Abstracts

Rationale: Patients with early-onset Alzheimer’s disease (AD) with amyloid precursor protein (APP) duplications or presenilin 2 (PSEN2) variants are at elevated risk of seizures within 5 years of diagnosis (Zarea et al, Neurology 2016). Yet little work has been done to assess how these clinically-relevant AD-associated risk genes differentially influence seizure susceptibility in well-established epilepsy models. PSEN2-N141I is a common variant associated with early-onset AD; patients with this variant experience a high incidence of reported seizures (Jayadev et al, Brain 2010). AD-associated mouse models are not routinely used for antiseizure drug (ASD) discovery but may represent a differentiated platform on which to identify novel molecular drivers of ictogenesis, as well as screen investigational therapies for epilepsy (Lehmann, Lo et al, Neurochem Res 2021). We have thus established the application of the corneal kindling model to reveal age-related changes in seizure susceptibility in mice with loss of normal PSEN2 function (Beckman et al, Neurobiol Dis 2020). We thus sought to define whether expression of specific AD-associated genetic variants in APP or PSEN2 in young male and female mice differentially influenced kindling susceptibility and ASD efficacy.

Methods: Male and female 2-month-old PSEN2-N141I and age-matched non-transgenic wild-type (WT-Tg) C57Bl/6J mice, and APP/PS1 and wild-type littermates (WT), were corneal kindled with a 3 sec 60 Hz 1.6-3 mA stimulus to kindling criterion (5 consecutive Racine stage 5 seizures). The duration of the kindled seizure was recorded 7-days post-kindling. The dose-related anticonvulsant efficacy of the prototype ASDs gabapentin, valproic acid, phenobarbital, lamotrigine, and levetiracetam were then profiled in fully kindled mice.

Results: Kindling acquisition was differentially affected by sex and AD genotype. Specifically, male APP/PS1 (n=9) took fewer (17.7±1.1) stimulations to attain kindling criterion vs WT mice (n=17; 21.2±0.96 stimulations, p=0.031). Female APP/PS1 (n=7) were no different from WT littermates (n=18; 13.3±1.6 vs 13.7±0.85 stimulations, p >0.8). Conversely, both male (n=13; 20.1±0.89) and female (n=7; 14.6±0.81) PSEN2-N141I took the same number of stimulations as WT-Tg mice (females: n=17; 13.0±0.56; males: n=25; 19.5±0.64). The acute dose-related anticonvulsant efficacy of several mechanistically distinct ASDs will be further discussed.

Conclusions: Young (2-month-old) male APP/PS1 mice are more susceptible to the development of kindled seizures than WT, in contrast to female APP/PS1 mice and both male and female PSEN2-N141I mice. This study highlights the value of including a diversity of AD-associated animal models and seizure-induction protocols evoked in both sexes to further explore the mechanisms of seizures in AD. While PSEN2 variants represent a small subset of early-onset AD cases, these data reveal significant heterogeneity in AD-associated genotypes, sensitivity to kindling, and suggest that further studies into the mechanisms of seizure susceptibility in the setting of PSEN2 variants are needed.

Funding: Please list any funding that was received in support of this abstract.: This work was supported by an American Epilepsy Society Junior Investigator Award to MBH.