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Article Dans Une Revue Nature Neuroscience Année : 2010

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

Résumé

Synaptic loss is the best pathological correlate of the cognitive decline in Alzheimer's Disease; yet, the molecular mechanisms underlying synaptic failure are unknown. Here we report 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. We show that, in spines, caspase-3 activates calcineurin which, in turn, triggers dephosphorylation and removal of the GluR1 subunit of AMPA-type receptor from post-synaptic sites. These molecular modifications lead to alterations of glutamatergic synaptic transmission and plasticity, and correlate with spine degeneration and a deficit in hippocampal-dependent memory. Importantly, pharmacological inhibition of caspase-3 activity in Tg2576 mice rescues the observed Alzheimer-like phenotypes. Therefore, we identify a novel caspase-3-dependent mechanism driving synaptic failure and contributing to cognitive dysfunction in Alzheimer's Disease. These findings point to caspase-3 as possible avenues for pharmacological therapy during early disease stages.
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Dates et versions

hal-00599967 , version 1 (12-06-2011)

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Marcello d'Amelio, Virve Cavallucci, Silvia Middei, Cristina Marchetti, Simone Pacioni, et al.. Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's Disease. Nature Neuroscience, 2010, ⟨10.1038/nn.2709⟩. ⟨hal-00599967⟩
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