These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions.

We recently generated an advanced mouse model of Alzheimer's disease (AD) by targeted knock-in of single-copy mutated human amyloid precursor-protein (APP) and tau genes, crossed with a non-symptomatic presenilin (PS1A246E) over-expressing mouse line. These PLB1Triple mice presented with age-dependent and AD-relevant phenotypes. Homozygous PLB1Triple mice aged 4-12 months were assessed here in a battery of spatial learning tasks: Exp.1 radial-arm water maze (spatial reference and working memory) Exp.2 open-field water maze (spatial reference memory); Exp.3 home cage observation system with spatial learning (IntelliCage); Exp.4 spontaneous object recognition (SOR; novel object and spatial object shift). A separate test with high-expression transgenic APP mice matching the design of experiment 1 was also performed. Spatial deficits in PLB1Triple mice were confirmed at 12, but not 4 months in both water maze tasks. PSAPP mice, by contrast, presented with severe yet non-progressive spatial learning deficits already at 4 months. During tests of spatial learning in SOR and IntelliCage, PLB1Triple mice neither acquired the location of the water-rewarded corner, nor recognize novel or spatially shifted objects at 4 months, indicating these protocols to be more sensitive than the water maze. Collectively and in line with AD symptomatology, PLB1Triple mice present with a graded and progressive age-dependent loss of spatial memory that can be revealed by the use of a battery of tasks. With the emergence of subtle deficits progressively increasing in severity, PLB1Triple mice may offer a more patho-physiologically relevant model of dementia than aggressive expression models.

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.