Abstracts

Rationale: Among patients over 65 years of age, the prevalence of epilepsy is 1.5%; twice the rate of younger adults. Epilepsy is also an underreported comorbidity of Alzheimer’s disease (AD). Both AD and epilepsy, although considered clinically distinct, are defined by temporal lobe atrophy, neuronal death, gliosis, neuritic alterations, and inflammation. The risk of unprovoked seizures in patients with early-onset AD increases up to 87-fold in individuals aged 50-59 years. Despite the overlapping pathology and high incidence of seizures in elderly patients, including those with AD, few preclinical studies have examined the impact of aging on seizure susceptibility, and even less data exists to understand the impact of AD-associated mutations on seizure risk. In this regard, the management of aged patients with epilepsy, and those with AD and epilepsy, is significantly under informed.Familial early-onset AD is associated with mutations in presenilin 2 (PSEN2). Individuals with AD harboring the most common PSEN2 mutation also exhibit a high incidence of seizures (32% of patients) and PSEN2 mutations show a loss of normal biochemical function. Thus, PSEN2 may be a novel target to understand the impact of an AD-associated mutation on long-term seizure susceptibility, as well as the pathophysiological overlap between AD and epilepsy. PSEN2 knockout (KO) mice exhibit normal development, viability up to 12 months of age, and breed robustly, thus providing a robust and cost-effective platform to simultaneously understand the longitudinal impact of aging and AD-associated mutations on risk for epilepsy. Methods: Male (n = 17) and female (n = 20) PSEN2 KO and age- and gender-matched wild-type (WT) C57Bl/6J mice were longitudinally evaluated for age-dependent changes in seizure threshold when aged 2, 4, 6, and 8 months using the minimal clonic and 6 Hz seizure threshold tests. Corneal kindling acquisition rates were also defined in a separate cohort of male (n = 20) and female (n = 22) PSEN2 KO mice and age- and gender-matched WT mice at 9-months-old (approximating a 50-year-old human). Performance of PSEN2 KO and WT mice in an anxiety-like behavioral task before and after kindling acquisition were also defined to demonstrate the impact of chronic seizures on this behavioral comorbidity of epilepsy. Results: At 2 months-old, the seizure thresholds of both genotypes in either test were not significantly different within genders. For example, male WT mice exhibited minimal clonic seizure thresholds of 6.925 mA [95% confidence intervals (CI): not defined], whereas PSEN2 KO mice had a threshold of 5.92 mA [95% CI: not defined]; for females, WT threshold was 6.28 [4.87-6.84] and PSEN2 KO threshold was [4.97-5.94]. By as early as 4 months-old, PSEN2 KO mice exhibited significant reductions in seizure threshold relative to WT mice. The minimal clonic seizure threshold of 4 month-old male WT and PSEN2 KO mice was 8.44 mA [95% confidence intervals: not defined] and 5.65 mA [4.41-6.38], respectively. In female WT and PSEN2 KO mice, this threshold was 6.60 mA [6.47-8.61] and 5.18 mA [4.16-5.78], respectively. This effect was also observed for the 6 Hz seizure threshold test and will be discussed in greater detail. Behavioral alterations pre- and post-kindling acquisition will also be discussed. Conclusions: Absence of PSEN2 function is associated with lower seizure threshold in vivo. PSEN2 may be an unexplored molecular contributor to seizure susceptibility, which may underlie an increased prevalence of seizures in patients with PSEN2 mutation-associated AD. Funding: This work was supported by the University of Washington Elmer M. Plein Fund, Institute of Translational Health Sciences, and the University of Washington School of Pharmacy.