Chronic evoked seizures in young pre-symptomatic APP/PS1 mice induce serotonin changes and accelerate onset on Alzheimer's disease-related neurpathology

Abstract

ObjectivePeople with early-onset Alzheimers disease (AD) are at elevated seizure risk. Further, chronic seizures in pre-symptomatic stages may disrupt serotonin pathway-related protein expression, precipitating the onset of AD-related pathology and burden of neuropsychiatric comorbidities. Methods2-3-month-old APP/PS1, PSEN2-N141I, and transgenic control mice were sham or corneal kindled for 2 weeks to model chronic seizures. Seizure-induced changes in glia, serotonin pathway proteins, and amyloid {beta} levels in hippocampus and prefrontal cortex were quantified. ResultsAPP/PS1 mice experienced worsened mortality versus kindled Tg-controls. APP/PS1 females were also more susceptible to chronic kindled seizures. These changes correlated with a marked downregulation of hippocampal tryptophan hydroxylase 2 and monoamine oxidase A protein expression compared to controls; these changes were not detected in PSEN2-N141I mice. Kindled APP/PS1 mice exhibited amyloid {beta} overexpression and glial overactivity without plaque deposition. PSEN2 protein expression was AD model-dependent. SignificanceSeizures evoked in pre-symptomatic APP/PS1 mice promotes premature mortality in the absence of pathological A{beta} deposition. Disruptions in serotonin pathway metabolism are associated with increased glial reactivity and PSEN2 downregulation without amyloid {beta} deposition. This study provides the first direct evidence that seizures occurring prior to amyloid {beta} plaque accumulation worsen disease burden in an AD genotype-specific manner. HighlightsO_LISeizures are a comorbidity in Alzheimers disease that may worsen disease burden. C_LIO_LIPathological overlap between both neurological disorders is understudied. C_LIO_LIYoung APP/PS1, but not PSEN2-N141I mice, have increased seizure-induced mortality. C_LIO_LISeizures reduce hippocampal serotonin pathway proteins only in young APP/PS1 mice. C_LIO_LIKindled young APP/PS1 mice have glial hyperactivity before amyloid {beta} accumulation. C_LI