Abstracts

Rationale: Both Alzheimer’s Disease (AD) and epilepsy have distinct clinical symptoms but also share some overlapping pathophysiology. Presenilin 2 (PSEN2) gene variants increase the risk of early-onset AD, as well as heighten risk of unprovoked seizures versus age-matched non-affected individuals. Seizures in people with AD negatively impact cognitive function, worsen disease burden, and increase mortality. Antiseizure medications (ASMs) may be thus beneficial for AD, but studies of ASMs efficacy have been historically conducted in healthy, young adult rodents despite frequent use in older people with epilepsy. Few studies have addressed how advanced age and AD-related genetic risk factors additively influence seizure susceptibility and ASM efficacy. PSEN proteolytic capacity may be a novel regulator of presynaptic hippocampal kainate-type glutamate receptors (KARs), with PSEN deletion reducing KAR availability and synaptic transmission in vitro (Barthet et al 2022). We thus hypothesized that aged mice would be more susceptible to kainic acid (KA)-induced seizures and that the ASM, lorazepam (LZP), would be differentially effective advanced age mice that expressed an AD-related genetic variant in PSEN2 (N141I).

Methods: We sought to evaluate how genotype and advanced age influence seizure susceptibility. We chemically evoked seizures with the systemic low-dose repeated administration of the KAR agonist, KA, and quantified the latency to first seizure (SZ) and status epilepticus (SE) in 21-22-month-old male PSEN2-N141I versus WT mice. Upon convulsive SE onset, we randomized mice (n=5-7 treatment group/genotype) to either immediate LZP (2 mg/kg, i.p.) or vehicle intervention and recorded seizure activity for 60 min after intervention. We also quantified survival 24-hours post-SE to determine whether LZP intervention could differentially improve SE-induced acute outcomes.

Results: Despite receiving similar total KA (mg/kg), AD genotype (PSEN2-N141I) significantly increased susceptibility to SZ in aged mice (X²=11.9, p=0.0006), but did not affect time from SZ to convulsive SE. Immediate LZP treatment significantly reduced convulsive seizure burden regardless of genotype in aged mice. LZP administration to PSEN2-N141I mice improved acute survival during the 60 min SE monitoring period (4/7 survived with VEH treatment versus 7/7 with LZP administration, X2=3.82, p=0.05). However, there was no difference in 24-hour survival in either genotype or treatment group.

Conclusions: The AD-associated genetic risk factor, PSEN2-N141I, increased preponderance for chemically-evoked seizure but did not affect latency from SZ to SE in aged mice. Immediate LZP treatment significantly suppressed acute seizures, which normalized survival of aged PSEN2-N141I mice. This study establishes that the PSEN2-N141I variant increases susceptibility of aged mice to seizures. Further, this study demonstrates that ASM administration can improve acute seizure-related outcomes in advanced age individuals with AD-related genotypes.

Funding: This work was supported by a University of Washington Plein Center Scholarship for Aging Research (YP) and NIA R01AG067788 (MBH).