Natural age-related sleep-wake alterations onset prematurely in the Tg2576 mouse model of Alzheimer’s disease

Abstract

Sleep insufficiency or decreased quality have been associated with Alzheimer 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. 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) mice and recorded vigilance states for 24 hours. 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, delta power appeared decreased in 6-month old Tg2576 mice in comparison to age-matched WT controls, yielding 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 the natural aging of WT mice. Therefore, our results indicate that at plaque-free stages of the disease, 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.

“Genetic and chemical disruption of Amyloid Precursor Protein processing impairs zebrafish sleep maintenance”

“…These sleep symptoms can manifest years before cognitive decline, and alterations in sleep can influence the deposition rates of Aymloid-β (Aβ) plaques that are the hallmark of AD, contributing to disease risk [2][3][4] . Consistent with this, some transgenic AD mouse models that overproduce Aβ display sleep disruptions prior to plaque formation, even without evident neuronal loss [5][6][7][8][9][10][11] . Recently, human studies have found that harbouring a high genetic risk for AD correlates with sleep changes, such as increased sleep rebound following sleep loss, even in young adults 12 .…”

“…Much less clear in this formulation is how the sleep and wake-dependent accumulation of Aβ in turn disrupts sleep, but AD-related cell death of critical sleep/wake regulatory neurons has been proposed as a possible mechanism (Fronczek et al, 2012; Lim et al, 2014; Manaye et al, 2013). However, sleep symptoms in AD patients often appear before cognitive impairment (Sterniczuk et al, 2013), and at least some transgenic AD mouse models show disrupted sleep phenotypes preceding plaque burden (Huitron-Resendiz et al, 2002; Jyoti et al, 2010; Kollarik et al, 2021; Platt et al, 2011; Roh et al, 2012; Sterniczuk et al, 2010; Wang et al, 2002), even in the absence of neuronal loss (Colby-Milley et al, 2015; Irizarry et al, 1997; Sethi et al, 2015). An alternative hypothesis is that Aβ itself acts as a signalling molecule to modulate sleep and that this normal sleep regulatory process is disrupted in AD progression by changes in Aβ oligomeric state or plaque formation.…”

Genetic and chemical disruption of amyloid precursor protein processing impairs zebrafish sleep maintenance

“… 2 , 3 , 4 Consistent with this, some transgenic AD mouse models that overproduce Aβ display sleep disruptions prior to plaque formation, even without evident neuronal loss. 5 , 6 , 7 , 8 , 9 , 10 , 11 Recently, human studies have found that harboring a high genetic risk for AD correlates with sleep changes, such as increased sleep rebound following sleep loss, even in young adults. 12 These observations suggest that there may be underlying early biological processes important for sleep regulation that are governed by AD susceptibility genes and contribute to disease progression.…”