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

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

doi:10.1038/nn.2709

Cited by 572Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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D'Amelio, Marcello, Cavallucci, Virve, Middei, Silvia, Marchetti, Cristina, Pacioni, Simone, Ferri, Alberto, Diamantini, Adamo, De Zio, Daniela +7 more·2011·Nature Neuroscience

DOI 10.1038/nn.2709

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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.

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Surface expression of the AMPAR GluA1 subunit is down-regulated in the hippocampal PSD fraction of 6-month-old Tg2576 mice.
“Consistent with our previous observations in 3-month-old animals25, the surface expression of the AMPAR GluA1 subunit was down-regulated in 6-month-old Tg2576 mice (Fig. 4i, Supplementary Figs 3d,e and 6c).”
From Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease (2017) · cites this paper as [25]

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Authors: D'Amelio, M., Cavallucci, V., Middei, S., Marchetti, C., Pacioni, S., Ferri, A., Diamantini, A., De Zio, D., Carrara, P., Battistini, L., Moreno, S., Bacci, A., Ammassari-Teule, M., Marie, H., & Cecconi, F.
Affiliations: Dulbecco Telethon Institute (IT)
Fondazione Santa Lucia (IT)
European Brain Research Institute (IT)
Roma Tre University (IT)
University of Rome Tor Vergata (IT)
Corresponding author: Cecconi, Francesco
ORCID: Cavallucci, Virve
Middei, Silvia
Marchetti, Cristina
Pacioni, Simone
Ferri, Alberto
Battistini, Luca
Moreno, Sandra
Bacci, Alberto
Marie, Hélène
Cecconi, Francesco
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2010-12-12
Volume: 14
Issue: 1
Pages: 69-76
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/nn.2709
OpenAlex: W2130473558
Cited by: 572
References: 52
Citations by year: 2026: 14 · 2025: 25 · 2024: 21 · 2023: 38 · 2022: 39 · 2021: 43 · 2020: 38 · 2019: 27 · 2018: 45 · 2017: 32 · 2016: 35 · 2015: 36 · 2014: 48 · 2013: 56 · 2012: 35
FWCI: 28.38
Type: journal article
Language: en
Open access: green
hal.science
Licence: other-oa
www.springer.com/tdm (tdm)
Locations: Nature Neuroscience (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion, other-oa)
Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
Iris (Roma Tre University) (submittedVersion)
Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: caspase-3, Alzheimer's disease, synaptic dysfunction, AMPA receptors, calcineurin, dendritic spines, hippocampus, fear memory, glutamatergic neurotransmission, synaptic plasticity, cognitive decline, caspase-3 inhibition
MeSH terms: Alzheimer Disease, Animals, Dipeptides, Disease Models, Animal, Gene Expression Regulation, Hippocampus, Memory Disorders, Mice, Transgenic, Nerve Degeneration, Synaptic Transmission, Oligopeptides, Polyglutamic Acid, Receptors, AMPA, Calcineurin, Long-Term Synaptic Depression, Dendritic Spines, Mice, Caspase 3, Caspase Inhibitors

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

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