title: Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease.
abstract: 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.
authors.affiliation: Dulbecco Telethon Institute at the Laboratory of Molecular Neuroembryology, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: D'Amelio
authors.forename: Virve
authors.initials: V
authors.lastname: Cavallucci
authors.forename: Silvia
authors.initials: S
authors.lastname: Middei
authors.forename: Cristina
authors.initials: C
authors.lastname: Marchetti
authors.forename: Simone
authors.initials: S
authors.lastname: Pacioni
authors.forename: Alberto
authors.initials: A
authors.lastname: Ferri
authors.forename: Adamo
authors.initials: A
authors.lastname: Diamantini
authors.forename: Daniela
authors.initials: D
authors.lastname: De Zio
authors.forename: Paolo
authors.initials: P
authors.lastname: Carrara
authors.forename: Luca
authors.initials: L
authors.lastname: Battistini
authors.forename: Sandra
authors.initials: S
authors.lastname: Moreno
authors.forename: Alberto
authors.initials: A
authors.lastname: Bacci
authors.forename: Martine
authors.initials: M
authors.lastname: Ammassari-Teule
authors.forename: Hélène
authors.initials: H
authors.lastname: Marie
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology; D009842:Oligopeptides / Q000494:pharmacology; D011099:Polyglutamic Acid / Q000494:pharmacology; D018091:Receptors, AMPA / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D019703:Calcineurin; D053148:Caspase 3; D061945:Caspase Inhibitors; D004151:Dipeptides; D009842:Oligopeptides; D011099:Polyglutamic Acid; D018091:Receptors, AMPA; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C505409:Casp3 protein, mouse