TY - JOUR
T1 - Caspase-9 mediates synaptic plasticity and memory deficits of Danish dementia knock-in mice
T2 - Caspase-9 inhibition provides therapeutic protection
AU - Tamayev, Robert
AU - Akpan, Nsikan
AU - Arancio, Ottavio
AU - Troy, Carol M.
AU - D'Adamio, Luciano
N1 - Funding Information:
We thank Dr. Guy S. Salvesen, for providing the XBIR3 recombinant protein. This work was supported by grants from the Alzheimer’s Association (IIRG-09-129984 and ZEN-11-201425), the Edward N and Della L. Thome Memorial Foundation grant and the National Institutes of Health (NIH; AG033007, AG041577 and AG041531) to LD and (NIH; R01NS049442) to OA.
PY - 2012
Y1 - 2012
N2 - 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§ssub§KI§esub§, which presents memory and synaptic plasticity deficits. We found that caspase-9 is activated in hippocampal synaptic fractions of FDD§ssub§KI§esub§ 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.
AB - 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§ssub§KI§esub§, which presents memory and synaptic plasticity deficits. We found that caspase-9 is activated in hippocampal synaptic fractions of FDD§ssub§KI§esub§ 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.
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U2 - 10.1186/1750-1326-7-60
DO - 10.1186/1750-1326-7-60
M3 - Article
C2 - 23217200
AN - SCOPUS:84872324395
SN - 1750-1326
VL - 7
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
IS - 1
M1 - 60
ER -