Alzheimer's Disease and Sleep-Wake Disturbances: Amyloid, Astrocytes, and Animal Models

Abstract

Sleep-wake abnormalities are common in patients with Alzheimer's disease, and can be a major reason for institutionalization. However, an emerging concept is that these sleep-wake disturbances are part of the causal pathway accelerating the neurodegenerative process. Recently, new findings have provided intriguing evidence for a positive feedback loop between sleep-wake dysfunction and β-amyloid (Aβ) aggregation. Studies in both humans and animal models have shown that extended periods of wakefulness increase Aβ levels and aggregation, and accumulation of Aβ causes fragmentation of sleep. This perspective is aimed at presenting evidence supporting causal links between sleep-wake dysfunction and aggregation of Aβ peptide in Alzheimer's disease, and explores the role of astrocytes, a specialized type of glial cell, in this context underlying Alzheimer's disease pathology. The utility of current animal models and the unexplored potential of alternative animal models for testing mechanisms involved in the reciprocal relationship between sleep disruption and Aβ are also discussed.Dual Perspectives Companion Paper: Microglia-Mediated Synapse Loss in Alzheimer's Disease by Lawrence Rajendran and Rosa Paolicelli.

Keywords: beta-amyloid; circadian rhythms; glia; neurodegeneration.

Figure 1.

Mechanisms linking sleep and Aβ aggregation: an astrocytic hypothesis. A, In the soluble state, Aβ has been shown to have diurnal oscillations associated with the sleep–wake cycle (Roh et al., 2012). Neuronal activity and wakefulness are thought to increase Aβ release from neurons. Mechanisms that may reduce extracellular levels of Aβ during sleep periods, such as ApoE-derived Aβ-clearance from astrocytes and other glial cells, would prevent Aβ oligomerization and aggregation. Oscillations of lactate are coupled with normal (balanced) behavioral changes in the sleep–wake cycle (Naylor et al., 2012) and extracellular Aβ levels (Roh et al., 2012). The ANLS hypothesis proposes that astrocytic uptake of activity-dependent glutamate release at synapses in turn triggers glucose uptake, which is then converted to lactate and supplied back to neurons to facilitate metabolic demand (Pellerin and Magistretti, 2012). B, Sleep decline, as occurs with normal aging, may slow Aβ-derived clearance mechanisms while simultaneously promoting the further release of wakefulness-induced Aβ release, thereby permitting Aβ oligomerization and subsequent plaque formation. The plaques would serve as a “sink” for Aβ oligomers, generating an Aβ concentration gradient. This Aβ gradient would attract astroglial-derived clearance mechanisms, mobilizing glia and preventing normal ANLS coupling, and the establishment of the underlying pathology of Alzheimer's disease. Without proper functioning astrocytes, excessive wakefulness would further increase glutamate release and generate excitotoxicity damage, leading to neurodegeneration and cognitive dysfunction. Thus, dysfunctional ANLS coupling would aggravate a vicious cycle linking sleep fragmentation with Aβ release, amyloid plaque formation, and progressive neuronal loss.