P4‐021: The first third‐generation Alzheimer mouse, PLB1: Assessment of spatial learning and memory in the water maze

Abstract

Background: Transgenic mice carrying the APP swe and PSEN1 (A246E) transgenes (independent mutations) are a well characterised animal model for Alzheimer's disease (AD), and develop a severe plaque load by 9-month of age. Since insomnia and disturbed sleep patterns are reported in patients suffering from AD we aimed to investigate circadian activity and EEG profiles in this APP/PSEN1 line, and compare it with our novel triple AD mouse model (PLB1, see respective posters). Methods: Transgenic mice were purchased from The Jackson Laboratories and breeding colonies set up. Long-term (24 hours) EEG was recorded using Neurologger microchips from freely moving mice in the Phenotyper observation cages as well as in the home cage environment. Two transgenic (tg) groups [APP/PSEN1 double tg (n¼12) and PSEN1 littermates (n¼17)] were compared for alterations in their activity and sleep patterns. Effects of genotype difference on sleep, activity and EEG patterns were assessed in young (5-6 months) and aged animals (19-20 months). Results: PhenoTyper data indicate significantly higher overall activity in the young APP/PSEN strain (p<0.001) compared to PSEN1 animals in the dark phase. Vigilance parameter (Wake, REM and NREM) analyses showed that APP/PSEN animals also present with a significant genotype-specific but age-independent increase in wakefulness (p<0.001) and a decrease in NREM (p<0.01) in PhenoTyper and home cages. Age-specific changes in vigilance states were limited to a significant decrease of percentage time spent in REM (p<0.05) during light phase in both environments. Averaged and normalized spectral EEG analysis revealed age-and genotype specific significant changes in the power of delta, theta and alpha frequencies. Specifically, hippocampal delta range was affected by genotype but not age, while the PFx delta range was mainly affected by age during REM. Old animals showed a robust genotype-dependent change in the theta and beta range during NREM events. Conclusions:Our results indicate that APP/PSEN1 mice exhibit abnormalities in activity patterns and sleep architecture. Both PhenoTyper and home cage EEG recordings confirmed an increase of wakefulness and decrease of NREM. This adds further information on this AD mouse line, and confirms the use of Phenotyper and Neurologger based EEG recordings as sensitive and translational disease endpoints.