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

Julio Pozueta, Roger Lefort, Elena M. Ribe, Carol M. Troy, Ottavio Arancio and Michael Shelanski ()
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Julio Pozueta: Columbia University
Roger Lefort: Columbia University
Elena M. Ribe: Columbia University
Carol M. Troy: Columbia University
Ottavio Arancio: Columbia University
Michael Shelanski: Columbia University

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2927

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