Strooper, B., Van Leuven, F. & Dom, R. Amyloid precursor protein accumulation in Lewy body dementia and Alzheimer’s disease. Dementia 6, 63–68 (1995)

    CAS  PubMed  Google Scholar 

  46. Palmert, M. R. et al. Antisera to an amino-terminal peptide detect the amyloid protein precursor of Alzheimer’s disease and recognize senile plaques. Biochem. Biophys. Res. Commun. 156, 432–437 (1988)

    Article  CAS  PubMed  Google Scholar 

  47. Bertram, L. & Tanzi, R. E. Alzheimer’s disease: one disorder, too many genes? Hum. Mol. Genet. 13, R135–R141 (2004)

    Article  CAS  PubMed  Google Scholar 

  48. Doyle, J. P. et al. Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell 135, 749–762 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Albrecht, S. et al. Activation of caspase-6 in aging and mild cognitive impairment. Am. J. Pathol. 170, 1200–1209 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Graham, R. K. et al. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125, 1179–1191 (2006)

    Article  CAS  PubMed  Google Scholar 

  51. Sabatier, C. et al. The divergent Robo family protein rig-1/Robo3 is a negative regulator of slit responsiveness required for midline crossing by commissural axons. Cell 117, 157–169 (2004)

    Article  CAS  PubMed  Google Scholar 

  52. Atwal, J. K. et al. PirB is a functional receptor for myelin inhibitors of axonal regeneration. Science 322, 967–970 (2008)

    Article  ADS  CAS  PubMed  Google Scholar 

  53. Chen, Z. et al. Alternative splicing of the Robo3 axon guidance Receptor governs the midline switch. Neuron 58, 325–332 (2008)

    Article  CAS  PubMed  Google Scholar 

  54. Higuchi, H., Yamashita, T., Yoshikawa, H. & Tohyama, M. Functional inhibition of the p75 receptor using a small interfering RNA. Biochem. Biophys. Res. Commun. 301, 804–809 (2003)

    Article  CAS  PubMed  Google Scholar 

  55. McLaughlin, T., Torborg, C. L., Feller, M. B. & O’Leary, D. D. Retinotopic map refinement requires spontaneous retinal waves during a brief critical period of development. Neuron 40, 1147–1160 (2003)

    Article  CAS  PubMed  Google Scholar 

  56. Pettmann, B. et al. Biological activities of nerve growth factor bound to nitrocellulose paper by western blotting. J. Neurosci. 8, 3624–3632 (1988)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Okada, A. et al. Boc is a receptor for sonic hedgehog in the guidance of commissural axons. Nature 444, 369–373 (2006)

    Article  ADS  CAS  PubMed  Google Scholar 

  58. Knudson, C. M. et al. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270, 96–99 (1995)

    Article  ADS  CAS  PubMed  Google Scholar 

  59. Lee, K. F. et al. Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69, 737–749 (1992)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank R. Axel, C. Bargmann, B. de Strooper, V. Dixit, C. Henderson, J. Lewcock, R. Scheller, R. Vassar, R. Watts, and members of the M.T.-L. laboratory for helpful discussions and suggestions, and critical reading of the manuscript, and A. Bruce for making the diagrams. We thank P. Hass and members of his laboratory (Genentech) for generation and purification of the DR6 ectodomain and APP(1–286), and W.-C. Liang and Y. Wu (Genentech) for binding experiments with purified proteins. Supported by Genentech (A.N. and M.T.-L.) and National Eye Institute grant R01 EY07025 (D.D.M.O.’L.).

Author Contributions A.N. performed most of the experiments, with the exception of the analysis of retinal projections and the experiments listed in the Acknowledgements, and co-wrote the paper. The retinotectal analysis was performed by T.M. and supervised by D.D.M.O.’L. M.T.-L. supervised or co-supervised all experiments, and co-wrote the paper.

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Correspondence to Marc Tessier-Lavigne.

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A.N. and M.T.-L. are employees of Genentech, Inc., which has a commercial interest in some of the molecules studied here.

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Nikolaev, A., McLaughlin, T., O’Leary, D. et al. RETRACTED ARTICLE: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457, 981–989 (2009). https://doi.org/10.1038/nature07767

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