Abstract
In addition to cognitive decline, individuals affected by Alzheimer’s disease (AD) can experience important neuropsychiatric symptoms including sleep disturbances. We characterized the sleep-wake cycle in the TgCRND8 mouse model of AD, which overexpresses a mutant human form of amyloid precursor protein resulting in high levels of β-amyloid and plaque formation by 3 months of age. Polysomnographic recordings in freely-moving mice were conducted to study sleep-wake cycle architecture at 3, 7 and 11 months of age and corresponding levels of β-amyloid in brain regions regulating sleep-wake states were measured. At all ages, TgCRND8 mice showed increased wakefulness and reduced non-rapid eye movement (NREM) sleep during the resting and active phases. Increased wakefulness in TgCRND8 mice was accompanied by a shift in the waking power spectrum towards fast frequency oscillations in the beta (14-20 Hz) and low gamma range (20-50 Hz). Given the phenotype of hyperarousal observed in TgCRND8 mice, the role of noradrenergic transmission in the promotion of arousal, and previous work reporting an early disruption of the noradrenergic system in TgCRND8, we tested the effects of the alpha-1-adrenoreceptor antagonist, prazosin, on sleep-wake patterns in TgCRND8 and non-transgenic (NTg) mice. We found that a lower dose (2 mg/kg) of prazosin increased NREM sleep in NTg but not in TgCRND8 mice, whereas a higher dose (5 mg/kg) increased NREM sleep in both genotypes, suggesting altered sensitivity to noradrenergic blockade in TgCRND8 mice. Collectively our results demonstrate that amyloidosis in TgCRND8 mice is associated with sleep-wake cycle dysfunction, characterized by hyperarousal, validating this model as a tool towards understanding the relationship between β-amyloid overproduction and disrupted sleep-wake patterns in AD.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder with a rapidly growing worldwide prevalence and no effective disease-modifying treatments
Polysomnographic recordings were analyzed to quantify the total time spent in wake, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep during the dark phase (DP) and light phase (LP) (Fig 1)
It is of note that circadian fluctuation was intact in TgCRND8 mice as shown by a significantly greater time spent awake and less time spent in NREM and REM sleep during the dark versus the light phase at 3, 7, and 11 months of age
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder with a rapidly growing worldwide prevalence and no effective disease-modifying treatments. In addition to memory loss, AD patients often experience important non-cognitive, neuropsychiatric symptoms, which include perturbations of the sleep-wake cycle [1,2,3]. Sleep disturbances occur in up to 40% of AD patients [4] and clinical manifestations of sleep-wake cycle dysfunction include difficulties falling asleep, fragmented sleep, early morning awakenings and excessive daytime sleepiness [4,5,6]. Identifying AD animal models that recapitulate the sleep-wake cycle patterns observed in AD will provide tools towards understanding the cause and progression of sleep dysfunction, which in turn, may have important implications for therapeutic intervention in AD patients
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