Abstracts

Rationale: Early-onset Alzheimer’s disease (EOAD) is associated with variants in one of three risk genes: amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2). AD patients are at a greater risk of spontaneous seizures than similarly aged, unaffected adults. While the effects of seizures on AD pathology are not completely understood, seizures can negatively impact disease burden in AD by promoting neuroinflammation and subsequent behavioral comorbidities of both epilepsy and AD, including depression, anxiety, and cognitive impairment. Using the corneal kindled mouse model of acquired epilepsy to evoke secondarily generalized focal seizures in two distinct aged EOAD-associated mouse models, we hypothesized that the combination evoked chronic seizures and EOAD genotype would lead to behavioral changes associated with comorbid conditions of AD.


Methods: Aged male and female EOAD-associated mice (10-20 months-old; n=26-60/group) were sham or corneal kindled with a 60 Hz twice daily electrical stimulus for 2-3 weeks. Genotypes were selected to model amyloid-β independent and dependent risk factors and included: PSEN2-N141I (amyloid-β independent model) versus age-matched wild-type (Tg Ctl) mice, and APP/PS1 (amyloid-β dependent model) versus age-matched wild-type littermates (Tg-). Acquisition rates to achieve the fully kindled criterion of 5 consecutive stage 5 seizures were used as a measure of seizure susceptibility while seizure duration was monitored as a measure of seizure severity. Fully kindled and sham kindled mice then underwent behavioral assessment in the saccharin preference test of anhedonia-like behavior, the Barnes maze test of spatial learning and memory, and a 3-day home cage analysis of activity, behavior, and circadian rhythms.

Results: There was no significant change in seizure susceptibility as measured by kindling acquisition rate in either EOAD-associated genotype. There was no significant genotype or kindling effect on saccharin preference; all mice preferred saccharin-infused water, suggesting no effect of seizures on anhedonia-like behavior in these AD models. Cognitive function testing in the Barnes maze revealed a significant kindling x genotype effect in APP/PS1 female mice. Specifically, mice failed to reduce the number of errors or escape hole encounter latency over time, consistent with previously reported sex-related cognitive impacts of seizures in another AD model (Knox et al, Exp Neurol 2023). However, kindling generally worsened the Barnes maze performance of male PSEN2-N141I and Tg Ctl mice. In the home cage monitoring task of circadian activity patterns, repeated seizure history generally increased exploratory behavior of APP/PS1 male and female mice.

Conclusions: This project begins to directly explore the functional and behavioral impacts of repeated seizures in the setting of both aging and a variety of AD-related risk factors. Most notably, this study reveals the heterogeneity of seizure-evoked consequences on spatial working memory and circadian patterns of behavior. Therapeutic management of seizures in AD is increasingly recognized to be an urgent public health concern.

Funding: This work was supported by NIA R01AG067788 (MBH).