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.

  • Article
  • Published:

Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease

Nature Neuroscience volume 14, pages 69–76 (2011)Cite this article

Subjects

Abstract

Synaptic loss is the best pathological correlate of the cognitive decline in Alzheimer's disease; however, the molecular mechanisms underlying synaptic failure are unknown. We found a non-apoptotic baseline caspase-3 activity in hippocampal dendritic spines and an enhancement of this activity at the onset of memory decline in the Tg2576-APPswe mouse model of Alzheimer's disease. In spines, caspase-3 activated calcineurin, which in turn triggered dephosphorylation and removal of the GluR1 subunit of AMPA-type receptor from postsynaptic sites. These molecular modifications led to alterations of glutamatergic synaptic transmission and plasticity and correlated with spine degeneration and a deficit in hippocampal-dependent memory. Notably, pharmacological inhibition of caspase-3 activity in Tg2576 mice rescued the observed Alzheimer-like phenotypes. Our results identify a previously unknown caspase-3–dependent mechanism that drives synaptic failure and contributes to cognitive dysfunction in Alzheimer's disease. These findings indicate that caspase-3 is a potential target for pharmacological therapy during early disease stages.

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

Access options

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

Figure 1: CFC performance and morphology of CA1 neuron dendrites in Tg2576 and wild-type mice.
Figure 2: Altered hippocampal GluR1 distribution in 3-month-old Tg2576 mice.
Figure 3: Altered basic glutamatergic synaptic transmission and enhanced LTD in 3-month-old Tg2576 mice.
Figure 4: Tg2576 hippocampal dendritic spines accumulate active caspase-3 in the postsynaptic compartment and show apoptotic features.
Figure 5: Inhibition of caspase-3 activity reduces GluR1 dephosphorylation and its removal from PSD and rescues glutamatergic synaptic transmission in Tg2576 mice.
Figure 6: Inhibition of caspase-3 activity reduces calcineurin cleavage and activity.
Figure 7: Caspase-3 inhibition in vivo influences GluR1 distribution and rescues spine head size and memory function in Tg2576 mice.

Similar content being viewed by others

References

  1. Arendt, T. Synaptic degeneration in Alzheimer′s disease. Acta Neuropathol. 118, 167–179 (2009).

    Article  Google Scholar 

  2. Morrison, J.H. & Hof, P.R. Life and death of neurons in the aging brain. Science 278, 412–419 (1997).

    Article  CAS  Google Scholar 

  3. Bookheimer, S.Y. et al. Patterns of brain activation in people at risk for Alzheimer′s disease. N. Engl. J. Med. 343, 450–456 (2000).

    Article  CAS  Google Scholar 

  4. Elias, M.F. et al. The preclinical phase of Alzheimer disease: a 22-year prospective study of the Framingham cohort. Arch. Neurol. 57, 808–813 (2000).

    Article  CAS  Google Scholar 

  5. Zhou, Y. et al. Abnormal connectivity in the posterior cingulate and hippocampus in early Alzheimer's disease and mild cognitive impairment. Alzheimers Dement. 4, 265–270 (2008).

    Article  Google Scholar 

  6. Scheff, S.W., Price, D.A., Schmitt, F.A., DeKosky, S.T. & Mufson, E.J. Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68, 1501–1508 (2007).

    Article  CAS  Google Scholar 

  7. Bourne, J.N. & Harris, K.M. Balancing structure and function at hippocampal dendritic spines. Annu. Rev. Neurosci. 31, 47–67 (2008).

    Article  CAS  Google Scholar 

  8. Ferrer, I., Guionnet, N., Cruz-Sánchez, F. & Tuñón, T. Neuronal alterations in patients with dementia: a Golgi study on biopsy samples. Neurosci. Lett. 114, 11–16 (1990).

    Article  CAS  Google Scholar 

  9. Lanz, T.A., Carter, D.B. & Merchant, K.M. Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype. Neurobiol. Dis. 13, 246–253 (2003).

    Article  CAS  Google Scholar 

  10. Mattson, M.P., Keller, J.N. & Begley, J.G. Evidence for synaptic apoptosis. Exp. Neurol. 153, 35–48 (1998).

    Article  CAS  Google Scholar 

  11. Hsiao, K. et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).

    Article  CAS  Google Scholar 

  12. Jacobsen, J.S. et al. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer′s disease. Proc. Natl. Acad. Sci. USA 103, 5161–5166 (2006).

    Article  CAS  Google Scholar 

  13. Kawarabayashi, T. et al. Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer′s disease. J. Neurosci. 21, 372–381 (2001).

    Article  CAS  Google Scholar 

  14. Irizarry, M.C., McNamara, M., Fedorchak, K., Hsiao, K. & Hyman, B.T. APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1. J. Neuropathol. Exp. Neurol. 56, 965–973 (1997).

    Article  CAS  Google Scholar 

  15. Westerman, M.A. et al. The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer′s disease. J. Neurosci. 22, 1858–1867 (2002).

    Article  CAS  Google Scholar 

  16. Janus, C. et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer′s disease. Nature 408, 979–982 (2000).

    Article  CAS  Google Scholar 

  17. Chen, G. et al. A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer′s disease. Nature 408, 975–979 (2000).

    Article  CAS  Google Scholar 

  18. Phillips, R.G. & LeDoux, J.E. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274–285 (1992).

    Article  CAS  Google Scholar 

  19. Lee, I. & Kesner, R.P. Differential contributions of dorsal hippocampal subregions to memory acquisition and retrieval in contextual fear-conditioning. Hippocampus 14, 301–310 (2004).

    Article  Google Scholar 

  20. Lajtha, A., Perez-Polo, J.R. & Rossner, S. Handbook of Neurochemistry and Molecular Neurobiology (Springer, New York, 2008).

  21. Li, S. et al. Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62, 788–801 (2009).

    Article  CAS  Google Scholar 

  22. Almeida, C.G. et al. Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol. Dis. 20, 187–198 (2005).

    Article  CAS  Google Scholar 

  23. Malinow, R. & Malenka, R.C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).

    Article  CAS  Google Scholar 

  24. Chapman, P.F. et al. Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat. Neurosci. 2, 271–276 (1999).

    Article  CAS  Google Scholar 

  25. Lee, H.K., Kameyama, K., Huganir, R.L. & Bear, M.F. NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron 21, 1151–1162 (1998).

    Article  CAS  Google Scholar 

  26. van Engeland, M., Nieland, L.J., Ramaekers, F.C., Schutte, B. & Reutelingsperger, C.P. Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31, 1–9 (1998).

    Article  CAS  Google Scholar 

  27. Green, D.R. & Kroemer, G. The pathophysiology of mitochondrial cell death. Science 305, 626–629 (2004).

    Article  CAS  Google Scholar 

  28. Schulze-Osthoff, K., Ferrari, D., Los, M., Wesselborg, S. & Peter, M.E. Apoptosis signaling by death receptors. Eur. J. Biochem. 254, 439–459 (1998).

    Article  CAS  Google Scholar 

  29. Hsieh, H. et al. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52, 831–843 (2006).

    Article  CAS  Google Scholar 

  30. Mukerjee, N., McGinnis, K.M., Park, Y.H., Gnegy, M.E. & Wang, K.K. Caspase-mediated proteolytic activation of calcineurin in thapsigargin-mediated apoptosis in SH-SY5Y neuroblastoma cells. Arch. Biochem. Biophys. 379, 337–343 (2000).

    Article  CAS  Google Scholar 

  31. Vicent, M.J. & Pérez-Payá, E. Poly-L-glutamic acid (PGA) aided inhibitors of apoptotic protease activating factor 1 (Apaf-1): an antiapoptotic polymeric nanomedicine. J. Med. Chem. 49, 3763–3765 (2006).

    Article  CAS  Google Scholar 

  32. Santamaría, B. et al. A nanoconjugate Apaf-1 inhibitor protects mesothelial cells from cytokine-induced injury. PLoS ONE 4, e6634 (2009).

    Article  Google Scholar 

  33. Salvesen, G.S. & Dixit, V.M. Caspases: intracellular signaling by proteolysis. Cell 91, 443–446 (1997).

    Article  CAS  Google Scholar 

  34. Bravarenko, N.I. et al. Caspase-like activity is essential for long-term synaptic plasticity in the terrestrial snail Helix. Eur. J. Neurosci. 23, 129–140 (2006).

    Article  CAS  Google Scholar 

  35. Huesmann, G.R. & Clayton, D.F. Dynamic role of postsynaptic caspase-3 and BIRC4 in zebra finch song-response habituation. Neuron 52, 1061–1072 (2006).

    Article  CAS  Google Scholar 

  36. Li, Z. et al. Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell 141, 859–871 (2010).

    Article  CAS  Google Scholar 

  37. Marín, N. et al. Beta-amyloid-induced activation of caspase-3 in primary cultures of rat neurons. Mech. Ageing Dev. 119, 63–67 (2000).

    Article  Google Scholar 

  38. Gervais, F.G. et al. Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation. Cell 97, 395–406 (1999).

    Article  CAS  Google Scholar 

  39. Stadelmann, C. et al. Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer's disease. Evidence for apoptotic cell death. Am. J. Pathol. 155, 1459–1466 (1999).

    Article  CAS  Google Scholar 

  40. Louneva, N. et al. Caspase-3 is enriched in postsynaptic densities and increased in Alzheimer′s disease. Am. J. Pathol. 173, 1488–1495 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  42. Hakem, R. et al. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94, 339–352 (1998).

    Article  CAS  Google Scholar 

  43. Kuida, K. et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94, 325–337 (1998).

    Article  CAS  Google Scholar 

  44. Cecconi, F., Alvarez-Bolado, G., Meyer, B.I., Roth, K.A. & Gruss, P. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94, 727–737 (1998).

    Article  CAS  Google Scholar 

  45. Takahashi, R.H. et al. Oligomerization of Alzheimer's beta-amyloid within processes and synapses of cultured neurons and brain. J. Neurosci. 24, 3592–3599 (2004).

    Article  CAS  Google Scholar 

  46. Manczak, M. et al. Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum. Mol. Genet. 15, 1437–1449 (2006).

    Article  CAS  Google Scholar 

  47. Cho, D.H. et al. S-nytrosylation of Drp1 mediates beta-amyloid–related mitochondrial fission and neuronal injury. Science 324, 102–105 (2009).

    Article  CAS  Google Scholar 

  48. Marie, H., Morishita, W., Yu, X., Calakos, N. & Malenka, R.C. Generation of silent synapses by acute in vivo expression of CaMKIV and CREB. Neuron 45, 741–752 (2005).

    Article  CAS  Google Scholar 

  49. Gylys, K.H., Fein, J.A., Wiley, D.J. & Cole, G.M. Rapid annexin-V labeling in synaptosomes. Neurochem. Int. 44, 125–131 (2004).

    Article  CAS  Google Scholar 

  50. Ferri, A. et al. Calcineurin activity is regulated both by redox compounds and by mutant familial amyotrophic lateral sclerosis-superoxide dismutase. J. Neurochem. 75, 606–613 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Animal Facility of the IRCCS Fondazione Santa Lucia/EBRI/CNR for the mouse work, Taconic for the Tg2576 mice, M. Acuña-Villa and M.W. Bennett for editorial and secretarial work, R. Nardacci, F. Fanelli and M. Nencini for research assistance and help with image processing, and A. Roberto and A. Pignataro for help with Neurolucida measurements. We are grateful to E. Pérez-Payá for providing us with the apoptosome inhibitor QM56. This work was supported in part by grants from the Telethon Foundation, Ricerca Corrente and Ricerca Finalizzata from the Italian Ministry of Health, the Italian Ministry of University and Research and Compagnia di San Paolo.

Author information

Author notes

  1. Hélène Marie

    Present address: Present address: Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Université Nice-Sophia Antipolis, Valbonne, France.,

Authors and Affiliations

  1. Dulbecco Telethon Institute at the Laboratory of Molecular Neuroembryology, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy

    Marcello D'Amelio, Virve Cavallucci & Francesco Cecconi

  2. Laboratory of Molecular Neuroscience, University Campus-Biomedico, Rome, Italy

    Marcello D'Amelio

  3. Consiglio Nazionale delle Ricerche (CNR) Institute of Neuroscience, IRCCS Fondazione Santa Lucia, Rome, Italy

    Silvia Middei & Martine Ammassari-Teule

  4. Laboratory of Molecular Mechanisms of Synaptic Plasticity, European Brain Research Institute, Rome, Italy

    Cristina Marchetti & Hélène Marie

  5. Laboratory of Cellular Physiology of Cortical Microcircuits, European Brain Research Institute, Rome, Italy

    Simone Pacioni & Alberto Bacci

  6. Department of Psychobiology and Psychopharmacology, CNR Institute of Neuroscience, Rome, Italy

    Alberto Ferri

  7. Laboratory of Neuroimmunology, IRCCS Fondazione Santa Lucia, Rome, Italy

    Adamo Diamantini & Luca Battistini

  8. Department of Biology, University of Rome 'Tor Vergata', Rome, Italy

    Daniela De Zio & Francesco Cecconi

  9. Department of Biology-Interdepartmental Laboratory of Electron Microscopy (LIME), University Roma Tre, Rome, Italy

    Paolo Carrara & Sandra Moreno

Authors
  1. Marcello D'Amelio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Virve Cavallucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvia Middei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cristina Marchetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Simone Pacioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alberto Ferri
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Adamo Diamantini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Daniela De Zio
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Paolo Carrara
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Luca Battistini
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sandra Moreno
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Alberto Bacci
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Martine Ammassari-Teule
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hélène Marie
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Francesco Cecconi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.D. and V.C. designed and carried out all of the molecular biology experiments and caspase-3 analysis. V.C. helped write the manuscript. S. Middei and M.A.-T. performed behavioral and dendritic spine analysis. S. Middei performed surgery. A.B. and S.P. performed LTP analysis. H.M. and C.M. performed patch-clamp and LTD experiments. A.F. carried out calcineurin activity assays. S. Moreno and P.C. performed immunoelectron microscopy analysis. L.B. and A.D. performed fluorescence-activated cell-sorting analysis. D.D.Z. analyzed the oxidative stress. M.D. and F.C. conceived and designed the study, supervised all of the experiments and wrote the manuscript. All of the authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Francesco Cecconi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–23 (PDF 2872 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

D'Amelio, M., Cavallucci, V., Middei, S. et al. Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease. Nat Neurosci 14, 69–76 (2011). https://doi.org/10.1038/nn.2709

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2709

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