Abstracts

This abstract has been invited to present during the Broadening Representation Inclusion and Diversity by Growing Equity (BRIDGE) poster session

Rationale: People with early-onset Alzheimer’s disease (AD) with amyloid precursor protein (APP) duplications or presenilin (PSEN) variants are at elevated risk of seizures within 5 years of diagnosis (Zarea et al, Neurology 2016). Yet the heterogeneity in seizure-related impact between AD-associated risk genes is infrequently assessed. Using the corneal kindled mouse model of chronically evoked focal seizures, we find that young adult mice with AD-related variants are differentially susceptible to kindling-induced mortality. We thus hypothesized that this occurrence represents a possible Sudden Unexpected Death in Epilepsy (SUDEP)-related phenotype that would exhibit differential serotonin pathway-related protein expression and neuroinflammation during and after kindling. We aimed to define whether kindling-induced mortality in AD-associated mice could represent a potentially novel and inducible SUDEP phenotype.

Methods: Male and female 2-month-old APP^swe/PS1^de9 and PSEN2-N141I and their respective wild-type (WT) counterparts underwent corneal kindling or sham kindling. Mice were electrically kindled twice-daily with a subthreshold stimulus (3 sec, 60 Hz, 1.6-3 mA) for 2 weeks until each mouse achieved kindling criterion, defined as five consecutive Racine stage 5 seizures (Beckman et al, 2020). Mice were euthanized (n=4-6 mice/sex/genotype) and left prefrontal cortex (PFC) and hippocampus (HPC) isolated from sham or fully kindled mice (4 days after attaining criterion). Kindling-induced changes in protein expression of PSEN 1 and 2, serotonin transporter (SERT), and serotonin 1A (5HT1A) receptor changes were measured by western blot (WB). Extent of neuroinflammation with GFAP (astrocytes) and Iba-1 (microglia), as well as amyloid beta plaque load, was also quantified by immunohistochemistry (IHC) in the right hemisphere. Data for WB and IHC was analyzed as the percent change versus sham kindled WT mice within each sex._x000D_
Results: Young adult APP/PS1 mice of both sexes were markedly more sensitive to corneal kindling and secondary mortality versus WT, whereas PSEN2-N141I mice did not differ from respective WTs. Further, analysis of HPC tissues showed significant kindling-induced upregulation of SERT expression in APP/PS1 mice [87% (sham) vs 104% (fully kindled), p< 0.05]. Surprisingly, there was significant kindling-induced upregulation of PSEN1 expression in APP/PS1 mice [110% (sham) vs 153% (fully kindled), p< 0.05]. However, PSEN2 expression was only impacted by genotype (F=47.11, p=0.001). There were no similar kindling-induced changes in serotonin pathway and PSEN1 or 2 protein expression in PSEN2-N141I mice. No differences in any protein marker were appreciated in isolated PFC in either strain. The extent of neuroinflammation and amyloid plaque deposition will be further discussed.