Sleep-Wake Transitions Are Impaired in the App ^NL-G-F Mouse Model of Early Onset Alzheimer's Disease

Poor sleep quality and reduced sleep duration are associated with Alzheimer's disease (AD)-related β-amyloid (Aβ) pathologies. We conducted two studies of sleep/wake, activity and body temperature in App ^NL-G-F mice, a strain that exhibits three mutations in the human App gene associated with elevated risk for early onset AD. First, App ^NL-G-F mice were compared to wildtype (WT) littermates at 14-18 and 18-22 months of age and, at both ages, were found to exhibit partial insomnia with more Wake and less NREM and REM sleep than WT littermates. This long wake/short sleep phenotype was evident during the dark phase at 14-18 months but occurred in both the light and dark phases at 18-22 months. App ^NL-G-F mice had fewer short (<60 sec) and more long (>260 sec) Wake bouts and were hyperactive at 18-22 months, which undoubtedly contributed to the increased Wake/reduced sleep. Despite this partial insomnia phenotype, App ^NL-G-F mice were no sleepier than WT mice and the sleep homeostat was functional in both strains. In the second study, sex differences in these parameters were assessed at 18-24 months. Partial insomnia was evident in both sexes of App ^NL-G-F mice but was clearly stronger in females. Wake and REM sleep bout durations were longer in both sexes of App ^NL-G-F mice than in WT littermates. EEG spectral power during NREM sleep was reduced in female App ^NL-G-F mice between 4.88-10.50 Hz compared to WT mice whereas, during REM sleep, both male and female App ^NL-G-F mice exhibited reduced spectral power in the theta range. These results suggest that Aβ deposition may impair state transition mechanism(s) in App ^NL-G-F mice and demonstrate that, as in human AD patients, female App ^NL-G-F mice exhibit a stronger insomniac-like phenotype, thus supporting the use of this strain as a model to investigate interventions that mitigate AD burden during early disease stages.