Sleep fragmentation and sepsis differentially impact blood–brain barrier integrity and transport of tumor necrosis factor-α in aging

Abstract

The factors by which aging predisposes to critical illness are varied, complex, and not well understood. Sepsis is considered a quintessential disease of old age because the incidence and mortality of severe sepsis increases in old and the oldest old individuals. Aging is associated with dramatic changes in sleep quality and quantity and sleep increasingly becomes fragmented with age. In healthy adults, sleep disruption induces inflammation. Multiple aspects of aging and of sleep dysregulation interact via neuroimmune mechanisms. Tumor necrosis factor-α (TNF), a cytokine involved in sleep regulation and neuroimmune processes, exerts some of its effects on the CNS by crossing the blood–brain barrier (BBB). In this study we examined the impact of sepsis, sleep fragmentation, and aging on BBB disruption and TNF transport into brain. We used the cecal ligation and puncture (CLP) model of sepsis in young and aged mice that were either undisturbed or had their sleep disrupted. There was a dichotomous effect of sepsis and sleep disruption with age: sepsis disrupted the BBB and increased TNF transport in young mice but not in aged mice, whereas sleep fragmentation disrupted the BBB and increased TNF transport in aged mice, but not in young mice. Combining sleep fragmentation and CLP did not produce a greater effect on either of these BBB parameters than did either of these manipulations alone. These results suggest that the mechanisms by which sleep fragmentation and sepsis alter BBB functions are fundamentally different from one another and that a major change in the organism’s responses to those insults occurs with aging.

Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment

“…Circulating RAGE ligands were increased in serum, and RAGE was up-regulated in brain structures. These data could indicate that the influx of peripheral RAGE ligands to the CNS is occurring, as sepsis-impaired BBB allows unspecific transport of pro-inflammatory mediators to the brain (10,11,60). Although the determination of RAGE ligands in total tissue does not reflect the extracellular content of these molecules in the CNS, they presented little or no variations, corroborating the hypothesis that RAGE in CNS is activated and up-regulated by peripherally-produced ligands and cytokines.…”

Cultivating a healthy neuro‐immune network: A health psychology approach

“…Experimental animal models demonstrate that sleep deprivation leads to increases in circulating markers of inflammation in the periphery (Gorczynski et al, ; Pandey & Kar, ). There is also evidence that sleep deprivation and sleep fragmentation increase the transport of inflammatory cytokines across the BBB, particularly in aged mice (Opp et al, ). In addition, prolonged sleep deprivation causes increased microglial activation in rodents, which is also associated with the development of neurocognitive decline and anxious behavior (Bellesi et al, ; Wadhwa et al, ; Wadhwa et al, ).…”

Blood–brain barrier and its function during inflammation and autoimmunity

“…Interestingly, recent observations have suggested the link between aging and BBB dysfunction. The drop in the quality and quantity of the sleep occurred during normal aging has found to influence the integrity of the BBB in old‐age rodent animals, possibly due to increased systemic inflammation . Interestingly, a recent report shows that sleep disturbance of C57BL/6 mice leads to increase in serum level of TNF and IFN‐γ, increased expression of adenosine A2A receptor, MMP9 and microglial activation in the hippocampal region, and overall increased permeability of BBB .…”

“…The drop in the quality and quantity of the sleep occurred during normal aging has found to influence the integrity of the BBB in old-age rodent animals, possibly due to increased systemic inflammation. 160,161 Interestingly, a recent report shows that sleep disturbance of C57BL/6 mice leads to increase in serum level of TNF and IFN-, increased expression of adenosine A2A receptor, MMP9 and microglial activation in the hippocampal region, and overall increased permeability of BBB. 162 Notably, such changes were not observed in BALB/c mice, which generally show predominant anti-inflammatory response compared to C57BL/6 mice, 162 suggesting that both local and systemic inflammatory pathways may play a critical role in regulating BBB permeability.…”