Natural Age-Related Slow-Wave Sleep Alterations Onset Prematurely in the Tg2576 Mouse Model of Alzheimer’s Disease

Abstract

Introduction: Sleep insufficiency or decreased quality have been associated with Alzheimer’s disease (AD) already in its preclinical stages. Whether such traits are also present in rodent models of the disease has been poorly addressed, somewhat disabling the preclinical exploration of sleep-based therapeutic interventions for AD. Methods: We investigated age-dependent sleep-wake phenotype of a widely used mouse model of AD, the Tg2576 line. We implanted electroencephalography/ electromyography headpieces into 6 months old (plaque-free, n=10) and 11 months old (moderate plaque-burdened, n=10) Tg2576 and age-matched wild-type (WT, 6 month old n =10, 11 month old n =10) mice and recorded vigilance states for 24 hours. Results: Tg2576 mice exhibited significantly increased wakefulness and decreased non-rapid eye movement sleep over a 24-hour period compared to WT mice at 6, but not at 11 months of age. Concomitantly, power in the delta frequency was decreased in 6-month old Tg2576 mice in comparison to age-matched WT controls, rendering a reduced slow-wave energy phenotype in the young mutants. Lack of genotype-related differences over 24 hours in overall sleep-wake phenotype at 11 months of age appears to be the result of changes in sleep-wake characteristics accompanying the healthy aging of WT mice. Discussion/Conclusion: Therefore, our results indicate that at plaque-free disease stage, diminished sleep quality is present in Tg2576 mice which resembles aged healthy controls, suggesting an early-onset of sleep-wake deterioration in murine AD. Whether such disturbances in the natural patterns of sleep could in turn worsen disease progression warrants further exploration.

Novel murine closed-loop auditory stimulation paradigm elicits macrostructural sleep benefits in neurodegeneration

“…Interestingly, we observed a lower number of auditory triggers delivered during NREM in TG AD mice in relation to WT AD . This observation aligns with the previously reported reductions in NREM sleep during the dark period and number of slow oscillations in 7-month-old TG AD mice of the Tg2576 line (Kollarik et al, 2022). Contrastingly, we observed a greater number of triggers during NREM sleep in TG PD mice in relation to WT PD .…”

“…AD mice present heightened NREM sleep fragmentation accompanied by a decrease in NREM sleep duration compared to WT animals (Kollarik et al, 2022). Increased sleep fragmentation is a distinctive feature of neurodegenerative diseases, being linked to accelerated microglia and astrocyte aging and activation, cognitive impairment in patients, increasing amyloid-beta deposition, tau phosphorylation and neuroinflammation, and decreasing AQP4 expression in older AD animals (Cai et al, 2019; Kaneshwaran et al, 2019; Vasciaveo et al, 2023).…”

“…Mice were implanted as described before (Kollarik et al, 2022; Morawska et al, 2021). Briefly, we placed 1 stainless steel screw per hemisphere, each located 2 mm posterior to Bregma and 2 mm lateral from midline.…”

“…We scored all recorded files using SPINDLE for animal sleep data (Miladinović et al, 2019), which was previously validated in our lab for rats and mice (Kollarik et al, 2022;Moreira et al, 2021). SPINDLE retrieved vigilance states (wakefulness, NREM and REM sleep) with 4s epoch resolution from EDF files with EEG/EMG signals.…”

Altered sleep behavior strengthens face validity in the ArcAβ mouse model for Alzheimer’s disease

“…Although the onset and time course of sleep changes from preclinical AD to the onset of mild cognitive impairment in human patients is yet to be defined, animal studies revealed sleep alterations already at prodromal AD-stages. Six-month old Tg2576 mice (amyloid mouse model) showed increased wakefulness and decreased sleep 14 prior to amyloid plaque deposition 15 and microglial activation 16 . Further, five-week-old Tg2576 mice showed early hyperexcitability in REMS marked by interictal spikes 17 , a finding paralleled by another study that observed hypersynchronous network activity 18 , underlining the early sleep disturbances linked to β-amyloid neuropathology in this model 17 .…”