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

Robert Tamayev,Carol M Troy,Luciano D’Adamio,Ottavio Arancio,Nsikan Akpan

doi:10.1186/1750-1326-7-60

Robert Tamayev, Carol M Troy + Show 3 more

Open Access

https://doi.org/10.1186/1750-1326-7-60

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Abstract

BackgroundMutations 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.ResultsHere, we tested whether a similar mechanism applies to the Danish BRI2/ITM2B mutation. We have generated a genetically congruous mouse model of FDD, called FDDKI, which presents memory and synaptic plasticity deficits. We found that caspase-9 is activated in hippocampal synaptic fractions of FDDKI mice and inhibition of caspase-9 activity rescues both synaptic plasticity and memory deficits.ConclusionThese 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.

Highlights

Mutations in either Aβ Precursor protein (APP) or genes that regulate APP processing, such as BRI2/ ITM2B and PSEN1/PSEN2, cause familial dementias
The prevailing pathogenic model for dementias caused by mutations in APP and genes that regulate APP processing (PSEN1, PSEN2 and BRI2/ITM2b) posits that amyloid peptides trigger dementia
In AD, the amyloid peptide is Aβ that derives from APP processing. βcleavage of APP, which is inhibited by BRI2, yields amino-terminal-soluble APPβ and β-carboxylterminal fragments (β-CTF)

Summary

Introduction

Mutations in either Aβ Precursor protein (APP) or genes that regulate APP processing, such as BRI2/ ITM2B and PSEN1/PSEN2, cause familial dementias. Owing to the loss of BRI2, processing of APP is increased in FDD [4,5], and sAPPβ/β-CTF, but not Aβ, trigger memory and synaptic deficits of FDDKI mice [4,6,7] These observations are consistent with the recent findings that β-processing of APP, but not Aβ, triggers pathological modifications associated with AD in human neurons derived from both familial and sporadic AD cases [8] and that a mutation in APP that reduces the BACE1 cleavage of APP protect elderly individual from sporadic AD and normal memory loss associated with ageing [9]. These similarities suggest that FDD shares common pathogenic mechanisms with FAD, involving synaptic-toxic APP metabolites distinct from Aβ

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