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Nat Neurosci. 2011 Jan;14(1):69-76. doi: 10.1038/nn.2709. Epub 2010 Dec 12.

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

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Dulbecco Telethon Institute at the Laboratory of Molecular Neuroembryology, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy.


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.

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