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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism*
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Alzheimer Disease / pathology
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Alzheimer Disease / physiopathology
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Animals
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Calcineurin / metabolism
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Caspase 3 / metabolism*
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Caspase Inhibitors
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Dendritic Spines / metabolism
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Dendritic Spines / pathology
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Dipeptides / pharmacology
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Disease Models, Animal
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Hippocampus / metabolism
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Hippocampus / physiopathology
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Long-Term Synaptic Depression / physiology*
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Memory Disorders / genetics
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Memory Disorders / physiopathology
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Mice
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Mice, Transgenic
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Nerve Degeneration / pathology
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Nerve Degeneration / physiopathology
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Oligopeptides / pharmacology
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Polyglutamic Acid / pharmacology
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Receptors, AMPA / metabolism
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Synaptic Transmission / physiology*
Substances
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Caspase Inhibitors
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Dipeptides
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N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
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Oligopeptides
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Receptors, AMPA
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benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
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Polyglutamic Acid
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Calcineurin
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Casp3 protein, mouse
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Caspase 3
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glutamate receptor ionotropic, AMPA 1