Are we getting enough sleep? Clinical investigation has revealed an inverse correlation between the accumulation of amyloid plaques in the brain (a hallmark of Alzheimer’s disease pathology) and the amount of sleep. Of course, these correlations do not prove causation, which requires a detailed analysis of the relationship between sleep and plaque formation. Now, a new study using mouse models of Alzheimer’s disease (AD) provides compelling genetic evidence linking sleep with AD pathology and concludes that getting more sleep will reduce amyloid-β (Aβ) plaque formation, at least in mice.
The primary constituent of amyloid plaques in the brains of patients with AD is the amyloidogenic peptide, Aβ. Aβ production is regulated by synaptic activity, with increased activity resulting in more Aβ production. Animal models that express the human amyloid precursor protein (APP), often with mutations to enhance production of Aβ, produce robust Aβ plaque pathology. Studies in these mice have shown that amyloid pathology disrupts sleep patterns and that reducing pathology can reverse these deficits. Furthermore, pharmacological inhibition of the wakefulness-modulating pathway, which is mediated by orexin signaling, reduced plaque formation. But genetic validation of the role of orexin signaling and the impact of modulating this pathway on sleep and amyloid plaque pathology remained to be explored.
In this issue, Roh et al. report data from two different mouse models of AD combined with genetic deletion of orexin. Loss of orexin resulted in decreased wakefulness (increased sleep) and a subsequent reduction in amyloid pathology and Aβ concentrations in brain. Two possible explanations for these results were tested: orexin may act directly on the neurons that overproduce Aβ, or, orexin may impact pathology as a result of modulating the sleep–wake cycle. The authors found that rescue of orexin in neurons that modulate sleep, but not directly in neurons in the region of plaque formation, increased wakefulness and thus increased amyloid pathology, supporting the second explanation. Sleep deprivation in AD mice that lacked orexin resulted in increased plaque formation, demonstrating a causal link between sleep and amyloid pathology.
The implications of these findings on human behavior and potential pharmacological approaches to prevent AD are far-reaching. The totality of data linking sleep and the risk of developing AD suggests that lack of sleep increases amyloid pathology and that increased amyloid pathology negatively impacts sleep. As a result, the risk of AD and the relationship to sleep are self-perpetuating. Furthermore, sleep modulation may be a viable consideration for drug development in AD, however the current evidence points towards prevention, rather than treatment of existing disease. These data also suggest that consideration should be given to lifestyle choices that place sleep as a priority. Increasing our quality and quantity of sleep may reduce the risk of developing amyloid pathology, ultimately protecting us from developing AD.
