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Background  Mutations in either  Aβ Precursor protein  ( APP ) or genes that regulate APP processing, such as  BRI2/ITM2B and PSEN1 / PSEN2 , cause familial dementias. Although dementias due to  APP / PSEN1 / PSEN2  mutations are classified as familial Alzheimer disease (FAD) and those due to mutations in  BRI2/ITM2B  as British and Danish dementias (FBD, FDD), data suggest that these diseases have a common pathogenesis involving toxic APP metabolites. It was previously shown that FAD mutations in  APP  and  PSENs  promote activation of caspases leading to the hypothesis that aberrant caspase activation could participate in AD pathogenesis.    Results  Here, we tested whether a similar mechanism applies to the Danish  BRI2/ITM2B  mutation. We have generated a genetically congruous mouse model of FDD, called FDD KI , which presents memory and synaptic plasticity deficits. We found that caspase-9 is activated in hippocampal synaptic fractions of FDD KI  mice and inhibition of caspase-9 activity rescues both synaptic plasticity and memory deficits.    Conclusion  These data directly implicate caspase-9 in the pathogenesis of Danish dementia and suggest that reducing caspase-9 activity is a valid therapeutic approach to treating human dementias.

Caspase-9 mediates synaptic plasticity and memory deficits of Danish dementia knock-in mice: caspase-9 inhibition provides therapeutic protection