Does Sleep “Clean” Our Brains?

Post by Lani Cupo

Why do we spend so much of our life asleep?

An Irish proverb states: “A good laugh and a long sleep are the best cures in the doctor’s book.” We spend almost one-third of our lives asleep, but what makes sleep restorative, and why do we need so much of it? Sleep has many benefits like facilitating memory consolidation and emotion regulation, but today we focus on the role sleep plays in clearing the brain of neurotoxins that accumulate during waking hours. During daily functioning, the brain accumulates proteins such as β-amyloid (Aβ), α-synuclein, and tau over the course of waking hours. Accumulation of these proteins over the lifespan may contribute to brain pathology, so it is important that concentrations of these proteins are regulated. Recent evidence suggests that sleep may in part fill this role, helping to protect the brain by clearing the excess of these proteins.

What do we know?

Brain tissue is composed of three main components: neural cells, vasculature, and the interstitial system (ISS) referring to the space between cells and blood vessels. Most recent research on the brain focuses on cells such as neurons and glia, however, the ISS forms the microenvironment of the brain. It occupies 15-20% of total brain volume and plays a pivotal role in healthy brain functioning. Evidence from mice suggests that during sleep, interstitial volume can increase up to 60% allowing for increased flow between interstitial fluid and cerebrospinal fluid (CSF), the fluid in which the brain is floating. This might facilitate the improved clearance of toxins from brain tissue. While the mechanism allowing for the change in volume is still unknown, one hypothesis is that support cells known as astrocytes shrink during sleep, resulting in the observed volumetric changes.

To examine whether sleep facilitates the clearance of metabolites via CSF, one study in humans injected individuals with a CSF tracer they could image with magnetic resonance imaging (MRI) and investigated the impact of acute (one night) sleep deprivation on tracer clearance as a proxy for metabolite clearance. Following a night of sleep deprivation, tracer clearance was reduced, suggesting less effective clearance of neurotoxins. This finding is significant not only because it presents some of the first live human evidence, but also because the authors were able to assess clearance in deep structures within the brain.

During wakefulness, ISS contraction increases tissue resistance, reducing the influx of CSF. This potentially alters not only the clearance of excess neurotransmitters but also aggregates of proteins in the brain. Circadian rhythms, which help regulate sleep cycles, may also impact clearance by altering the permeability of the blood-brain barrier, the interface between circulating blood and the central nervous system. During sleep, this barrier becomes more porous, further impacting the clearance of proteins. Examining the clearance of the Aβ protein, one study in mice found the protein was cleared twice as fast during sleep as compared to wakefulness. This holds important implications for neurodegenerative disorders, as the accumulation of Aβ plaques is a hallmark of Alzheimer’s Disease (AD) pathology.

What are the implications for Alzheimer’s Disease?

Sleep is an important factor in the emergence of neurodegenerative disorders, such as AD and Parkinson’s Disease. When there is an imbalance between Aβ production and clearance in the brain, the protein can stick together causing aggregates, known as plaques, to form. Excess tau protein can also get stuck together forming “tangles”. The formation of Aβ plaques and tau tangles contribute to the loss of neurons and their connections. Similar to human studies, rodent models show that sleep deprivation elevates concentrations of Aβ, with concentrations increasing consistently over prolonged sleep deprivation. While an increased risk for AD has been associated with a shorter duration of sleep, the causal link between sleep deprivation and heightened risk for AD remains to be determined. It also remains unclear whether the mechanistic link between sleep disturbances and AD involves neurotoxin clearance.

The specific mechanism of toxin clearance from the brain is still unknown, although preliminary research implicates a specific water channel known as aquaporin-4 in the removal of interstitial waste. Recent studies implicate a brain region known as the locus coeruleus (LC) in the regulation of sleep - signaling from the LC is associated with states of wakefulness. This region displays volumetric abnormalities in AD, suggesting that it may be related to the pathophysiology of the disease.

What is the takeaway message?

During the time we sleep our brain tissues undergo changes that facilitate more efficient cleansing of the toxins and waste that naturally accumulate in our brains over the course of the day. This mechanism could underlie the observed association between neurological disorders like AD and sleep disturbance, however, it remains unclear whether sleep deprivations exacerbate AD pathology or if AD pathology exacerbates sleep disruption. Of course, if you don’t get enough sleep it does not mean that you will develop a neurological disorder, however, the research strongly suggests that sleep is a critical factor in brain health. Overall, the benefits of sleep are many-fold, and we are still learning exactly how sleep supports and protects our brain.

References

Albrecht, et al. Circadian Clocks and Sleep: Impact of Rhythmic Metabolism and Waste Clearance on the Brain. Trends in Neurosciences. (2018). Access the original scientific publication here.

Eide, et al. Sleep Deprivation Impairs Molecular Clearance from the Human Brain. Brain: Journal of Neurology. (2021). Access the original scientific publication here.

Goldstein & Walker. The role of sleep in emotional brain function. Annu Rev Clin Psychol. (2014). Access the original scientific publication here.

Huang, et al. Sleep, Major Depressive Disorder and Alzheimer’s Disease: A Mendelian Randomisation Study. Neurology. (2020). Access the original scientific publication here.

Lei, et al. The Brain Interstitial System: Anatomy, Modeling, in Vivo Measurement, and Applications. Progress in Neurobiology (2017). Access the original scientific publication here.

Mendelsohn & Larrick. Sleep Facilitates Clearance of Metabolites from the Brain: Glymphatic Function in Aging and Neurodegenerative Diseases. Rejuvenation Research (2013). Access the original scientific publication here.

Xie, et al. Sleep Drives Metabolite Clearance from the Adult Brain. Science (2013).Access the original scientific publication here.