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Review
. 2020 Aug 25:14:894.
doi: 10.3389/fnins.2020.00894. eCollection 2020.

The Bidirectional Relationship Between Sleep and Inflammation Links Traumatic Brain Injury and Alzheimer's Disease

Tabitha R F Green  1   2 , J Bryce Ortiz  1   2 , Sue Wonnacott  3 , Robert J Williams  3 , Rachel K Rowe  1   2   4
Affiliations
Review

The Bidirectional Relationship Between Sleep and Inflammation Links Traumatic Brain Injury and Alzheimer's Disease

Tabitha R F Green et al. Front Neurosci. .

Abstract

Traumatic brain injury (TBI) and Alzheimer's disease (AD) are diseases during which the fine-tuned autoregulation of the brain is lost. Despite the stark contrast in their causal mechanisms, both TBI and AD are conditions which elicit a neuroinflammatory response that is coupled with physical, cognitive, and affective symptoms. One commonly reported symptom in both TBI and AD patients is disturbed sleep. Sleep is regulated by circadian and homeostatic processes such that pathological inflammation may disrupt the chemical signaling required to maintain a healthy sleep profile. In this way, immune system activation can influence sleep physiology. Conversely, sleep disturbances can exacerbate symptoms or increase the risk of inflammatory/neurodegenerative diseases. Both TBI and AD are worsened by a chronic pro-inflammatory microenvironment which exacerbates symptoms and worsens clinical outcome. Herein, a positive feedback loop of chronic inflammation and sleep disturbances is initiated. In this review, the bidirectional relationship between sleep disturbances and inflammation is discussed, where chronic inflammation associated with TBI and AD can lead to sleep disturbances and exacerbated neuropathology. The role of microglia and cytokines in sleep disturbances associated with these diseases is highlighted. The proposed sleep and inflammation-mediated link between TBI and AD presents an opportunity for a multifaceted approach to clinical intervention.

Keywords: Alzheimer’s disease; concussion; cytokines; inflammation; microglia; neurodegeneration; sleep; traumatic brain injury.

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Figures

FIGURE 1
FIGURE 1
TBI to AD, an inter-disease trajectory. TBI disrupts the blood brain barrier (BBB) upon insult which results in an infiltration of peripheral pro-inflammatory cytokines and any soluble pools of amyloid-β (Aβ) and Tau. Together, these can precipitate AD. As some pro-inflammatory cytokines have dual (opposing) roles as sleep regulatory substances, their increase can also lead to sleep disturbances, a characteristic that commonly precedes the cognitive decline in AD. Pro-inflammatory cytokines upregulate the activation of microglia, which act as a positive feedback mechanism, resulting in increased pro-inflammatory cytokine production and an increased breach of the BBB. Unregulated cytokine release also sustains microglial activation and priming which results in a chronic pro-inflammatory microenvironment. This includes astrocytosis, hypoxia, reactive oxygen species (ROS), elevated cytokine levels, and microglial activation. The movement of amyloid-β (Aβ) and Tau through the breach in the BBB could potentially seed protein oligomerization and aggregation, thereby acting as possible drivers of central plaque and tangle pathology. Such aggregates in the brain further contribute to microglial activation, the pro-inflammatory microenvironment, and neuronal apoptosis. Together, these contribute to cognitive dysfunction and brain atrophy, the key pathological features of AD. Both brain atrophy and neuronal death help to sustain the pro-inflammatory microenvironment creating a self-perpetuating feedback loop.
FIGURE 2
FIGURE 2
Depiction of a coronal brain slice showing the global expanse of microglial phenotypes in TBI and AD. The left illustrates localized effects of TBI which include increased microglial activation near the injury site and decreased activation in distal regions. In comparison, the right represents the AD brain with widespread changes in microglia morphology, gross structural changes to the cortex, and an enlargement of ventricles (gray). Both TBI and AD lead to increased inflammation and activated microglia. Despite this similarity, distinct microglial morphologies are observed in these conditions. (1) Microglia are activated, migrate to the injury site, and display an amoeboid or phagocytic morphology. (2) Rod-cell morphology is often observed in the cortex after TBI and have also been documented in AD tissue. However, the function of this cell phenotype is currently unknown, and the morphology is not restricted to TBI/AD or the region in which they are shown. (3) Distal to the injury site, microglia are ramified and occur at a lower density. (4) Microglia that surround amyloid-β plaques show activated, amoeboid, and dystrophic morphologies. Cells of each phenotype pictured are not restricted to the brain regions shown.
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