title: Caspase-9 mediates synaptic plasticity and memory deficits of Danish dementia knock-in mice: caspase-9 inhibition provides therapeutic protection.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Tamayev
authors.forename: Nsikan
authors.initials: N
authors.lastname: Akpan
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.forename: Carol M
authors.initials: CM
authors.lastname: Troy
authors.forename: Luciano
authors.initials: L
authors.lastname: D'Adamio
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D053453:Caspase 9 / Q000378:metabolism*; D002386:Cataract / Q000201:enzymology* / Q000235:genetics; D002524:Cerebellar Ataxia / Q000201:enzymology* / Q000235:genetics; D003638:Deafness / Q000201:enzymology* / Q000235:genetics; D003704:Dementia / Q000201:enzymology* / Q000235:genetics; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D055879:Gene Knock-In Techniques; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques
chemical_list: D004791:Enzyme Inhibitors; D053453:Caspase 9