Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Caspase activation precedes and leads to tangles

Nature volume 464, pages 1201–1204 (2010)Cite this article

Subjects

Abstract

Studies of post-mortem tissue have shown that the location of fibrillar tau deposits, called neurofibrillary tangles (NFT), matches closely with regions of massive neuronal death1,2, severe cytological abnormalities3, and markers of caspase activation and apoptosis4,5,6, leading to the idea that tangles cause neurodegeneration in Alzheimer’s disease and tau-related frontotemporal dementia. However, using in vivo multiphoton imaging to observe tangles and activation of executioner caspases in living tau transgenic mice (Tg4510 strain), we find the opposite: caspase activation occurs first, and precedes tangle formation by hours to days. New tangles form within a day. After a new tangle forms, the neuron remains alive and caspase activity seems to be suppressed. Similarly, introduction of wild-type 4-repeat tau (tau-4R) into wild-type animals triggered caspase activation, tau truncation and tau aggregation. Adeno-associated virus-mediated expression of a construct mimicking caspase-cleaved tau into wild-type mice led to the appearance of intracellular aggregates, tangle-related conformational- and phospho-epitopes, and the recruitment of full-length endogenous tau to the aggregates. On the basis of these data, we propose a new model in which caspase activation cleaves tau to initiate tangle formation, then truncated tau recruits normal tau to misfold and form tangles. Because tangle-bearing neurons are long-lived, we suggest that tangles are ‘off pathway’ to acute neuronal death. Soluble tau species, rather than fibrillar tau, may be the critical toxic moiety underlying neurodegeneration.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Tangle-bearing neurons can be imaged for several days in the living brain, and caspase activation is not associated with acute neuronal death.
Figure 2: New tangles form very rapidly in cells with activated caspases.
Figure 3: Caspase activation in Tg4510 correlates with the presence of truncated forms of tau, which appears in multiple models of tauopathy.
Figure 4: Caspase-cleaved tau can nucleate pathological conformation of tau, and can recruit additional tau molecules.

Similar content being viewed by others

References

  1. Ramsden, M. et al. Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J. Neurosci. 25, 10637–10647 (2005)

    Article  CAS  Google Scholar 

  2. Gómez-Isla, T. et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann. Neurol. 41, 17–24 (1997)

    Article  Google Scholar 

  3. Augustinack, J. C., Schneider, A., Mandelkow, E. M. & Hyman, B. T. Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol. 103, 26–35 (2002)

    Article  CAS  Google Scholar 

  4. Ramalho, R. M. et al. Apoptosis in transgenic mice expressing the P301L mutated form of human tau. Mol. Med. 14, 309–317 (2008)

    Article  CAS  Google Scholar 

  5. 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  Google Scholar 

  6. Rohn, T. T. et al. Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer’s disease. Am. J. Pathol. 158, 189–198 (2001)

    Article  CAS  Google Scholar 

  7. Santacruz, K. et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–481 (2005)

    Article  ADS  CAS  Google Scholar 

  8. Spires, T. L. et al. Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. Am. J. Pathol. 168, 1598–1607 (2006)

    Article  CAS  Google Scholar 

  9. Spires-Jones, T. L. et al. In vivo imaging reveals dissociation between caspase activation and acute neuronal death in tangle-bearing neurons. J. Neurosci. 28, 862–867 (2008)

    Article  CAS  Google Scholar 

  10. de Calignon, A., Spires-Jones, T. L., Pitstick, R., Carlson, G. A. & Hyman, B. T. Tangle-bearing neurons survive despite disruption of membrane integrity in a mouse model of tauopathy. J. Neuropathol. Exp. Neurol. 68, 757–761 (2009)

    Article  CAS  Google Scholar 

  11. Styren, S. D., Hamilton, R. L., Styren, G. C. & Klunk, W. E. X-34, a fluorescent derivative of Congo red: a novel histochemical stain for Alzheimer’s disease pathology. J. Histochem. Cytochem. 48, 1223–1232 (2000)

    Article  CAS  Google Scholar 

  12. Velasco, A. et al. Detection of filamentous tau inclusions by the fluorescent Congo red derivative FSB [(trans,trans)-1-fluoro-2,5-bis(3-hydroxycarbonyl-4-hydroxy)styrylbenzene]. FEBS Lett. 582, 901–906 (2008)

    Article  CAS  Google Scholar 

  13. Rissman, R. A. et al. Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J. Clin. Invest. 114, 121–130 (2004)

    Article  CAS  Google Scholar 

  14. Zhang, Q., Zhang, X. & Sun, A. Truncated tau at D421 is associated with neurodegeneration and tangle formation in the brain of Alzheimer transgenic models. Acta Neuropathol. 117, 687–697 (2009)

    Article  CAS  Google Scholar 

  15. Basurto-Islas, G. et al. Accumulation of aspartic acid421- and glutamic acid391-cleaved tau in neurofibrillary tangles correlates with progression in Alzheimer disease. J. Neuropathol. Exp. Neurol. 67, 470–483 (2008)

    Article  CAS  Google Scholar 

  16. Guillozet-Bongaarts, A. L. et al. Tau truncation during neurofibrillary tangle evolution in Alzheimer’s disease. Neurobiol. Aging 26, 1015–1022 (2005)

    Article  CAS  Google Scholar 

  17. Delobel, P. et al. Analysis of tau phosphorylation and truncation in a mouse model of human tauopathy. Am. J. Pathol. 172, 123–131 (2008)

    Article  CAS  Google Scholar 

  18. 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  Google Scholar 

  19. Guillozet-Bongaarts, A. L. et al. Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivo. J. Neurochem. 97, 1005–1014 (2006)

    Article  CAS  Google Scholar 

  20. Jaworski, T. et al. AAV-tau mediates pyramidal neurodegeneration by cell-cycle re-entry without neurofibrillary tangle formation in wild-type mice. PLoS One 4, e7280 (2009)

    Article  ADS  Google Scholar 

  21. Andorfer, C. et al. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J. Neurochem. 86, 582–590 (2003)

    Article  CAS  Google Scholar 

  22. Gamblin, T. C. et al. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc. Natl Acad. Sci. USA 100, 10032–10037 (2003)

    Article  ADS  CAS  Google Scholar 

  23. Yin, H. & Kuret, J. C-terminal truncation modulates both nucleation and extension phases of tau fibrillization. FEBS Lett. 580, 211–215 (2006)

    Article  CAS  Google Scholar 

  24. Ding, H., Matthews, T. A. & Johnson, G. V. Site-specific phosphorylation and caspase cleavage differentially impact tau-microtubule interactions and tau aggregation. J. Biol. Chem. 281, 19107–19114 (2006)

    Article  CAS  Google Scholar 

  25. Mocanu, M. M. et al. The potential for β-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy. J. Neurosci. 28, 737–748 (2008)

    Article  CAS  Google Scholar 

  26. Wang, Y. et al. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum. Mol. Genet. 18, 4153–4170 (2009)

    Article  CAS  Google Scholar 

  27. Park, S. Y., Tournell, C., Sinjoanu, R. C. & Ferreira, A. Caspase-3- and calpain-mediated tau cleavage are differentially prevented by estrogen and testosterone in β-amyloid-treated hippocampal neurons. Neuroscience 144, 119–127 (2007)

    Article  CAS  Google Scholar 

  28. Gossen, M. & Bujard, H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc. Natl Acad. Sci. USA 89, 5547–5551 (1992)

    Article  ADS  CAS  Google Scholar 

  29. Mayford, M. et al. Control of memory formation through regulated expression of a CaMKII transgene. Science 274, 1678–1683 (1996)

    Article  ADS  CAS  Google Scholar 

  30. Skoch, J., Hickey, G. A., Kajdasz, S. T., Hyman, B. T. & Bacskai, B. J. in Amyloid proteins: methods and protocols (ed. Sigurdsson, E. M.) 349–364 (Humana Press, 2004)

    Book  Google Scholar 

Download references

Acknowledgements

This work was supported by AG08487, AG 026249, K99 AG033670-01A1, Alzheimer’s disease Drug Discovery Foundation, Harvard Medical School Shore Award. We thank W. E. Klunk for his generous gift of compound X-34. A.d.C. is a student in the B2M programme (Université Pierre and Marie Curie, Paris, France) and the results in this manuscript will be presented in her thesis.

Author Contributions A.d.C. and L.M.F. carried out the experiments described and helped design the experiments; A.d.C. wrote the manuscript. T.L.S.-J. developed the caspase reagents and contributed to experimental design and analysis and manuscript preparation. R.P. and G.A.C. provided the Tg4510 animals and contributed to characterization of this line. B.J.B. contributed to experimental design and development of multiphoton imaging protocols to allow multicolour, multiday imaging. B.T.H. assisted with conception and design of the experiments, assisted with data analysis, manuscript preparation, and provided funding for the study.

Author information

Authors and Affiliations

  1. Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Alzheimer’s Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA,

    Alix de Calignon, Leora M. Fox, Brian J. Bacskai, Tara L. Spires-Jones & Bradley T. Hyman

  2. Université Pierre and Marie Curie, Paris 75005, France

    Alix de Calignon

  3. McLaughlin Research Institute, Great Falls, Montana 59401, USA,

    Rose Pitstick & George A. Carlson

Authors
  1. Alix de Calignon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leora M. Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rose Pitstick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. George A. Carlson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brian J. Bacskai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tara L. Spires-Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bradley T. Hyman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bradley T. Hyman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-6 with legends. (PDF 948 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

de Calignon, A., Fox, L., Pitstick, R. et al. Caspase activation precedes and leads to tangles. Nature 464, 1201–1204 (2010). https://doi.org/10.1038/nature08890

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature08890

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing