Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice

Nat Commun. 2013;4:1939. doi: 10.1038/ncomms2927.

Abstract

Caspases have critical roles in Alzheimer's disease pathogenesis. Here we show that caspase-2 is required for the cognitive decline seen in human amyloid precursor protein transgenic mice (J20). The age-related changes in behaviour and dendritic spine density observed in these mice are absent when they lack caspase-2, in spite of similar levels of amyloid beta (Aβ) deposition and inflammation. A similar degree of protection is observed in cultured hippocampal neurons lacking caspase-2, which are immune to the synaptotoxic effects of Aβ. Our studies suggest that caspase-2 is a critical mediator in the activation of the RhoA/ROCK-II signalling pathway, leading to the collapse of dendritic spines. We propose that this is controlled by an inactive caspase-2/RhoA/ROCK-II complex localized in dendrites, which dissociates in the presence of Aβ, allowing for their activation and entry in the spine. These findings directly implicate caspase-2 as key driver of synaptic dysfunction in Alzheimer's disease and offer novel therapeutic targets.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Protein Precursor / metabolism*
  • Amyloid beta-Protein Precursor / toxicity
  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Behavior, Animal / physiology*
  • Blotting, Western
  • Caspase 2 / deficiency
  • Caspase 2 / metabolism*
  • Cells, Cultured
  • Dendritic Spines / drug effects
  • Dendritic Spines / enzymology*
  • Dendritic Spines / pathology
  • Down-Regulation / drug effects
  • Enzyme Activation / drug effects
  • Hippocampus / pathology
  • Humans
  • Immunoprecipitation
  • Memory Disorders / enzymology
  • Memory Disorders / pathology
  • Mice
  • Mice, Transgenic
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Protein Transport / drug effects
  • Rats
  • Synapses / drug effects
  • Synapses / metabolism
  • Synapses / pathology
  • rho-Associated Kinases / metabolism
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • rho-Associated Kinases
  • Casp2 protein, mouse
  • Caspase 2
  • rhoA GTP-Binding Protein