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.

Calcineurin inhibition rescues early synaptic plasticity deficits in a mouse model of Alzheimer's disease / V., Cavallucci; N., Berretta; A., Nobili; Nistico', ROBERT GIOVANNI; N. B., Mercuri; M., D'Amelio. - In: NEUROMOLECULAR MEDICINE. - ISSN 1535-1084. - 15:(2013), pp. 541-548. [10.1007/s12017-013-8241-2]

Calcineurin inhibition rescues early synaptic plasticity deficits in a mouse model of Alzheimer's disease.

NISTICO', ROBERT GIOVANNI;
2013

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.
2013
Alzheimer Disease; physiopathology/prevention /&/ control, Animals, CA1 Region; Hippocampal; drug effects/metabolism/physiopathology, Calcineurin; antagonists /&/ inhibitors, Caspase 3; metabolism, Dendrites; drug effects/ultrastructure, Disease Models; Animal, Drug Evaluation; Preclinical, Excitatory Postsynaptic Potentials; drug effects, Guanylate Kinase; biosynthesis/genetics, Long-Term Synaptic Depression; drug effects, Male, Membrane Proteins; biosynthesis/genetics, Methoxyhydroxyphenylglycol; analogs /&/ derivatives/pharmacology, Mice, Mice; Transgenic, Neuroprotective Agents; pharmacology/therapeutic use, Phosphorylation; drug effects, Phosphoserine; metabolism, Post-Synaptic Density; drug effects, Protein Processing; Post-Translational; drug effects, Receptors; AMPA; metabolism, Receptors; Metabotropic Glutamate; agonists, Tacrolimus; pharmacology/therapeutic use
01 Pubblicazione su rivista::01a Articolo in rivista
Calcineurin inhibition rescues early synaptic plasticity deficits in a mouse model of Alzheimer's disease / V., Cavallucci; N., Berretta; A., Nobili; Nistico', ROBERT GIOVANNI; N. B., Mercuri; M., D'Amelio. - In: NEUROMOLECULAR MEDICINE. - ISSN 1535-1084. - 15:(2013), pp. 541-548. [10.1007/s12017-013-8241-2]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/625127
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