Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer’s disease mouse model
© Nygaard et al.; licensee BioMed Central. 2015
Received: 11 September 2014
Accepted: 19 February 2015
Published: 5 May 2015
Recent studies have shown that several strains of transgenic Alzheimer’s disease (AD) mice overexpressing the amyloid precursor protein (APP) have cortical hyperexcitability, and their results have suggested that this aberrant network activity may be a mechanism by which amyloid-β (Aβ) causes more widespread neuronal dysfunction. Specific anticonvulsant therapy reverses memory impairments in various transgenic mouse strains, but it is not known whether reduction of epileptiform activity might serve as a surrogate marker of drug efficacy for memory improvement in AD mouse models.
Transgenic AD mice (APP/PS1 and 3xTg-AD) were chronically implanted with dural electroencephalography electrodes, and epileptiform activity was correlated with spatial memory function and transgene-specific pathology. The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.
We report that in two transgenic mouse models of AD (APP/PS1 and 3xTg-AD), the presence of spike-wave discharges (SWDs) correlated with impairments in spatial memory. Both ethosuximide and brivaracetam reduce mouse SWDs, but only brivaracetam reverses memory impairments in APP/PS1 mice.
Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models. Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs. Our data indicate that SWDs are not a reliable surrogate marker of appropriate target engagement for reversal of memory dysfunction in APP/PS1 mice.
Despite significant advances in the understanding of Alzheimer’s disease (AD), an effective disease-modifying intervention has not yet been identified. It is now well established that patients with AD have an increased risk of seizures . In sporadic AD, the frequency of seizures vary considerably between studies, with more recent reports estimating an incidence of approximately 4 to 5 per 1,000 persons per year [2,3]. Epilepsy is common in familial AD, with an incidence as high as 83% in these patients . Several groups, including ours, have shown that mice overexpressing the amyloid precursor protein (APP) also have seizures [4-6]. These findings have led to the hypothesis that amyloid-β (Aβ), the peptide derived from APP and widely believed to play a critical role in AD pathogenesis, may trigger neuronal hyperexcitability, seizures, and ultimately worsen neuronal dysfunction in AD. This hypothesis was partly tested in two recent studies where transgenic AD mice underwent chronic treatment with the antiepileptic drug (AED) levetiracetam [7,8]. In the initial report, treatment with levetiracetam was described as strongly reducing epileptiform discharges (single spikes), ameliorating memory impairments and reversing markers of hyperexcitability, including calbindin D28 and neuropeptide Y. The same drug was recently shown to improve select hippocampal function in human subjects diagnosed with amnestic mild cognitive impairment (aMCI) , suggesting a potential therapeutic benefit of levetiracetam in aMCI and possibly AD.
The mechanisms underlying the improvements seen in AD mice treated with levetiracetam are presumed to involve a reduction in neuronal excitability, and, although this hypothesis has not been directly tested, targeting epileptiform discharges has emerged as a potential therapeutic approach in AD [7,10]. This is supported by recent work showing that a genetic reduction in either endogenous tau protein or cellular prion protein (PrPC), both of which reverse impairment in spatial memory in AD mice, is associated with a reduction in aberrant neuronal activity in rodent models of AD [6,11,12]. These findings would suggest that a reduction in epileptiform discharges can predict a therapeutic reversal in spatial memory impairments, with reduced neuropathology, in transgenic AD mice. This would be important because behavioral testing in mice, still considered an important step in preclinical drug development, requires significant time and resources that could be optimized by availability of a reliable surrogate marker of drug efficacy.
Using continuous in vivo electroencephalography (EEG) recording, coupled with spatial memory testing, we studied whether epileptiform discharges in transgenic AD mice could be used as a marker of drug efficacy for memory improvement. We report that in two transgenic AD models, APP/PS1  and 3xTg-AD , the presence of spike-wave discharges (SWDs) correlate with impairments in spatial memory, although a weaker correlation was seen in 3xTg-AD mice. Biochemical and immunohistochemical analyses indicated that these epileptiform discharges were not associated with changes in Aβ metabolism or deposition. We further demonstrate that SWDs can be suppressed by the AEDs ethosuximide and brivaracetam, with no effect seen when phenytoin was used. Interestingly, brivaracetam, but not ethosuximide, reversed memory deficits in APP/PS1 mice, despite both drugs causing a strong reduction in epileptiform discharges. Our data indicate that SWDs are associated with poor cognitive performance in APP/PS1 mice, but that the reduction of this abnormal network activity does not reliably predict therapeutic reversal of age-associated impairments in spatial memory in this mouse model. We confirm that targeting synaptic vesicle protein 2A (SV2A), which results in broad-spectrum anticonvulsant action, reverses memory impairments in the APP/PS1 model of AD.
The use of mice in this study was approved by the Yale Animal Resources Center according to internationally recognized guidelines. All mice were housed with a 12-hour light/12-hour dark cycle and fed ad libitum. Coinjected congenic APPswe/PSEN1dE9 transgenic mice  on a pure C57BL/6J background were obtained from The Jackson Laboratory (Bar Harbor, ME, USA). 3xTg-AD mice were a gift from Dr Frank LaFerla (UC Irvine, CA, USA) and were obtained via Dr Paul Lombroso (Yale University). They express the mutated knockin gene PS1M146V, as well as APPswe and tauP301L, at the same locus, both under control of the mouse Thy1.2 regulatory element . 3xTg-AD mice were on a mixed C57BL/6J × 129/Sv background as described elsewhere . For chronic drug experiments, mouse groups were sex-matched, with 40% to 60% of each sex in different cohorts.
For experiments correlating epileptiform activity, animals underwent EEG monitoring prior to behavioral testing. Animals tested for behavior during treatment with AEDs did not have EEG electrodes implanted. Animals were randomized, and the experimenter was blinded to genotype for the duration of behavioral testing. Morris water maze testing  based on previously described methods  was performed over the course of 3 days. Each swim was performed at room temperature in an open-water pool approximately 1.3 m in diameter, utilizing a submerged, nonvisible escape platform located in the center of one of the pool’s four quadrants. This location remained constant for the 3 days of testing. Over the course of each testing day, an animal swam a total of eight times—four times in the morning, constituting one “block” of swims, and four times in an afternoon block. The interval between blocks was approximately 2 hours. For each block, the mice would begin their swim in one of four distinct locations around the wall of the pool and were timed for its latency and path length to reach the escape platform for a maximum time of 1 minute. If the mouse did not find the submerged platform by 1 minute, it was placed on the platform for approximately 10 seconds before being removed from the pool. The water maze probe trial was performed 48 hours following the third and last day of the memory acquisition phase and in the same 1.3-m pool described above. For the purposes of the probe trial, the platform was removed from the pool. All mice were started from a location opposite to the platform location and allowed to swim for 1 minute. To ensure that all mice were equal in terms of swim speed, motivation and visual acuity, a block of five swims to a visible platform was conducted after the probe trial. Mice were excluded from the study if the latency to the visible platform exceeded 3 standard deviations above the average latency for control mice, as previously described . By this criterion, one APP/PS1 mouse with SWDs was excluded. Latency to the platform, swim speed, path length and resting time were automatically recorded using Panlab SMART video tracking and analysis program, v2.5 (Panlab, Cornellà de Llobregat, Spain).
Brain tissue collection
Mice were deeply anesthetized with isoflurane and immediately perfused with ice-cold 0.9% NaCl for 2 minutes. Their brains were then dissected out and placed in ice-cold 0.9% NaCl. For biochemical analysis, the right hemibrain was weighed and immediately frozen in liquid nitrogen, followed by storage at −80°C. To extract the soluble cytosolic fraction, the brains were homogenized in 3 volumes (w/v) of 50 mM Tris-HCl, 150 mM NaCl, pH 7.6 (TBS), containing a protease inhibitor cocktail (cOmplete Protease Inhibitor Cocktail, catalog number 10745000; Roche Diagnostics, Mannheim, Germany), 1 mM sodium orthovanadate and 50 mM sodium fluoride. Tissue was homogenized using an ultrasonic cell disruptor (Branson Ultrasonics Corporation, Danbury, CT, USA) and ultracentrifuged at 100,000 × g for 20 minutes at 4°C. The pellet was then resuspended to the same volume as the original homogenate in TBS with 2% Triton X-100 (AmericanBio, Natick, MA, USA), 0.1% SDS (AmericanBio), a protease inhibitor cocktail (cOmplete Protease Inhibitor Cocktail), 1 mM sodium orthovanadate and 50 mM sodium fluoride. Tissue was homogenized and ultracentrifuged at 100,000 × g for 20 minutes. The supernatant was mixed with 4× SDS-PAGE loading buffer, boiled for 5 minutes and stored for subsequent analysis.
One hemibrain was immersed in fresh 4% paraformaldehyde (PFA) overnight. After the brains were fixed, they were embedded in 10% gelatin and placed in 4% PFA for 20 hours at 4°C. Parasagittal sections (30 μm) were then cut using a Leica VT1000 S vibratome (Leica Biosystems, Buffalo Grove, IL, USA). For immunohistochemistry, sections were blocked in 10% donkey serum for 1 hour, followed by incubation with primary antibody overnight at room temperature. Primary antibodies were diluted in phosphate-buffered saline (PBS) with 0.2% Triton X-100 (AmericanBio). The following antibodies were used: Aβ antibody (catalog number 2454, Cell Signaling Technology, Danvers, MA, USA; and clone 6E10, monoclonal antibody 1560, EMD Millipore, Billerica, MA, USA: both diluted 1:250), rabbit anti-PSD-95 polyclonal antibody (1:250 dilution, catalog number 51-6900; Invitrogen, Camarillo, CA, USA) and anti-calbindin D28 antibody (1:1,000 dilution; Swant, Marly, Switzerland). Following incubation, the sections were washed three times with PBS and incubated in Alexa Fluor fluorescent secondary antibody (donkey anti-rabbit or anti-mouse, all at 1:500 dilution; Invitrogen) for 2 hours at room temperature. The slices were then washed three times and transferred to PBS. Sections were also stained with secondary antibody alone to rule out nonspecific staining. Each free-floating section was mounted on a microscope slide (Fisherbrand Superfrost Plus; Fisher Scientific, Pittsburgh, PA, USA) and coverslipped using VECTASHIELD mounting medium (H-1000; Vector Laboratories, Burlingame, CA, USA).
Imaging and analysis
All images and analyses were generated by personnel who had no knowledge of the mouse genotype. Aβ images were obtained using a Zeiss Axio Imager Z1 fluorescence microscope (Carl Zeiss Microscopy, Jena, Germany) with a 10× lens objective. Mosaic images of the entire cortex and hippocampus of each animal were obtained and analyzed, and plaque burden was calculated using ImageJ software (National Institutes of Health, Bethesda, MD, USA). This was done by isolating the cortex or hippocampus, thresholding to a standard value and calculating the area occupied. Using an UltraVIEW VoX spinning disc confocal microscope (PerkinElmer, Waltham, MA, USA), hippocampal PSD-95 immunoreactive puncta were imaged with a 60× lens objective and digitally magnified to × 100. Two images were obtained in the molecular layer of the dentate gyrus with two slices from each mouse analyzed. Puncta from the dentate gyrus were analyzed and counted using ImageJ, excluding cell somata. Hippocampal calbindin D28 images were obtained using a Zeiss Axio Imager Z1 fluorescence microscope with a 20× lens objective. Mosaic images of the entire hippocampus of each animal were obtained and analyzed. All histologic analyses were done using ImageJ and analyzed statistically by Student’s t-test, or by analysis of variance (ANOVA) with post hoc comparisons as indicated, using SPSS software (IBM, Armonk, NY, USA).
Immunoblotting and enzyme-linked immunoassay experiments
Precast 10% Tris-glycine or 10–20% Tris-tricine gels were used (Bio-Rad Laboratories, Hercules, CA, USA). After transfer, the polyvinylidene fluoride membranes (catalog number 162-0174; Bio-Rad Laboratories) were incubated in blocking buffer for 1 hour at room temperature (catalog number 927-4000, Odyssey blocking buffer; LI-COR Biosciences, Lincoln, NE, USA). Membranes were then washed five times in a mixture of Tris-buffered saline and Tween 20 (TBST) and incubated overnight in primary antibodies. The following antibodies were used: clone 6E10 (MAB1560, 1:1,000 dilution; EMD Millipore), clone 22C11 (MAB348, 1:100 dilution; EMD Millipore) and actin (catalog number sc-1616, 1:200 dilution; Santa Cruz Biotechnology, Santa Cruz, CA, USA). All antibodies were diluted in Odyssey blocking buffer, and membranes were incubated overnight at 4°C. Following primary antibody incubation, the membranes were washed five times with TBST, and secondary antibodies were applied for 1 hour at room temperature (Odyssey donkey anti-mouse or anti-goat IRDye (LI-COR Biosciences) at 680 or 800 nm). Membranes were then washed, and proteins were visualized using a LI-COR Odyssey Infrared imaging system. Blots were analyzed using ImageJ and normalized to actin optical density. Total Aβ enzyme-linked immunosorbent assay (ELISA) experiments on TBS-soluble mouse brain lysates were performed according to the manufacturer’s instructions (Invitrogen).
Continuous electroencephalography video monitoring
For dural electrode implantation, the mice anesthetized and maintained with inhaled isoflurane and mounted in a stereotaxic frame (David Kopf Instruments, Tujunga, CA, USA). A midline incision was made, and two bilateral burr holes were manually drilled anterolateral and posterolateral to the bregma. Four presoldered intracranial screw electrodes (catalog number 8403; Pinnacle Technology, Lawrence, KS, USA) or a prefabricated headmount (catalog number 8201; Pinnacle Technology) was inserted and secured with a layer of dental cement (catalog number 526000; A-M Systems, Sequim, WA, USA). In the case of presoldered screw electrodes, the electrode wires were soldered onto a six-pin surface mount connector (catalog number 8235-SM; Pinnacle Technology) and secured by a final layer of dental cement. All mice were allowed to recover for 7 days prior to chronic EEG recordings.
Mice were video-recorded using an in vivo EEG video monitoring system (8200-K1-SE3, 8236; Pinnacle Systems). EEGs were sampled at 400 Hz with 100× preamplifier gain and filtered at 30 Hz. Each mouse underwent 72 hours of continuous EEG video recording and was maintained on a regular 12-hour light/12-hour dark cycle with full access to food and water. EEG traces were scored manually by an investigator, blinded to genotype, using Pinnacle Technology software. A convulsive seizure was defined as an abrupt onset of evolving SWDs lasting >30 seconds, associated with tonic-clonic activity by synchronized video analysis, and followed by postictal attenuation of cerebral EEG rhythms. A SWD was defined as a burst of sharp-wave discharges, with an amplitude of at least twice the background amplitude and 1 to 2 seconds in duration. A single spike was defined as a sharp discharge at least twice the background amplitude and <100 milliseconds in duration. SWDs were manually correlated with synchronized video analysis and scored as with or without behavioral arrest. Twenty-four-hour EEGs were manually scored for single spikes. A full 72 hours of EEG were manually screened for SWDs for each mouse, comprising 24 hours before drug delivery and 48 hours afterward. Epileptiform discharges were analyzed using Student’s t-test.
Each mouse received a single intraperitoneal (IP) injection of drug as indicated. All drugs were dissolved in normal saline. Each mouse underwent a 1-week washout with verification of a return to baseline SWD frequency prior to subsequent drug injection. Each mouse first received an IP injection of levetiracetam, followed by ethosuximide, phenytoin and brivaracetam. For long-term drug delivery, ethosuximide was delivered in the drinking water at a concentration of 30 mg/ml. Brivaracetam was continuously administered IP for 28 days using an osmotic minipump (ALZET Osmotic Pumps, Cupertino, CA, USA) at a rate of 8.5 mg/kg/day. Owing to the short half-life of ethosuximide in mice (1 hour) , periodic injections were not feasible. Minipump infusions could not be used, because the amount required exceeded the solubility of ethosuximide. Therefore, drinking water was chosen as the route of administration for ethosuximide. For brivaracetam, an osmotic minipump is the most reliable route of administration for continuous dosing.
Transgenic Alzheimer’s disease mice have frequent epileptiform discharges
Spike-wave discharges correlate with impairments in spatial memory in APP/PS1 and 3xTg-AD mice
Spike-wave discharges do not affect amyloid-β metabolism of plaque deposition in APP/PS1 mice
Ethosuximide and brivaracetam reduce spike-wave discharges in Alzheimer’s disease mice
Brivaracetam, but not ethosuximide, reverses impairments in spatial memory in APP/PS1 mice
To assess the role of ethosuximide in APP/PS1 mouse phenotypes, we treated 16-month-old mice chronically (45 days), followed by measurements of spatial memory, APP metabolism and Aβ levels, synapse loss, and hippocampal calbindin D28 immunoreactivity. Drug was delivered by dissolving ethosuximide in drinking water (30 mg/ml). This dose yields a chronic plasma drug concentration of 55 μg/ml after 1 week of dosing in a separate dose range test. In the 1-week dose range test, SWDs detected by EEG were reduced from 25/hr to 6/hr, a 76% reduction. Chronic therapy with this dosage over 45 days did not reverse impairments in spatial memory in APP/PS1 mice (Figure 5C,D; Additional file 2: Figure S2), nor did this treatment affect soluble Aβ levels or Aβ plaque (Figure 6D,E). Ethosuximide did not reverse the loss of hippocampal PSD-95-positive puncta (Figure 6F) or hippocampal calbindin D28 immunoreactivity (data not shown). Thus, although both brivaracetam and ethosuximide significantly reduced SWDs in APP/PS1 mice, only brivaracetam reversed memory impairments in this model.
Seizures and epileptiform discharges have been observed in several strains of AD mice, including J20 and APP/PS1 transgenic models [4,6]. In the former model, seizures and single spikes have been reported, whereas the latter model also displays longer runs of epileptiform discharges resembling SWDs seen in models of absence epilepsy [18,23]. It is widely believed that seizures and epileptiform discharges play a role in the pathophysiology of AD. Chronic treatment with the anticonvulsants levetiracetam and topiramate reverses impairments in spatial memory in J20 and APP/PS1 AD mice and may affect the dynamics of both Aβ and tau protein [7,8]. Moreover, genetic knockouts found to reverse the pathologic phenotypes in AD mice also eliminate cortical hyperexcitability, including the reduction of tau protein and removal of PrPC [6,11]. A low dose of levetiracetam was recently shown to reduce hippocampal hyperactivity during encoding processes in patients with aMCI . This reduction showed slight improvements in select hippocampal function, suggesting that neuronal hyperactivity in aMCI may be a pathologic rather than compensatory response to neurodegeneration and reduced connectivity. Thus, accumulating indirect evidence suggests that cortical hyperactivity may play an important role in the pathophysiology of AD, making chronic EEG recordings a promising marker of target engagement and efficacy for new drugs for AD.
We found that SWDs constitute the most frequent epileptiform discharges in APP/PS1 mice, in contrast to the J20 mice, in which single spikes seem to predominate . SWDs correlate with worsened memory performance in APP/PS1 mice, which we considered as a promising feature for a possible surrogate marker of both disease and drug efficacy. However, the pharmacologic elimination of SWDs does not consistently predict improvements in spatial memory. Indeed, although both ethosuximide and brivaracetam significantly reduced SWDs in APP/PS1 mice, only the latter reversed impairments in spatial memory performance in these mice. These findings suggest that a reduction in SWDs does not represent a robust surrogate marker of drug efficacy in APP/PS1 mice. Our data further emphasize the role of drugs targeting SV2A, such as levetiracetam and brivaracetam, in reversing spatial memory impairments across several AD mouse strains . Further, our conclusion that chronic ethosuximide administration does not reverse memory impairments in APP/PS1 mice is important as, apart from its antiepileptic effects, ethosuximide has previously been shown to have neuroprotective properties and thus is seen as a candidate to alleviate aging and age-related disease. In a screen of compounds that affect longevity in the Caenorhabditis elegans model, ethosuximide was found to extend lifespan by an average of 17% . The underlying mechanism was later found to be modulation of sensory perception by ethosuximide with reduced sensorineural activity . Ethosuximide has also been shown to prevent cochlear injury in a mouse model of sensorineural hearing loss, again linked to reducing neuronal activity . Despite these interesting findings, ethosuximide does not appear to have a therapeutic effect in the APP/PS1 model of AD.
Several limitations of our data must be considered. We focused on SWDs as these are the most frequent epileptiform discharges unique to APP/PS1 mice compared with their nontransgenic littermates. However, it is not yet known which, if any, epileptiform discharges predominate in patients with AD. We note that Sanchez et al.  reported single spikes as the predominant epileptiform activity in the J20 mouse model of AD. Although it is likely these findings represent strain differences, their importance in AD pathophysiology is unclear. Seizures have been studied for decades in humans with AD, but the presence of epileptiform discharges, which requires EEG recordings, are not well characterized. In the largest study to date, researchers examined routine EEG recordings from 1,674 patients with various cognitive disorders, including 510 with AD and 225 with MCI . Of the former, 2% had epileptiform discharges on routine EEG, the same as the percentage seen among patients with “subjective complaints.” There was no correlation between the presence of epileptiform discharges and performance on bedside neuropsychological testing, and it was concluded that routine EEG could not be recommended as part of routine clinical workup in AD. In another study, the investigators reported a frequency of epileptiform discharges of 16% in patients with AD . In a more recent report, authors showed a frequency of 62% in aMCI and AD patients known to have epilepsy and 6% in patients without seizures . The presence of epileptiform discharges also predicted earlier cognitive decline . None of the studies published to date have differentiated various types of epileptiform discharges, thus limiting the correlation to SWDs reported here. The current evidence would suggest that epileptiform activity is less prominent in sporadic AD than in mouse models of autosomal dominant disease. However, prospective studies with long-term EEG monitoring are needed to further characterize cortical hyperexcitability in AD, the relationship of EEG profiles to AD pathophysiology, and whether the presence and reduction of epileptiform discharges may represent a marker of drug efficacy.
Our primary objective was to establish whether epileptiform discharges could be used as a marker for overall drug efficacy in improving memory function in an AD mouse model. Thus, we did not test whether a subgroup of mice, all displaying SWDs, would respond better to ethosuximide therapy compared with a mixed group with varying SWD frequencies. Our findings do suggest that a reduction in SWDs is not sufficient to reverse memory impairments in APP/PS1 mice, but future studies using a different experimental design are required to extend the generalizability of this finding. We also note that both J20 and APP/PS1 mice have prominent epilepsy, and our divergent findings with ethosuximide and brivaracetam with respect to reversal of impairments in spatial memory may be explained by the efficacy of treating partial versus generalized seizures. Ethosuximide is exclusively used for absence seizures in humans, with a narrow antiepileptic spectrum, whereas brivaracetam has broad antiepileptic action.
Our study is the first to demonstrate efficacy of brivaracetam in treating impairments in spatial memory in AD mice. Brivaracetam interacts with SV2A, and is closely related to the widely used anticonvulsant levetiracetam. As noted, two previous studies in J20 and APP/PS1 mice have shown clear benefits of levetiracetam in reversing memory impairments in this model, suggesting that targeting SV2A alleviates AD symptoms across AD models. We also show that, despite some promise as a neuroprotective agent in other model systems, chronic ethosuximide treatment does not reverse impairments in spatial memory in APP/PS1 mice. Moreover, whereas SWDs in APP/PS1 mice correlate with impairments in spatial memory, the reduction of these discharges is not a reliable surrogate marker of preclinical drug efficacy in the APP/PS1 AD mouse model.
Amnestic mild cognitive impairment
Analysis of variance
Amyloid precursor protein
Enzyme-linked immunosorbent assay
- PrPC :
Cellular prion protein
Synaptic vesicle protein 2A
50 mM Tris-HCl, 150 mM NaCl
Tris-buffered saline and Tween 20 mixture
This work was supported in part by a Sponsored Research Agreement to SMS from UCB Pharma, the company which holds patent rights to brivaracetam. The work was also supported by grants to SMS from the National Institutes of Health, the Falk Medical Research Trust, the Alzheimer’s Association and the BrightFocus Foundation.
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