EVALUATING THE IMPACT OF EARLY-LIFE SEIZURES ON ALZHEIMER’S DISEASE PROGRESSION IN A 5XFAD MOUSE MODEL

Alzheimer’s disease (AD) is increasingly recognised as a disorder of abnormal neuronal network activity, including hyperexcitability and epileptiform discharges, beyond classical amyloid-β and tau pathology. Whether seizure activity arising during early-stage AD influences later behavioural, electrophysiological, or pathological outcomes remains unclear. This study examined the longitudinal impact of early seizure induction on behaviour, spontaneous seizures, and amyloid pathology in the 5xFAD mouse model.

Forty 5xFAD mice and wild-type(WT) littermates underwent stereotaxic electrode implantation at 8 weeks of age and were assigned to amygdala kindling(15 stimulations) or sham procedures, generating four groups. Behavioural assessments were conducted at 3, 6, and 10 months. One-week continuous video-EEG recordings quantified spontaneous seizures and high-frequency oscillations (HFOs). Amyloid plaque burden was assessed at 10 months using Thioflavin S staining in the hippocampus and cortex.

Across kindling sessions, seizure severity and duration progressively increased in both genotypes(p<0.0001). Compared with WT mice, 5xFAD mice exhibited greater seizure susceptibility, including higher seizure class, longer duration, lower after-discharge thresholds, fewer stimulations to reach Class V seizures, and more Class V events. Spontaneous seizures occurred only at 3 months and did not differ between genotypes. Behavioural effects were task-specific: Y-maze performance was preserved, whereas Morris water maze training latency at 6 months was influenced by both genotype and kindling. Increased immobility and impaired nest building were observed in kindled and 5xFAD mice. Importantly, kindling did not alter amyloid plaque burden in 5xFAD groups.

Overall, early-stage seizure induction revealed heightened epileptogenic vulnerability and selective behavioural changes without exacerbating amyloid pathology.