Increased fragmentation of sleep-wake cycles in the 5XFAD mouse model of Alzheimer's disease

Abstract

Sleep perturbations including fragmented sleep with frequent night-time awakenings and daytime naps are common in patients with Alzheimer's disease (AD), and these daily disruptions are a major factor for institutionalization. The objective of this study was to investigate if sleep-wake patterns are altered in 5XFAD mice, a well-characterized double transgenic mouse model of AD which exhibits an early onset of robust AD pathology and memory deficits. These mice have five distinct human mutations in two genes, the amyloid precursor protein (APP) and Presenilin1 (PS1) engineered into two transgenes driven by a neuron-specific promoter (Thy1), and thus develop severe amyloid deposition by 4 months of age. Age-matched (4-6.5 months old) male and female 5XFAD mice were monitored and compared to wild-type littermate controls for multiple sleep traits using a non-invasive, high throughput, automated piezoelectric system which detects breathing and gross body movements to characterize sleep and wake. Sleep-wake patterns were recorded continuously under baseline conditions (undisturbed) for 3 days and after sleep deprivation of 4h, which in mice produces a significant sleep debt and challenge to sleep homeostasis. Under baseline conditions, 5XFAD mice exhibited shorter bout lengths (14% lower values for males and 26% for females) as compared to controls (p<0.001). In females, the 5XFAD mice also showed 12% less total sleep than WT (p<0.01). Bout length reductions were greater during the night (the active phase for mice) than during the day, which does not model the human condition of disrupted sleep at night (the inactive period). However, the overall decrease in bout length suggests increased fragmentation and disruption in sleep consolidation that may be relevant to human sleep. The 5XFAD mice may serve as a useful model for testing therapeutic strategies to improve sleep consolidation in AD patients.

Keywords: amyloid beta; diurnal rhythm; sleep; sleep fragmentation; sleep homeostasis.

Fig. 1

Sleep-wake patterns in 5XFAD and WT littermates under baseline conditions. Average percent sleep across 3 consecutive days analyzed over (A) 24 hours, (B) dark phase, and (C) light phase. Female but not male 5XFAD mice show reduction in sleep duration across 24 h and during the dark phase. (D to F) depicts average bout length in seconds (s) over (D) 24 h (E) dark phase, and (F) light phase. 5XFAD mice of both sexes had shorter average bout lengths across all phases in both the sexes. Values represent means ± SEM. *: P < 0.05; **P <0.01, ***P < 0.001

Fig. 2

Representative sleep-wake profiles for 5XFAD mice (A and C) and control littermates (B and D). The percent wake plotted on the Y axis is represented as a sliding average over a 2 hour window. Hours of recording are plotted on the X-axis where 0 represents the midnight of day 1. Broken vertical lines demarcate the dark phase, which is also indicated by a heavy horizontal black line at the bottom.

Fig. 3

Comparison of the sleep-wake patterns of WT and 5XFAD mice after a sleep deprivation of 4 h. Average percent sleep in males (A), females (B), and average bout length in male (C) and female mice (D) was analyzed for 6 h of the recovery period. No genotype difference was found using Mixed ANOVA.