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

Author

Listed:
  • Julio Pozueta

    (Columbia University
    New York)

  • Roger Lefort

    (Columbia University
    New York)

  • Elena M. Ribe

    (Columbia University
    New York
    Present address: Division of Psychological Medicine and Old Age Psychiatry, Institute of Psychiatry, King’s College London, London SE5 8AF, UK)

  • Carol M. Troy

    (Columbia University
    New York)

  • Ottavio Arancio

    (Columbia University
    New York)

  • Michael Shelanski

    (Columbia University
    New York)

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.

Suggested Citation

  • Julio Pozueta & Roger Lefort & Elena M. Ribe & Carol M. Troy & Ottavio Arancio & Michael Shelanski, 2013. "Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice," Nature Communications, Nature, vol. 4(1), pages 1-12, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2927
    DOI: 10.1038/ncomms2927
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