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

ABSTRACT

OBJECTIVE: People with early-onset Alzheimer's 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. METHODS: 2-3-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. RESULTS: APP/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. SIGNIFICANCE: Seizures evoked in pre-symptomatic APP/PS1 mice promotes premature mortality in the absence of pathological amyloid 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.