Early-life chronic sleep impairment potentiates neurodegeneration and neurodegenerative diseases such as Alzheimer’s disease

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Abstract

Sleep deprivation is a common issue in the contemporary world. It has long been theorized that sleep loss can lead to neurodegenerative disorders such as Alzheimer’s disease (AD). However, the mechanisms that cause early-life chronic sleep impairment to lead to the onset of AD have not been definitively stated. In this review, we seek to better understand and contextualize the relationship between sleep impairment and neurodegeneration. To do this, we looked in depth at both human and animal studies conducted under periods of chronic sleep loss, to study the accumulation of neuronal proteins, Tau and Amyloid-Beta, in subjects undergoing sleep deprivation, to see if the findings suggest any correlation with an increased risk of AD. In addition, several studies on mice have shown that chronic sleep disruption can cause neural injuries, which are a precursor to dementia. Therefore, considering how alterations or disturbances in the sleep-wake cycle may potentiate AD, further research is necessary to determine interventions that could prevent neural injuries from sleep loss and reduce the likelihood of developing AD at an early age while investigating the implementation of solutions such as using sleep-sensitive windows to achieve the goal of earlier-life prevention.

Introduction

Sleep is critical for brain development and function in all stages of life. The National Sleep Foundation, USA, recommends a minimum of 7-8 hours of daily sleep for an adult human being1. Sleep plays a critical role in maintaining and supporting a balance in the body’s systems, through a process known as Metabolic Homeostasis1. Normal sleep has been associated with improved thermoregulation, tissue repair, memory consolidation, homeostatic restoration, and preservation of neuroimmune-endocrine integrity2. However, despite the importance of getting enough sleep, close to 100 million individuals in the USA suffer from a chronic sleep disorder that affects their health and daily life3. Sleep disorders usually manifest in one of the following ways: A failure to sustain continuous sleep (middle insomnia, disrupted sleep, difficulty sustaining sleep), failure to get the needed amount of quality sleep (Sleep Deprivation), and disruptive events occurring during sleep such as restless leg syndrome4.

Sleep disorders can cause stress, mental and semantic issues such as depression, memory loss, anxiety, chronic diseases like hypertension, cardiovascular diseases, cancer, diabetes, reduced quality of life, and increased mortality rates((Sadeghmousavi, Shaghayegh, et al. “The Effect of Insomnia on Development of Alzheimer’s Disease – Journal of Neuroinflammation.” BioMed Central, 6 Oct.2020, https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-020-01960-9)). Chronic sleep impairment refers to insufficient sleep or experiencing a lack of sleep for an extended period. Both sleep deprivation and sleep restriction associated with chronic sleep impairment affect the overall health, including decreasing an individual’s cognitive function. Thus, a chronic sleep disorder can contribute to neurodegenerative diseases as it exerts a negative impact on the brain and disturbs circadian physiology 1. Therefore, sleep disorders may contribute to the development of neurodegenerative disorders such as Alzheimer’s Disease (AD) and deserve more research attention, diagnosis, and treatment. This research is meant to show the relationship between chronic sleep disorders and neurodegenerative disorders, like Alzheimer’s Disease. Sleep deprivation can occur as a primary or secondary condition. For example, enlarged adenoids and tonsils cause significant cases of primary sleep deprivation in children. In addition, research suggests that sleep impairment can occur as a result of metabolic, neurological, genetic, medication, respiratory, endocrine, and other physical factors influencing the change in sleep patterns in both children and adults. Parenting styles, emotional state, and attitude also largely influence sleeping patterns in children5. Additionally, the knowledge and awareness about problematic sleeping habits also contribute to the duration the sleep pattern takes to resolve.

The amount of sleep needed for an individual varies from person to person however sleep is traditionally divided into 5 essential categories all of which are required to maintain mental and physical health. The order of categories in which sleep occurs is wake, N1, N2, N3, and REM sleep. Sleep deprivation occurs in two stages: Non-Rapid Eye Movement (NREM), which is comprised of stages N1-N3, and Rapid Eye Movement (REM). Every step is uniquely characterized. While eye movements, the strength of the muscle, and depth and wave patterns characterize NREM sleep, irregular brain wave action, muscle atonia, and increased movements of the eyeball characterize REM sleep. The Circadian rhythm and homeostatic process work independently to stimulate the rapid eye movement stage. The circadian rhythm is driven by a clock in the suprachiasmatic nucleus (SCN) in the hypothalamus. The SCN controls the sleep-wake cycles in response to inputs from the retina. At the same time, the homeostatic process compensates for the lost sleep through sporadic naps that extend the subsequent sleep when an individual is awake 1. Owen et al. 2021 states that chronic sleep impairment injures the brain, causing a significant risk of neurodegeneration6. The neurodegenerative symptoms of sleep loss depend on the duration of the sleep loss and the number of frequent sleep disruptions, leading to more incidence of rapid cognitive decline and dementia7. Further, sleep deprivation plays a vital role in causing major degenerative ailments such as Parkinson’s and Alzheimer’s disease. Staying awake for more extended periods disrupts circadian physiology, affecting the brain and other associated behavioral functions1. In addition, sleep deprivation leads to a considerable impact on the clearance of particular aggregates of neurotoxic proteins such as misfolded Amyloid-Beta and hyperphosphorylated Tau. High levels of these neurotoxic aggregates have been associated with cognitive decline8, indicative of neurodegenerative diseases such as Alzheimer’s and others9. Furthermore, clinical studies have shown that chronic sleep disturbances are often present in AD patients for years prior to the appearance of the symptomatic stages of neurodegenerative diseases10. In this review, we seek to better understand and contextualize how chronic sleep impairment is associated with the later onset of cognitive neurodegenerative disorders like Alzheimer’s. To do this, we looked in depth at both human and animal studies conducted under periods of chronic sleep impairment, to study the accumulation of neurotoxic, hyperphosphorylated Tau and misfolded Amyloid-Beta, in subjects undergoing sleep deprivation to see if the findings suggest any correlation with an increased risk of AD.

Removal of Tau and Amyloid-Beta during Sleep

Alzheimer’s disease is a neurodegenerative disorder marked by the loss of neurons, intracellular tau tangle and deposits of extracellular amyloid plaques, memory impairment, circadian rhythm disruptions, and behavioral changes. Amyloid-Beta exists naturally in the brain’s interstitial fluid (ISF) however, in the brains of AD patients, abnormally high levels of Amyloid-Beta peptides, clump together forming distinctive amyloid plaques that aggregate between neurons and disrupt cell function11. The means by which Amyloid-Beta is removed from the brain and its direct relation to neurodegenerative diseases, such as AD, are not yet clearly understood; however, sleep is thought to play a vital role in clearing this metabolic waste product12. Research on animals has shown increased levels of ISF Amyloid-Beta in chronic sleep-restricted rats13 and higher accumulation of Amyloid-Beta in sleep-deprived Drosophila14. In 2018, Shokri-Kojori et al.12, conducted research on 20 healthy human subjects, ages 22-72, to further look at the correlation between sleep deprivation and the accumulation of Amyloid-Beta in the brain. Using a PET scan, shown in Figure 1, this study monitored the Amyloid-Beta levels in the participants after a full night of sleep and then again following 31 hours of continuous wake, and discovered an approximately 5% increase in the level of Amyloid-Beta accumulation following sleep deprivation compared to regular sleep in the participants, with 19 of the 20 participants showing clear and robust increases in Amyloid-Beta plaques marked by radioisotopes.

This figure was taken from the experimental outputs of Shokri-Kojori et al. 201812.  which aimed to measure and compare the binding of radioactive tracer, 18F-florbetaben (FBB), serving as a marker for Amyloid-beta burden in the brain (ABB) in the brain of 20 human test subjects following a period of chronic and acute sleep deprivation (SD). Of note, higher FBB (by extension, ABB) were measured hippocampal, and thalamic regions of the brain, as represented by Figure 1. A robust increase in FBB can be observed in 19/20 participants in Figure 2, implying a 5% increase of ABB the period of SD compared to regular sleep.

Furthermore, another brain protein associated with AD is Tau, a vital microtubule-associated protein that aids in regulating proper signaling between the neuronal cells15. Balanced phosphorylation of Tau attaches it to the microtubules, brings together the microtubules, and assists in maintaining the neurons’ stability and structure15. However, when Tau becomes hyperphosphorylated, it aggregates and results in neurofibril tangles formation15 which disrupts cytoskeleton function and leads to neuronal damage and increased apoptosis16. These are among the significant indications of AD. Various studies have shown that sleep deprivation escalates the deposit of Amyloid-Beta and the formation of neurofibril tangles associated with Tau aggression which are hypothesized to ultimately contribute to the development of Alzheimer’s disease17,18. Of particular interest, is a study looking into the effects of sleep deprivation on Tau aggregates in both mice and human subjects which, as seen in Figure 2, found that interspinal fluid tau levels increased following acute sleep deprivation in mice and that sleep deprivation levels as low as 1 night are sufficient in increasing Tau levels by up to 50% in the human cerebral spinal fluid19. Therefore, based on ongoing research, the increase of both Amyloid-beta and Tau, the primary pathological factors in AD, are thus directly correlated with the subjective and objective changes in sleep.

This figure was taken from the experimental outputs of Holth et al. 201920 conducted to observe the level of Tau in human cerebrospinal fluid (CSF) in a group healthy adults, aged 30-60 following 1 night of normal sleep and 1 night of sleep deprivation. Figure A shows the measure of CSF Tau in the sleep deprived and non-sleep deprived subjects. The results of Figure A reveal that CSF Tau was increased in the participants by over 50% following the single night of sleep deprivation.

Sleep Disruption and Impaired Phagocytosis

Astrocytes are the most abundant cell type in the Central Nervous System (CNS) and are capable of performing a variety of tasks including axon guidance and synaptic support to control the blood-brain barrier and maintain extracellular homeostasis21. Although microglial cells are the primary macrophages of the CNS22, astrocytes can also phagocytose neuronal materials including neurotoxins present in neurodegenerative diseases such as amyloid plaques in AD and \alpha-synuclein in Parkinson’s disease to help maintain internal homeostasis. Phagocytosis is the mechanism by which cells engulf and digest particles, typically greater than 0.5 microns, and this process is critical for proper neuronal circuit development as waste products such as synapses, apoptotic cells, and debris must continually be removed by phagocytic cells in order for neuronal function and internal homeostasis22. However, failures in the regulation of phagocytic processes may have negative unintended consequences, leading to neurodegeneration22.

Sleep disruptions have been associated with increased astrocytic phagocytosis (AP). Bellesi et al. (2017) measured the occurrence of AP after 6-8 hours of sleep, spontaneous sleep, or sleep deprivation following a 5-day period of chronic sleep restriction placed on the mice. The study’s results on mice, detailed in Figure 3, determined that AP increased following an acute and chronic loss of sleep compared to the periods of sleep-wake cycles. The astrocytic phagocytosis of synaptic elements increases following a few hours of sleep loss23.

This figure is taken from the experimental outputs of Bellesi et al. 201723. This experiment studied the occurrence of astrocyte phagocytosis (AP) in 4 different groups of mice that either slept, were spontaneously awake, sleep deprived, or had chronic short sleep. Figure A shows the experimental design for each group of mice. Figure B measures the occurrence of AP in each group of mice, indicating the AP occurred more frequently in SD and CSR mice than in regular S mice, suggesting that sleep loss promoted AP as a whole.

This increased AP is greater after acute and chronic sleep loss which suggests that it may contribute to the housekeeping of well-established and heavily used synapses caused by increased neural activities following long hours of staying awake. In contrast, chronic sleep restriction, rather than acute sleep loss, leads to the increased phagocytic activity of microglia without notable neuroinflammation23, thus leaving the brain susceptible to other kinds of damage such as neurodegeneration as a result of persistent microglial activation24. It is currently proposed that increased microglial activation (microglial priming) occurs during chronic short sleep due to an accumulation of amyloid-beta plaques resulting from sleep deprivation25 which in turn promotes microglial priming26, making the microglia more susceptible to secondary inflammatory stimulus and other pathological states including neurodegeneration24.

A similar study on mice observed twice as many synapses of astrocyte activity in mice who were sleep-deprived compared to the others who had received enough rest27 while another study observed increased microglia and astrocyte activation in the hippocampus of sleep-deprived rats28. Sleep deprivation thus causes astrocytes to break down more debris from the brain and its connection, although it is yet to be determined whether this carries benefits. Therefore, from the results of both studies, the cell activities of mice are found to increase due to sleep deprivation. This situation is worrying since the increased activity of the microglial cells, observed in a state of sleep deprivation, makes the brain more vulnerable to harm6. The same is also associated with Alzheimer’s disease and other neurodegeneration. Sleep deprivation suppresses the body’s response against antigens, reducing the total leukocytes and lymphocytes, and reducing the total cell number29. Furthermore, studies have determined an increase in circulating phagocytes and inflammatory molecules29. All these observations show the interrelationship between sleep and the immune and nervous system functioning.

Sleep Disruption Induced Neurodenegeneration

Sleep impairment is a common issue in the contemporary world. Early-life chronic sleep impairment increases the risk of neurodegeneration, contributing to conditions like Alzheimer’s disease (AD)15. Owen et al. 2020 defines neurodegeneration as the loss, damage, and death of neurons associated with impairments in behaviors. The loss of volume in some brain regions is usually used to replace neural loss as an indicator of neurodegeneration. Overall, the reduction in regional brain volume usually signifies injury. However, volume loss can also be caused by changes in neurites, myelin, and vasculature, when there is no neural loss. Generally, although earlier injuries can be reversed, an increase in the sleep loss period results in cumulative brain injury or neurodegeneration30.

Noorafshan et al. 2017 reported that chronic sleep restriction in rats for over three to four weeks resulted in a reduction in the volume of two of their brainstem respiratory nuclei and in the medial prefrontal cortex31. Consequently, on observing the medial prefrontal cortex for three to four weeks post-recovery, Noorafshan et al. 2017 determined that the volume reduction in this region was not reversed31. Furthermore, cell loss has also been determined in several regions following sleep disruption30. The formation of new neurons in the brain occurs throughout one’s life, however, it decreases as one advances into old age, leading to impaired learning and memory capacities as well as pathological conditions such as those present in Alzheimer’s disease32. Sleep deprivation slows the rate of neurogenesis since volume and cell loss occur in various regions of the brain after sleep loss.

The main mechanisms that lead to neurodegeneration are oxidative stress, accumulation and misfolding of abnormal proteins, neuroinflammation, and mitochondrial dysfunction33. Alzheimer’s disease, a common neurodegenerative condition, is signified through the accumulation of neurofibrillary tangles and Amyloid-Beta, which cause the neurons to be inflamed, leading to cell death34. Sleep aids in removing harmful proteins such as Amyloid-Beta from the brain. Conversely, sleep deprivation causes the accumulation of such harmful proteins leading to inflammation, which ultimately causes neurodegeneration. The effect of sleep loss on neurodegeneration varies with the duration of sleep deprivation30. Overall, sleep loss influences Tau, Amyloid-Beta, and Alpha-Synuclein, leading to faster progression of neurodegenerative disorders such as AD. The mechanisms that cause early-life chronic sleep deprivation to lead to the onset of neurodegenerative disorders have not been definitively stated. However, studies show that sleep deprivation causes an immediate release of a protein associated with Alzheimer’s disease known as Beta-Amyloid15. Another main neurological hallmark of Alzheimer’s disease is Tau, a microtubule-associated protein in the neurons responsible for maintaining the structure and stability of neurons15. Current proposals imply that sleep deprivation may cause the accumulation of Tau and Beta-amyloid. Therefore, the research evaluated chronic sleep impairment as a factor associated with tau and beta-amyloid accumulation in the brain’s cerebrospinal fluid35. The findings indicated that alteration of sleep duration throughout the lifespan could result in tau and beta-amyloid accumulation.

To find out how sleep impairment and Alzheimer’s disease correlate, it is imperative to understand how pathologies of Tau and Beta-Amyloid interact and affect sleep regulation in the brain. Several studies have documented animal models exhibiting sleep disturbances. For instance, one study suggested that mice models with a higher tau buildup show Alzheimer’s disease-like sleep disturbances implying that tau has a role in sleep disturbances evident in Alzheimer’s disease19. Also, research states that the deprivation of sleep in mice acutely increases the levels of Tau and Beta-amyloid in the hippocampal extracellular space6. Lastly, in-vivo Microdialysis of mice found that the levels of beta-amyloid in the mice’s brain are correlated with their wakefulness15. Hence, chronic sleep impairment may accelerate the beta-amyloid burden in the mice’s brain.

Discussion

This study assessed the association of chronic short sleep induced aggregate amyloid-beta and tau on the pathology of AD. Several scientific studies support the idea that sleep deprivation may lead to neurodegenerative disorders like Alzheimer’s. For instance, short sleep duration and poor sleep quality are linked to neurodegeneration and beta-amyloid accumulation. Critically, in 2020, 5.8 million American citizens over the age of 65 were experiencing AD, with total treatment costs expected to be around 379 and more than500 billion annually by 204036. Furthermore, several experimental findings have indicated that misfolded Amyloid-beta and Tau correlate sleep with Alzheimer’s disease. For instance, aggregate tau and beta-amyloid are distinctive features of AD pathology, and their levels increase in cases of chronic sleep impairment.

Studies on mice have shown that sleep deprivation can cause neural injury, which is a precursor to neurodegeneration. The neural injuries are consequently evident for a long period post-exposure to sleep deprivation in young adults, and the patterns of injury overlap with some Alzheimer’s disease features. This research, therefore, supports sleep deprivation in early life as a threat to brain health later in life. Considering how alterations or disturbances in the sleep-wake cycle may potentiate Alzheimer’s disease, further research is required to prove the definitive link between chronic short sleep induced phosphorylated Tau and Amyloid-beta aggregates with the development of Alzheimer’s disease. Such studies could be used to determine interventions that could prevent neural injuries from sleep loss and reduce the likelihood of developing AD due to chronic sleep deprivation at an early age.

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