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

Marcello D'Amelio, Virve Cavallucci, Silvia Middei, Cristina Marchetti, Simone Pacioni, Alberto Ferri, Adamo Diamantini, Daniela De Zio, Paolo Carrara, Luca Battistini, Sandra Moreno, Alberto Bacci, Martine Ammassari-Teule, Hélène Marie, Francesco Cecconi

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)69-79
Number of pages11
JournalNature Neuroscience
Issue number1
Publication statusPublished - Jan 2011

ASJC Scopus subject areas

  • Neuroscience(all)


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