Mechanisms linking circadian clocks, sleep, and neurodegeneration

Abstract

Disruptions of normal circadian rhythms and sleep cycles are consequences of aging and can profoundly affect health. Accumulating evidence indicates that circadian and sleep disturbances, which have long been considered symptoms of many neurodegenerative conditions, may actually drive pathogenesis early in the course of these diseases. In this Review, we explore potential cellular and molecular mechanisms linking circadian dysfunction and sleep loss to neurodegenerative diseases, with a focus on Alzheimer's disease. We examine the interplay between central and peripheral circadian rhythms, circadian clock gene function, and sleep in maintaining brain homeostasis, and discuss therapeutic implications. The circadian clock and sleep can influence a number of key processes involved in neurodegeneration, suggesting that these systems might be manipulated to promote healthy brain aging.

Figure 1. Impact of sleep, central, and peripheral circadian rhythms on brain homeostasis

The SCN synchronizes circadian rhythms in the cellular clocks of cells in the brain, the sleep wake cycle, and peripheral organs. Cellular clocks within neurons and glia in turn regulate transcription of genes involved in critical processes such as redox homeostasis, inflammation, proteostasis, and metabolism. Sleep influences many of the same pathways, perhaps in some cases through interaction with the clock. Circadian regulation of peripheral metabolism, inflammation, and hormone secretion also impacts the brain.

Figure 2. Proposed mechanisms linking sleep loss, Aβ, and neurodegeneration in AD

Sleep deprivation or fragmentation can result from aging, other diseases, environmental influences, circadian clock (SCN) dysfunction, or neurodegeneration. Increased wakefulness, which is promoted by orexin, causes increased neuronal activity, leading to elevated Aβ production and aggregation. Wakefulness also increases sympathetic output, suppressing glymphatic system function. This could result in decreased clearance of pathogenic proteins (such as Aβ, tau, or synuclein). Sleep loss and clock disruption also promotes oxidative stress, inflammation and a loss of synaptic homeostasis. These insults combine to promote neurodegeneration, which in turn causes more circadian and sleep dysfunction.

Figure 3. Core clock genes in the brain regulate neurodegeneration

A. Schematic depicting the core circadian clock. Bmal1 drives transcription of a wide array of clock-controlled genes, which regulate key processes involved in neurodegeneration. The circadian transcriptome could vary between neurons, astrocytes, and microglia. B. Disruption of the cellular clock in the brain with sparing of SCN function, achieved in Nestin-Cre;Bmal1flox/flox mice, causes severe reactive astrogliosis in cerebral cortex (as assessed by GFAP staining), and promotes oxidative stress and neuronal injury.