Abstract
Caspases play critical roles in Alzheimer’s disease (AD) pathogenesis. Here we show that caspase-2 is required for the cognitive decline seen in hAPP transgenic mice (J20). The age-related changes in behavior and dendritic spine density observed in these mice are absent when they lack caspase-2, in spite of similar levels of 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 signaling 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 AD and offer novel therapeutic targets.
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