Caspase-9 mediates synaptic plasticity and memory deficits of Danish dementia knock-in mice: caspase-9 inhibition provides therapeutic protection
- Robert Tamayev†1,
- Nsikan Akpan2,
- Ottavio Arancio2, 4,
- Carol M Troy2, 3, 4 and
- Luciano D’Adamio†1Email author
© Tamayev et al.; licensee BioMed Central Ltd. 2012
Received: 15 October 2012
Accepted: 5 December 2012
Published: 10 December 2012
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.
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 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.
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.
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. β-cleavage of APP, which is inhibited by BRI2, yields amino-terminal-soluble APPβ (sAPPβ) and β-carboxyl-terminal fragments (β-CTF). Processing of β-CTF by the γ-secretase complex, of which PSEN1 and PSEN2 constitute the catalytic components, releases Aβ. In FDD and FBD the amyloidogenic peptides, called ADan and ABri respectively, are generated from the mutant BRI2 proteins.
To model FDD we generated FDDKI mice that, like FDD patients , carry a wild type Bri2/Itm2b allele and a Danish mutated allele . FDDKI mice develop progressive synaptic and memory deficits due to loss of BRI2 protein . 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  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 . These similarities suggest that FDD shares common pathogenic mechanisms with FAD, involving synaptic-toxic APP metabolites distinct from Aβ.
We and others have shown that FAD mutations in APP and PSENs could promote activation of caspases [10–14]. These observations suggested that activation of caspases could play a pathogenic role in AD. In the ensuing years, a vast literature has linked Aβ to caspase activation, especially caspase-3, but a functional link has not been proven . However, other reports have indicated that APP metabolites derived either from sAPPβ or the intracellular portion of β-CTF, and distinct from Aβ, also can promote activation of caspases [16–19]. Most caspases are mainly involved in the orchestration of the controlled demise of a cell after an apoptotic signal. These caspases are divided into those that initiate the apoptotic cascade (caspase-2, -8, -9 and −10, “initiator” caspases) and those that that execute apoptosis (caspase-3, -6, and −7, “effector” caspases). Initiator caspases are usually activated by dimerization, while effector caspases are activated by cleavage by initiator caspases . Several recent observations show that apoptotic caspases also regulate other pathways including synaptic plasticity . Based on these observations we tested whether caspases take part in the pathogenesis of memory loss and synaptic plasticity deficits of FDDKI mice.
The caspase inhibitors Z-VAD-fmk and Z-LEHD-fmk, but not Z-DEVD-fmk, rescue the synaptic plasticity deficits of FDDKImice
Most caspases are expressed in the hippocampus. To start dissecting which caspase(s) play(s) a role in LTP deficits in FDDKI mice, we analyzed the effect of Z-LEHD-fmk and Z-DEVD-fmk, which have partially overlapping inhibitory patterns of caspases inhibition. As shown in Figure 1, Z-LEHD-fmk behaved similarly to Z-VAD-fmk (i.e. it fully rescued the LTP deficit of FDDKI mice, without imposing on normal synaptic plasticity). In contrast, LTP Z-DEVD-fmk delayed, but did not rescue, the insurgence of LTP deficits in FDDKI mice (Figure 1). The evidence indicates that some, but perhaps not any, caspases are involved in the pathogenesis of LTP deficits of FDDKI mice.
The caspase inhibitor Z-LEHD-fmk, but not Z-DEVD-fmk, rescues the object recognition deficits of FDDKImice
The initiator caspase-9 is active in FDDKImice hippocampal synaptic fractions
To determine whether active caspase-9 was present in synaptic fractions, we repeated the experiment and performed bVAD pull-downs from synaptosomal fractions. As shown in Figure 3B, active caspase-9 was also isolated from synaptosomal fractions of FDDKI but not WT mice. Blotting for caspase-3, -6 and −8 showed once more absence of detectable active caspase-3, -6 or −8 in these synaptosomal preparations (data not shown). To formally exclude that the differences between WT and FDDKI mice illustrated above did not depend on disparity of bVAD delivery in vivo, we prepared organotypic hippocampal cultures from 5 month-old WT and FDDKI mice. BVAD trapped significantly more active caspase-9 from organotypic hippocampal culture of FDDKI mice than WT littermates (Figure 3C). Once again, we could not detect active FL-caspase-8, cl.-caspase-3 and cl.-caspase-6 neither in WT nor in FDDKI sample. Altogether these data indicate that caspase-9 is excessively activated in Danish dementia mice. Moreover, the data suggest that, if the Danish mutation triggers a cascade of caspase activation, caspase-9 is the apical caspase in such a cascade.
Specific inhibition of caspase-9 with Pen1-XBIR3 provides therapeutic rescue of the object recognition deficit
We have tested whether caspases are involved in the pathogenesis of synaptic plasticity deficits and memory loss in FDDKI mice and have used an unbiased approach to identify caspases that are critical for these pathological processes. Our data show that caspase-9 is a mediator of synaptic plasticity and memory deficits in FDDKI mice. We have used active caspase trapping with bVAD, an irreversible pan-caspase inhibitor. This method provides a reliable measurement of caspase activity through biochemical pull-down of active caspases and has been shown to isolate active caspases-2, -3, -7 -8, or −9 from cell lines , in primary neuron cultures  and in vivo in the CNS . With this method we show that FDDKI mice have high levels of active caspase-9 in hippocampal synaptosomes. This is the first demonstration of a catalytically active initiator caspase in the hippocampus of animal models of familial dementia.
Transgenic mice overexpressing human FAD mutant APP (Tg2576 mice) display an Aβ-dependent enhanced caspase-3 activation, and Z-DEVD-fmk restores cognitive decline in Tg2576 mice . It has also been shown that XBIR2, but not XBIR3, rescues the hippocampal LTP deficits induced in vitro by synthetic Aβ . The BIR2 domain of XIAP inhibits active caspase-3 and caspase-7 . Altogether, these results have lead to the conclusion that caspase-3, but not caspase-9, mediates the inhibition of LTP by synthetic Aβ. This is in contrast with the observations that only caspase-9 is hyperactive in FDDKI mice and that memory deficits of FDDKI mice are rescued by Z-LEHD-fmk and XBIR3 but not Z-DEVD-fmk. Those differences are consistent with the hypothesis that the deficits of FDDKI mice are Aβ-independent. Based on these dissimilarities it could be argued that FDDKI and Tg2576 mice represent dementias caused by distinct pathogenic mechanisms, involving either sAPPβ/β-CTF and caspase-9 or Aβ and caspase-3, respectively. Alternatively, these mice may reproduce distinct stages of a common pathway leading to human dementia. It is also possible that either FDDKI or Tg2576 mice develop synaptic/memory deficits that are triggered by artificial harmful effects unrelated to the pathogenesis of human dementias. In this regard, it is important to emphasize that the mouse model that we have analyzed, unlike transgenic mice, is genetically congruous to the human disease, suggesting that the mechanisms underlying synaptic and memory impairments in FDDKI mice faithfully reproduce the pathogenesis of human dementia.
When aberrant caspase-9 activation is confined to synaptic compartments, it leads to synaptic-memory deficits, as it is the case for FDDKI mice (Figure 5D and E). However, if activation of caspase-9 is recurring and sustained, it may lead to dystrophy of neurites and to the demise of any given neuron in which active caspase-9 leaks into the neuronal cell body triggering effector caspases and leading to genomic DNA fragmentation (Figure 5F). Over time, these changes can result in neuronal loss and neuritic dystrophy that are typical features of advanced neurodegenerative diseases.
Our study suggests that inhibiting caspase-9 activity may be a viable therapeutic option in human dementias. Here, we have used intraventricular administration of Pen1-XBIR3 that provides direct delivery to the brain. In a previous paper we have shown that direct parenchymal or intranasal delivery of Pen1-XBIR3 is therapeutically effective in rat models of stroke . From a therapeutic perspective, intranasal delivery is a very attractive treatment strategy for CNS disorders because it provides direct, noninvasive access to the brain via the olfactory pathway. Intranasal delivery combined with the cell-permeant peptide Pen1 makes Pen1-XBIR3 an attractive therapeutic compound for treatment of human dementias.
Ethical statement regarding the use and well fare of mice
Mice were handled according to the Ethical Guidelines for Treatment of Laboratory Animals of Albert Einstein College of Medicine. The procedures were described and approved in animal protocol number 20100404.
Materials and methods
FDDKI, mice are on a C57BL/6 J background and were generated and maintained at the Animal facility of the Albert Einstein College of Medicine. Mice were handled according to the Ethical Guidelines for Treatment of Laboratory Animals of Albert Einstein College of Medicine. The procedures were described and approved in animal protocol number 200404.
Transverse hippocampal slices (400 μm) from 13–14 month old WT and FDDKI mice were transferred to a recording chamber where they were maintained at 29°C and perfused with artificial cerebrospinal fluid (ACSF) continuously bubbled with 95% O2 and 5% CO2. The ACSF composition in mM was: 124 NaCl, 4.4 KCl, 1 Na2HPO4, 25 NaHCO3, 2 CaCl2, 2 MgSO4, and 10 glucose. CA1 field-excitatory-post-synaptic potentials (fEPSPs) were recorded by placing both the stimulating and the recording electrodes in CA1 stratum radiatum. After 90 minutes incubation, 10 μM Z-VAD-fmk was added. For LTP experiments, a 30 min baseline was recorded every minute at an intensity that evoked a response approximately 35% of the maximum evoked response. LTP was induced using a θ-burst stimulation (four pulses at 100 Hz, with bursts repeated at 5 Hz and each tetanus including one ten-burst train). Responses were recorded for 90 min after tetanization and plotted as percentage of baseline fEPSP slope. Z-VAD-fmk is from R&D Systems.
Brain cannulation and injections
Dr. Xiaosong Li at the Animal Physiology core of the Albert Einstein College of Medicine surgically implanted the cannula. Using stereotaxic surgery performed under ketamine/xylazine anesthesia, mice were implanted with cannula (Plastics One Inc.) into the lateral ventricle (coordinates from bregma: A/P −0.4 mm, M/L − 1 mm, D/V −2.5 mm) or hippocampus (coordinates from bregma: A/P −2.45 mm, M/L − 1.5 mm, D/V −1.7 mm). Z-LEHD-fmk (800 nM), Z-DEVD-fmk (800 nM), or saline were delivered into the lateral ventricle at the rate of 1 μl per minute using a CMA 400 syringe pump, for a total volume of 1 μl. Pen1-XBIR3 (23 μM), Pen1-CrmA (16 μM), or saline were delivered into the lateral ventricle at a rate of 1 μl per minute using a CMA 400 syringe pump, for a total volume of 2 μl. Z-LEHD-fmk and Z-DEVD-fmk are from R&D Systems.
In vivocaspase activity assay
Biotin-Val-Ala-Asp(OMe)-fluoromethylketone (bVAD; MP Biomedicals) was used as an in vivo molecular trap for active caspases. 5 μl of bVAD (100 nmol) was injected into one hippocampus along with a blue dye using a CMA 400 syringe pump at a rate of 1 μl per minute. Mice were sacrificed 2 hrs later, and the region with the blue dye was isolated from the rest of the hippocampus. The same region was collected on the contralateral hippocampus as the untreated/control. These regions were lysed separately in 10% glycerol, 150nM NaCl, 0.2% NP-40, 20 mM Tris–HCl (pH 7.3) with protease and phosphatase inhibitors. For bVAD-caspase complex precipitation, protein lysates were precleared by rocking with Sepharose beads (GE Healthcare) for 1 h at 4°C. Precleared lysate was centrifuged, and the supernatant was transferred to 30 μl of streptavidin-agarose beads (Sigma) and rocked gently overnight at 4°C. Beads were washed/centrifuged (300 μl washes, 5000 rpm for 1 min) 15 times with bVAD lysis buffer. After the final wash/pelleting, caspase-bVAD complexes were boiled off of streptavidin beads into 1× SDS sample buffer without reducing agent. Beads were pelleted at 14,000 rpm for 10 min, and the supernatant was transferred to a fresh tube and resolved by SDS-PAGE.
Organotypic hippocampal slices caspase activity assay
Organotypic hippocampal slices were prepared and cultured as described previously . Briefly, 400 μm slices were prepared using a tissue chopper. Slices were transferred onto a cell culture insert that was placed into a 6-well plate in an incubator with 5% CO2 and 78% O2. The plate contained 1 ml of culture media (MEM with Glutamax-1 supplemented with D-glucose, horse serum, nystatin, HEPES, EBSS, and Pen-Strep). The slices were cultured in the interface method. After 24 h of culture, the media was replaced with culture media containing 45 μM bVAD for 3 h after which the slices were collected and lysed separately in 10% glycerol, 150nM NaCl, 0.2% NP-40, 20 mM Tris–HCl (pH 7.3) with protease and phosphatase inhibitors. bVAD-caspase complex precipitation was performed by preclearing with Sepharose beads and isolation with streptavidin-agarose beads as described in the preceding chapter. After the final wash/pelleting, caspase-bVAD complexes were boiled off of streptavidin beads into 1× SDS sample buffer without reducing agent. Beads were pelleted at 14,000 rpm for 10 min, and the supernatant was transferred to a fresh tube and resolved by SDS-PAGE.
Open field and novel object recognition
The mice were acclimated to the testing room for 30 min after being moved. Each mouse was placed into a 40 cm × 40 cm open field chamber with opaque walls, 2 ft high. Each mouse was allowed to habituate to the normal open field box for 10 min, and repeated again 24 h later, in which we manually recorded the number of entries into and time spent in the center of the locomotor arena. As previously reported , open field studies showed that FDDKI mice have no defects in habituation, sedation, risk assessment and anxiety-like behavior in novel environments.
Novel object recognition began 24 h after the second open field session, and was performed as previously described [3, 33]. Briefly, NOR consisted of two sessions 24 h apart. In the first session, the mice were placed into the open field chamber with two identical, non-toxic objects, 12 cm from the back and sidewalls of the open field box, and 16 cm apart from each other. An 8 min session, in which the time exploring each object was recorded; an area 2 cm2 surrounding the object is defined such that nose entries within 2 cm of the object were recorded as time exploring the object. We will refer to this as training trial. The animal was then returned to its home cage and 24 h late, placed into the open field box again. This time, there was one object identical to the previous one, and one novel object. We will refer to this as the test trial. The mice were given another 6 min to explore, and the amount of time exploring each object was recorded. Mice that spent < 7 seconds exploring the objects were omitted from the analysis . Results were recorded as Time Spent Exploring each object an object discrimination ratio (ODR), which is calculated by dividing the time the mice spent exploring object 1 (for the training trial) or the novel object (for the test trial) by the total amount of time exploring the two objects.
Synaptosome preparation and Western blot analysis
For synaptic preparations, isolated hippocampi were homogenized (w/v = 10 mg tissue/100 ml buffer) in Hepes-sucrose buffer (20 mM Hepes/NaOH pH 7.4, 1 mM EDTA, 1 mM EGTA, 0.25 M sucrose) supplemented with protease and phosphatase inhibitors. Homogenates were centrifuged at 800 g for 10 min. The supernatant (S1) was separated into supernatant (S2) and pellet (P2) by spinning at 9,200 g for 15 min. Synaptosome fractions represent: S1, post-nuclear-supernatant; S2, cytosol, soluble proteins and light membrane; P2, crude synaptosomal fraction. The S1 and P2 fractions were analyzed by western blot using the following antibodies: α-caspase-3 (9662/Cell signaling); α-caspase-6 (9762/Cell Signaling); α-caspase-8 (4790/Cell Signaling); α-caspase-9 (ab28131/Abcam. Secondary antibodies conjugated with horse-radish peroxidase are from Southern Biotechnology.
Image scanning and analysis
Western blot images were scanned with Epson Perfection 3200 Photo scanner and were analyzed with NIH ImageJ software.
All data are shown as mean ± s.e.m. Statistical tests included two-way ANOVA for repeated measures and t-test when appropriate. All experiments were performed in a blinded fashion.
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.
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