Higher susceptibility to 6 Hz corneal kindling and lower responsiveness to antiseizure drugs in mouse models of Alzheimer's disease

Abstract

Objective: Epileptic spikes and seizures seem present early in the disease process of Alzheimer's disease (AD). However, it is unclear how soluble and insoluble amyloid beta (Aβ) and tau proteins affect seizure development in vivo. We aim to contribute to this field by assessing the vulnerability to 6 Hz corneal kindling of young female mice from two well-characterized transgenic AD models and by testing their responsiveness to selected antiseizure drugs (ASDs).Methods: We used 7-week-old triple transgenic (3xTg) mice that have both amyloid and tau mutations, and amyloid precursor protein Swedish/presenillin 1 dE9 (APP/PS1) mice, bearing only amyloid-related mutations. We assessed the absence of plaques via immunohistochemistry and analyzed the concentrations of both soluble and insoluble forms of Aβ 1-42 and total tau (t-tau) in brain hippocampal and prefrontal cortical tissue. Seven-week-old mice of the different genotypes were subjected to the 6 Hz corneal kindling model. After kindling acquisition, we tested the anticonvulsant effects of three marketed ASDs (levetiracetam, brivaracetam, and lamotrigine) in fully kindled mice. Results:No Aβ plaques were present in either genotype. Soluble Aβ 1-42 levels were increased in both AD genotypes, whereas insoluble Aβ 1-42 concentrations were only elevated in APP/PS1 mice compared with their respective controls.

Chronic evoked seizures in young pre-symptomatic APP/PS1 mice induce serotonin changes and accelerate onset of Alzheimer’s disease-related neuropathology

“…There were also no significant changes in the seizure burden and stimulation sessions to achieve kindling criterion in either male or female PSEN2-N141I mice relative to Tg-control mice (Figure 1K-L, O-P). Thus, kindled seizure susceptibility is highly genotype-specific at pre-symptomatic stages and this impact is particularly more evident in female APP/PS1 mice, aligning with our earlier published studies using the 6 Hz kindling protocol 27 .…”

“…These effects were not observed in PSEN2-N141I mice when compared to their matched Tg controls. These present findings are reminiscent of earlier work demonstrating greater susceptibility of young APP/PS1 and 3xTg mice to 6 Hz kindling 27 and of aged Tg2576 mice to amygdala kindling 36 , but further illustrates stark differences in kindling susceptibility of mice with PSEN2 variants or loss of normal function 6 .Further, we herein illustrate that expression of an AD-associated genotype alone does not drive seizure-induced mortality risk and that this mortality can arise well-before Aβ deposition is detected. Interestingly, our present study demonstrated that kindled seizures greatly influenced the expression of 5-HT synthesis and degradation enzymes exclusively in the isolated HPC of APP/PS1 mice, suggesting possible deficits in 5-HT release as a result.…”

“…Considering the observations of extensive and inducible mortality in young APP/PS1 mice subjected to 60 Hz corneal kindling, as well as our earlier similar mortality findings with the 6 Hz kindling model 32 , we hypothesized that this outcome could be linked to possible changes in molecular pathways associated with SUDEP risk in epilepsy. The 5-HT pathway may represent a critical component of the pathology of both epilepsy and AD, and 5-HT system dysfunction is heavily implicated in the pathobiology of SUDEP in epilepsy 15 .…”

“…A primary goal of this study was to compare the 60 Hz kindled seizure susceptibility in two AD mouse models prior to the age when Aβ accumulation is widespread, thereby extending our earlier published works with PSEN2 null 6 and APP/PS1 32 mice. Two-month-old APP/PS1 females kindled significantly faster compared to their respective Tg-littermates (Figure 1A, B).…”

“…PSEN2 variant models are also relevant to study the non-neuronal contributions to AD without Aβ plaque accumulation 24 . We have previously demonstrated that young APP/PS1 mice establish a hyperexcitable neuronal network faster than non-transgenic mice and that chronic seizures increase unintended mortality 27 . We thus quantified the seizure susceptibility and seizure-induced 5-HT system changes in young-adult (2-3 months-old) APP/PS1 and PSEN2-N141I EOAD mouse models to define whether chronic seizures evoked prior to potential neuropathological alterations conferred genotype-specific effects on seizure susceptibility, mortality, and 5-HT system regulation 24 .…”