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

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.

Tuning of Glutamate, But Not GABA, Release by an Intrasynaptic Vesicle APP Domain Whose Function Can Be Modulated by β- or α-Secretase Cleavage

“…Thus, APP may contain an ISVAID (Ex/TM) as well as a "cytosolic SV-interacting domain" (JCasp), suggesting a presynaptic role of APP in SV function. The functional significance of SV-APP C-terminal interactions was investigated using the peptide JCasp linked to the cellpenetrating peptide Penetratin1 (Pen1) (Tamayev et al, 2012a). Pen1-JCasp, which is delivered inside neurons at hippocampal SC-CA3ϾCA1 synapses (Fanutza et al, 2015), reduced the release probability (Pr) of glutamatergic SV.…”

Design, Synthesis, and Optimization of Novel Epoxide Incorporating Peptidomimetics as Selective Calpain Inhibitors

“…Many other cysteine proteases, including pro-apoptotic caspases have frequently been proposed as targets for inhibition in AD, dementia, and neurodegenerative disorders. 47, 48 Notably, CathB has variously been proposed as a drug target for inhibition in AD therapy. 49, 5051 The introduction of P2 histidine into epoxusuccinate Cal1 inhibitors by Cuerrier et al led to selectivity for Cal1 over Cal2, and cathepsins, including CathB.…”

“…Diversity was achieved by developing a divergent synthetic route leading to 36 . Increased selectivity for Cal1 was an objective of this study, however, several cysteine proteases, including caspases and Cath B have been proposed as targets for AD, dementia, and neurodegenerative disorders, 47-51 and would not be appropriate counter screens predictive of adverse effects, therefore papain was used as a counter screen for selectivity. Retention of the electrophilic epoxide in the present work was deemed as important for the preparation of a Cal1 inhibitor ( 32 ) that could be used in future as an ABPP chemical probe for identification of on-target and off-target proteins to aid in further refinement of both drug targets and drug optimization.…”

An Intracellular Threonine of Amyloid-β Precursor Protein Mediates Synaptic Plasticity Deficits and Memory Loss

“…Inhibition of γ-secretase, the enzyme that processes β-CTF to yield Aß, worsens memory deficits and is associated with an accumulation of ß-CTF [10], [16], [17]. In addition, caspase-9 in activated in FDD KI mice and caspase-9 activity mediates memory/synaptic plasticity deficits [18]. Overall, these results suggest that ß-CTF, rather than Aß, is a major toxic species causing dementia.…”