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

• Published in: Nature neuroscience Vol. 14; no. 1; pp. 69 - 76
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2011; Nature Publishing Group
• Subjects: 631/378/1689/364; 631/378/2591; 631/378/548; 692/699/375/365/1283; Age; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer's disease; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain research; Calcineurin - metabolism; Caspase 3 - metabolism; Caspase Inhibitors; Dendritic Spines - metabolism; Dendritic Spines - pathology; Development and progression; Dipeptides - pharmacology; Disease Models, Animal; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Hippocampus - metabolism; Hippocampus - physiopathology; Long-Term Synaptic Depression - physiology; Memory; Memory Disorders - genetics; Memory Disorders - physiopathology; Mice; Mice, Transgenic; Nerve Degeneration - pathology; Nerve Degeneration - physiopathology; Neural transmission; Neurobiology; Neurons; Neurosciences; Oligopeptides - pharmacology; Physiological aspects; Polyglutamic Acid - pharmacology; Proteases; Receptors, AMPA - metabolism; Synaptic Transmission - physiology; Italy; Rome Italy; molecular biology; Signal Transduction; cell death; Neurodegeneration; Synaptic Transmission; Plasticity
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/nn.2709

In a mouse model of Alzheimer's disease, the authors find that early loss of AMPA receptors at synapses at onset of cognitive dysfunction is a result of activation of the phosphatase calcineurin by caspase-3. Inhibition of caspase activity rescued both synapse density and fear memory in this model. 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.