Abstracts

Rationale: Familial early-onset AD is associated with mutations in presenilin 2 (PSEN2). Individuals with PSEN2-associated AD exhibit a high incidence of seizures (Jayadev et al, Brain 2010). Despite the high incidence of seizures in elderly patients, including those with AD, few studies have examined the impact of aging on seizure susceptibility, and even less data exists to understand the impact of AD-associated mutations on risk for epilepsy. Whether approved antiseizure drugs (ASD) are differentially effective in preclinical models of AD is also unclear. PSEN2 is a valid and unexplored molecular target to understand the pathophysiological impact of aging and AD-associated mutations on risk for epilepsy and ASD efficacy. Methods: Male (n = 20-30/age/genotype) and female (n = 19-20/age/genotype) PSEN2 KO and age- and gender-matched wild-type (WT) C57Bl/6J mice were corneal kindled at 2-months and 8-months of age (approximating a 50-year-old human). Fully kindled mice were challenged with escalating doses of the prototype ASDs valproic acid, levetiracetam, and carbamazepine, to define the age-dependent median effective doses (ED50) in mice with and without PSEN2 deletion. Results: Corneal kindling acquisition was significantly delayed in 2-month-old male and female PSEN2 KO mice relative to WT age-matched mice. Male WT mice took 24.3±1.3 (S.E.M.) corneal stimulations to achieve kindling criterion of 5 consecutive Racine stage 5 seizures, whereas age-matched PSEN2 KO male mice took 41.2±1.1 corneal stimulations (p<0.0001). Similarly, WT female mice took 26.5±0.6 stimulations to achieve kindling criterion, but PSEN2 KO females required 34.9±1.1 stimulations (p<0.0001). Interestingly, this difference in the rate of kindling acquisition was no longer apparent in 8-month-old mice. Aged male WT mice required 22.4±0.8 stimulations vs. PSEN2 KO males requiring 22.9±1.0 stimulations (p>0.6). Aged female mice required a similar number of stimulations to achieve criterion. Aged WT females required 19.4±0.7 stimulations and PSEN2 KO females required 19.7±0.8 stimulations (p>0.8). There were no genotype-specific differences in pharmacosensitivity to the ASDs tested at the ages tested. For example, the ED50 of carbamazepine in young WT female mice was determined to be 18.7 mg/kg [95% confidence interval: 15.0-27.2] vs an ED50 of 11.3 mg/kg [7.50-19.4] in young PSEN2 KO female mice. Aged WT female mice had an ED50 of 10.5 mg/kg [3.65-68.1] vs an ED50 of 9.17 [1.0-37.5] in aged PSEN2 KO female mice. In aged male WT mice, carbamazepine had an ED50 of 8.35 mg/kg [5.75-12.3] and in PSEN2 KO mice, the ED50 was 7.56 mg/kg [4.47-11.2]. Additional ED50 data with valproic acid and levetiracetam will be discussed further. Conclusions: Absence of PSEN2 is associated with age-dependent increases in seizure susceptibility in vivo. Interestingly, aged mice demonstrate equivalent kindling acquisition rates, regardless of genotype, in stark contrast to the acquisition rates of young mice. PSEN2 loss may thus disproportionally accelerate the susceptibility to epileptogenesis with age. PSEN2 may be an unexplored molecular contributor to seizure susceptibility, underlying the increased prevalence of seizures in patients with PSEN2 mutation-associated AD. Funding: This work was supported by the University of Washington School of Pharmacy Elmer M. Plein Fund, the University of Washington Royalty Research Fund, and the Institute of Translational Health Sciences (MBH).