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

Nat Neurosci. 2011 Jan;14(1):69-76. doi: 10.1038/nn.2709. Epub 2010 Dec 12.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Alzheimer Disease / physiopathology
  • Animals
  • Calcineurin / metabolism
  • Caspase 3 / metabolism*
  • Caspase Inhibitors
  • Dendritic Spines / metabolism
  • Dendritic Spines / pathology
  • Dipeptides / pharmacology
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Long-Term Synaptic Depression / physiology*
  • Memory Disorders / genetics
  • Memory Disorders / physiopathology
  • Mice
  • Mice, Transgenic
  • Nerve Degeneration / pathology
  • Nerve Degeneration / physiopathology
  • Oligopeptides / pharmacology
  • Polyglutamic Acid / pharmacology
  • Receptors, AMPA / metabolism
  • Synaptic Transmission / physiology*


  • Caspase Inhibitors
  • Dipeptides
  • N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
  • Oligopeptides
  • Receptors, AMPA
  • benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
  • Polyglutamic Acid
  • Calcineurin
  • Casp3 protein, mouse
  • Caspase 3
  • glutamate receptor ionotropic, AMPA 1