Abstract
Functional and ultrastructural investigations support the concept that altered brain connectivity, exhausted neural plasticity, and synaptic loss are the strongest correlates of cognitive decline in age-related neurodegenerative dementia of Alzheimer’s type. We have previously demonstrated that in transgenic mice, expressing amyloid-β precursor protein-Swedish mutation active caspase-3 accumulates in hippocampal postsynaptic compartments leading to altered postsynaptic density (PSD) composition, increased long-term depression (LTD), and dendritic spine loss. Furthermore, we found strong evidence that dendritic spine alteration is mediated by calcineurin activation, a calcium-dependent phosphatase involved in synapse signaling. In the present work, we analyzed the molecular mechanism linking alteration of synaptic plasticity to the increase of calcineurin activity. We found that acute treatment of young and plaque-free transgenic mice with the calcineurin inhibitor FK506 leads to a complete rescue of LTD and PSD composition. Our findings are in agreement with other results reporting that calcineurin inhibition improves memory function and restores dendritic spine density, confirming that calcineurin inhibition may be explored as a neuroprotective treatment to stop or slowdown synaptic alterations in Alzheimer’s disease.
Similar content being viewed by others
References
Balducci, C., Mehdawy, B., Mare, L., Giuliani, A., Lorenzini, L., Sivilia, S., et al. (2011). The γ-secretase modulator CHF5074 restores memory and hippocampal synaptic plasticity in plaque-free Tg2576 mice. Journal of Alzheimers Disease, 24, 799–816.
Cavallucci, V., D’Amelio, M., & Cecconi, F. (2012). Aβ toxicity in Alzheimer’s disease. Molecular Neurobiology, 45, 366–378.
Cimini, A., Moreno, S., D’Amelio, M., Cristiano, L., D’Angelo, B., Falone, S., et al. (2009). Early biochemical and morphological modifications in the brain of a transgenic mouse model of Alzheimer’s disease: A role for peroxisomes. Journal of Alzheimers Disease, 18, 935–952.
D’Amelio, M., Cavallucci, V., Middei, S., Marchetti, C., Pacioni, S., Ferri, A., et al. (2011). Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer’s disease. Nature Neuroscience, 14, 69–76.
D’Amelio, M., & Rossini, P. M. (2012). Brain excitability and connectivity of neuronal assemblies in Alzheimer’s disease: From animal models to human findings. Progress in Neurobiology, 99, 42–60.
D’Amelio, M., Sheng, M., & Cecconi, F. (2012). Caspase-3 in the central nervous system: Beyond apoptosis. Trends in Neurosciences, 35, 700–709.
de Calignon, A., Fox, L. M., Pitstick, R., Carlson, G. A., Bacskai, B. J., Spires-Jones, T. L., et al. (2010). Caspase activation precedes and leads to tangles. Nature, 464, 1201–1204.
de Calignon, A., Polydoro, M., Suárez-Calvet, M., William, C., Adamowicz, D. H., Kopeikina, K. J., et al. (2012). Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron, 73, 685–697.
Dineley, K. T., Hogan, D., Zhang, W. R., & Taglialatela, G. (2007). Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice. Neurobiology of Learning and Memory, 88, 217–224.
Dineley, K. T., Kayed, R., Neugebauer, V., Fu, Y., Zhang, W., Reese, L. C., et al. (2010). Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice. Journal of Neuroscience Research, 88, 2923–2932.
Esteban, J. A., Shi, S. H., Wilson, C., Nuriya, M., Huganir, R. L., & Malinow, R. (2003). PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nature Neuroscience, 6, 136–143.
Gladding, C. M., Collett, V. J., Jia, Z., Bashir, Z. I., Collingridge, G. L., & Molnár, E. (2009). Tyrosine dephosphorylation regulates AMPAR internalisation in mGluR-LTD. Molecular and Cellular Neuroscience, 40, 267–279.
He, K., Song, L., Cummings, L. W., Goldman, J., Huganir, R. L., & Lee, H. K. (2009). Stabilization of Ca2 + -permeable AMPA receptors at perisynaptic sites by GluR1-S845 phosphorylation. Proceedings of the National Academy of Sciences of the United States of America, 106, 20033–20038.
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., et al. (1996). Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science, 274, 99–102.
Lee, S. H., Kim, B. C., Yang, D. H., Park, M. S., Choi, S. M., Kim, M. K., et al. (2008). Calcineurin inhibitor-mediated bilateral hippocampal injury after bone marrow transplantation. Journal of Neurology, 255, 929–931.
Li, Z., Jo, J., Jia, J. M., Lo, S. C., Whitcomb, D. J., Jiao, S., et al. (2010). Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell, 141, 859–871.
Middei, S., Houeland, G., Cavallucci, V., Ammassari-Teule, M., D’Amelio, M., & Marie, H. (2013). CREB is necessary for synaptic maintenance and learning-induced changes of the AMPA receptor GluA1 subunit. Hippocampus, 23, 488–499.
Moult, P. R., Gladding, C. M., Sanderson, T. M., Fitzjohn, S. M., Bashir, Z. I., Molnár, E., et al. (2006). Tyrosine phosphatases regulate AMPA receptor trafficking during metabotropic glutamate receptor-mediated long-term depression. Journal of Neuroscience, 26, 2544–2554.
Mukerjee, N., McGinnis, K. M., Park, Y. H., Gnegy, M. E., & Wang, K. K. (2000). Caspase-mediated proteolytic activation of calcineurin in thapsigargin-mediated apoptosis in SH-SY5Y neuroblastoma cells. Archives of Biochemistry and Biophysics, 379, 337–343.
Nisticò, R., Cavallucci, V., Piccinin, S., Macrì, S., Pignatelli, M., Mehdawy, B., et al. (2012a). Insulin receptor β-subunit haploinsufficiency impairs hippocampal late-phase LTP and recognition memory. NeuroMolecular Medicine, 14, 262–269.
Nisticò, R., Pignatelli, M., Piccinin, S., Mercuri, N. B., & Collingridge, G. (2012b). Targeting synaptic dysfunction in Alzheimer’s disease therapy. Molecular Neurobiology, 46, 572–587.
Rozkalne, A., Hyman, B. T., & Spires-Jones, T. L. (2011). Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice. Neurobiology of Disease, 41, 650–654.
Schreiber, S. L., & Crabtree, G. R. (1992). The mechanism of action of cyclosporin A and FK506. Immunology Today, 13, 136–142.
Wijdicks, E. F., Wiesner, R. H., Dahlke, L. J., & Krom, R. A. (1994). FK506-induced neurotoxicity in liver transplantation. Annals of Neurology, 35, 498–501.
Wu, H. Y., Hudry, E., Hashimoto, T., Kuchibhotla, K., Rozkalne, A., Fan, Z., et al. (2010). Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. Journal of Neuroscience, 30, 2636–2649.
Acknowledgments
MDA is financially supported by a grant from the Alzheimer’s Association (NIRG-11-204588). We thank Cecilia Giusti for technical support. Tg2576 mice used in the present study were kindly provided by Prof. Francesco Cecconi.
Conflict of interest
The authors declare that they have no competing interests.
Author information
Authors and Affiliations
Corresponding author
Additional information
Virve Cavallucci and Nicola Berretta contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
12017_2013_8241_MOESM1_ESM.eps
Supplementary Fig. S1 a Immunoblot analysis of GluA1, PSD-95, synaptophysin, and Rab11 demonstrating the purity of the synaptic fractionation. Representative immunoblots of the PSD-enriched fraction (TxP) and of the microsomal-enriched fraction (P3) are shown. b PSD (TxP) and microsome-enriched protein (P3) preparations (9 μg protein) from wild-type (WT) and Tg2576 (Tg) mice injected with saline (Ctrl) or calcineurin inhibitor FK506 were separated by SDS-PAGE and stained with Coomassie Brilliant Blue. No major differences are seen at this level of resolution. (EPS 2896 kb)
Rights and permissions
About this article
Cite this article
Cavallucci, V., Berretta, N., Nobili, A. et al. Calcineurin Inhibition Rescues Early Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease. Neuromol Med 15, 541–548 (2013). https://doi.org/10.1007/s12017-013-8241-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12017-013-8241-2