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

Pozueta et al. NATURE COMMUNICATIONS | 4:1939 | DOI: 10.1038/ncomms2927 (Impact Factor 14.7)

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 (Ab) 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 Ab. 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 Ab, 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.

Julio Pozueta1,*, Roger Lefort1,*, Elena M. Ribe1,w, Carol M. Troy1, Ottavio Arancio1 & Michael Shelanski1

1 Department of Pathology and Cell Biology and The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain v, Columbia University, New York, New York 10032, USA. * These authors contributed equally to this work. w Present address: Division of Psychological Medicine and Old Age Psychiatry,

Institute of Psychiatry, King’s College London, London SE5 8AF, UK

NATURE COMMUNICATIONS | 4:1939 | DOI: 10.1038/ncomms2927