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.
|Titolo:||Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease|
|Data di pubblicazione:||2011|
|Citazione:||D’Amelio, M., Cavallucci, V., Middei, S., Pacioni, S., Marchetti, C., Ferri, A., et al. (2011). Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease. NATURE NEUROSCIENCE, 14, 69-76.|
|Appare nelle tipologie:||1.1 Articolo in rivista|