Journal
NATURE COMMUNICATIONS
Volume 4, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms2927
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Funding
- Wallace Foundation for Research
- Taub Foundation
- [NIHAG08702]
- [NS15076]
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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 (A beta) 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 A beta. 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 A beta, 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.
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