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Calcineurin Inhibition Rescues Early Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease

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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.

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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.

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Correspondence to Marcello D’Amelio.

Additional information

Virve Cavallucci and Nicola Berretta contributed equally to this work.

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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)

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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

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  • DOI: https://doi.org/10.1007/s12017-013-8241-2

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