@article {Pozo2023.01.05.522897, author = {Aaron del Pozo and Kevin M. Knox and Leanne Lehmann and Stephanie Davidson and Suman Jayadev and Melissa Barker-Haliski}, title = {Chronic seizure-induced serotonin pathway dysregulation coincides with mortality in Alzheimer{\textquoteright}s disease mouse models}, elocation-id = {2023.01.05.522897}, year = {2023}, doi = {10.1101/2023.01.05.522897}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Objective People with early-onset Alzheimer{\textquoteright}s disease (AD) with amyloid precursor protein (APP) duplications or presenilin (PSEN) variants are at elevated seizure risk within 5 years of diagnosis. Further, seizures in AD may increase neuropsychiatric comorbidity burden. We thus hypothesized that disruptions in serotonin pathway-related protein expression was impacted by 60 Hz corneal kindled seizures in an AD-genotype-related manner.Methods Male and female 2-3-month-old APP/PS1, PSEN2-N141I, and respective transgenic (Tg) control mice underwent corneal or sham kindling for 2 weeks until reaching kindling criterion defined as five consecutive Racine stage 5 seizures. Chronic seizure-induced changes in serotonin pathway protein expression in hippocampus were then quantified by western blot.Results Young female APP/PS1 mice kindled significantly faster than Tg-controls, whereas PSEN2-N141I mice kindled no differently versus their Tg controls. APP/PS1 mice subjected to corneal kindling were at extremely elevated mortality risk relative to kindled Tg-controls, as well as sham-kindled APP/PS1 and Tg-control mice, whereas PSEN2-N141I mice were not adversely affected by kindling. Kindled APP/PS1 mice demonstrated a marked downregulation of hippocampal tryptophan hydroxylase 2 and monoamine oxidase A protein expression versus kindled Tg- and sham-kindled APP/PS1 groups. Serotonin pathway protein expression in PSEN2-N141I mice was unchanged from Tg. Importantly, all changes in serotonin pathway protein expression in kindled APP/PS1 mice occurred in the absence of amyloid β (Aβ) deposition.Significance The co-occurrence of seizures in the APP/PS1 mouse is sufficient to evoke unexpected mortality well ahead of pathological Aβ deposition synonymous with a symptomatic AD model. The presence of another AD-associated variant (PSEN2-N141) does not lead to seizure-induced mortality, suggesting that AD-associated risk genes differentially influence vulnerability to chronic seizure-associated mortality. Further, disruptions in serotonin pathway synthesis coincide with heightened mortality risk exclusively in adult APP/PS1 mice, suggesting a possible non-canonical sudden unexpected death in epilepsy (SUDEP)-related phenotype.Key points (3-5 total)Sudden unexpected death is a devasting consequence of uncontrolled epilepsySerotonin pathway dysfunction may increase risk of premature mortality in epilepsyAPP/PS1 mice are at higher risk of seizure-induced mortality versus other AD modelsSeizures downregulate hippocampal serotonin pathway proteins solely in APP/PS1 miceSeizure-induced mortality in APP/PS1 mice does not require amyloid β accumulationCompeting Interest StatementThe authors have declared no competing interest.}, URL = {https://www.biorxiv.org/content/early/2023/01/05/2023.01.05.522897}, eprint = {https://www.biorxiv.org/content/early/2023/01/05/2023.01.05.522897.full.pdf}, journal = {bioRxiv} }