Rationale: Early-onset Alzheimer’s disease (AD) is associated with variants in presenilin 2 (PSEN2), presenilin 1 (PSEN1), and amyloid precursor protein (APP). Patients with early-onset AD who express APP duplications or PSEN2 variants are at a significantly elevated risk of developing seizures. For example, 31.2% of patients with APP duplications and 28.6% of patients with PSEN2 variants experienced at least one seizure within five years of AD diagnosis (Zarea et al, Neurology 2016). We have established that corneal kindling of mice with loss of normal PSEN2 function (PSEN2 knockout) demonstrate age-related delays in corneal kindling (Beckman et al, Neurobiol Dis 2020). PSEN2 is a particularly attractive candidate to explore susceptibility to chronic seizures because PSEN2 variant models do not demonstrate accumulated amyloid-beta (Aβ), in contrast to APP-overexpressing mouse models. PSEN2-N141I is the most common PSEN2 gene variant associated with early-onset AD; patients with this variant are known to experience seizures (Jayadev et al, Brain 2010). We sought to establish whether transgenic expression of this AD-associated variant in mice altered the rate of kindling acquisition vs. the rate of a common line of mice that overexpress APP (APPSWE/PS1dE9). Methods: Male PSEN2-N141I and age-matched non-transgenic wild-type (WT-Tg) C57Bl/6J mice, and Male APP/PS1 and wild-type littermates (WT) C57Bl/6J, were corneal kindled with a three second 60 Hz 1.6-3 mA current to kindling criterion (five consecutive Racine stage 5 seizures) at two months old. The duration of the kindled behavioral seizure was recorded seven-days post-kindling acquisition to define the kindled seizure severity in mice with and without these AD-associated genetic risk factors. The exploratory behavior of fully kindled mice was also then assessed ten days post-kindling criterion in a non-habituated open field to quantify the potential for chronic seizure-induced changes in anxiety-like behaviors and spatial working memory deficits. Results: The rate of corneal kindling acquisition was significantly affected by AD genotype. Specifically, male APP/PS1 mice (n=5) took fewer (17.0±1.98) stimulations to attain the fully kindled state vs WT littermates (n=9; 21.2±0.91 stimulations, p< 0.05). Conversely, PSEN2-N141I mice took significantly more stimulations (n=13; 21.2±0.91) vs WT-Tg mice (n=11; 17.5±0.49; p< 0.01). Further, APP/PS1 mice demonstrated kindled seizures of significantly greater duration than WT littermates. The fully kindled seizure in APP/PS1 mice lasted on average 81.4±10.8 sec versus 40.6±1.58 sec of WT (p< 0.01). Conversely, the kindled seizure duration of two-month-old PSEN2-N141I mice (50.6±3.16 sec) was no different from WT-Tg mice (51.4±2.99 sec). The activity of fully kindled mice in the open field will then be further discussed. Conclusions: We presently demonstrate that APP/PS1 mice are more susceptible to the development of corneal kindled seizure than WT mice, in contrast to PSEN2-N141I mice that are less susceptible to corneal kindling vs WT-Tg mice. Our present observations that young-adult PSEN2-N141I mice demonstrate a significant delay in corneal kindling acquisition is consistent with our prior findings in young PSEN2 knockout mice (Beckman et al, 2020). We herein demonstrate that Aβ-dependent and -independent mechanisms may influence seizure susceptibility in early-onset AD. Further, this study highlights the value of including a diversity of AD-associated animal models and seizure-induction protocols to further explore the mechanisms of seizures in AD, as well as epilepsy in the elderly in general. Funding: Please list any funding that was received in support of this abstract.: Friends of Alzheimer’s and R01NS072395 (SJ). NCATS/ITHS KL2 TR002317 and American Epilepsy Society Junior Investigator Award (MBH).
