The nexus of Aβ, aging, and sleep

Abstract

Roh et al. report a positive feedback loop between sleep-wake irregularities and aggregation of β-amyloid peptide, suggesting that sleep alterations could be an early event in Alzheimer's disease.

Fig. 1. Aβ and the sleep-wake cycle.

(A) Sleep amount and quality decline with age. This effect is even more pronounced in AD patients. Aβ aggregation increases during AD and is associated with a decline in sleep. (B) In the absence of Aβ aggregation, ISF Aβ in mice and CSF Aβ in humans show diurnal oscillations associated with sleep (S) and awake (W) states (2). Following Aβ aggregation, the diurnal oscillation of Aβ is lost in mice and the animals spend more time awake (↑W). Whether the loss of diurnal CSF Aβ associated with Aβ aggregation contributes to increased wakefulness in humans with early AD remains to be determined. (C) ApoE derived from astrocytes and other glial cells is believed to facilitate Aβ clearance in the extracellular space of the brain (1). In the absence of Aβ aggregation, there is coupling of lactate with diurnal oscillations in ISF Aβ, and a normal sleep-wake rhythm. The astrocyte-neuron-lactate shuttle hypothesis (9) posits metabolic coupling of the sleep-wake cycle to astrocyte function (4). (D) In this model, lactate metabolic coupling with diurnal oscillation of Aβ would be lost after Aβ aggregation, and wakefulness would increase. One way that coupling could be lost is that astrocytes responsible for clearing Aβ and also glutamate become mobilized by Aβ plaques (6), moving toward the plaques and away from neurons. This could initiate a positive feedback loop in which astrocytes would no longer metabolize Aβ or glutamate from nearby neurons, leading to further aggregation of Aβ and increased excitotoxicity and neuronal injury due to glutamate accumulation.