Metabolite Clearance During Wakefulness and Sleep

Abstract

Mechanisms for elimination of metabolites from ISF include metabolism, blood-brain barrier transport and non-selective, perivascular efflux, this last being assessed by measuring the clearance of markers like inulin. Clearance describes elimination. Clearance of a metabolite generated within the brain is determined as its elimination rate divided by its concentration in interstitial fluid (ISF). However, the more frequently measured parameter is the rate constant for elimination determined as elimination rate divided by amount present, which thus depends on both the elimination processes and the distribution of the metabolite in the brain. The relative importance of the various elimination mechanisms depends on the particular metabolite. Little is known about the effects of sleep on clearance via metabolism or blood-brain barrier transport, but studies with inulin in mice comparing perivascular effluxes during sleep and wakefulness reveal a 4.2-fold increase in clearance. Amongst the important brain metabolites considered, CO is eliminated so rapidly across the blood-brain barrier that clearance is blood flow limited and elimination quickly balances production. Glutamate is removed from ISF primarily by uptake into astrocytes and conversion to glutamine, but also by transport across the blood-brain barrier. Both lactate and amyloid-β are eliminated by metabolism, blood-brain barrier transport and perivascular efflux and both show decreased production, decreased ISF concentration and increased perivascular clearance during sleep. Taken altogether available data indicate that sleep increases perivascular and non-perivascular clearances for amyloid-β which reduces its concentration and may have long-term consequences for the formation of plaques and cerebral arterial deposits.

The “glymphatic” mechanism for solute clearance in Alzheimer's disease: game changer or unproven speculation?

“…Aβ peptides are generated from the amyloid precursor protein, a transmembrane protein expressed on neurons, by the action of various proteases (40). Monomeric Aβ can be cleared from the brain by several mechanisms, including intracellular and extracellular degradation, accumulation in plaques, transcytosis across the blood‐brain barrier, and bulk clearance into the CSF (4, 41). Soluble oligomers of Aβ, which are thought to be the toxic form of the peptide, have high membrane affinity and do not move freely in the ECS (42).…”

“…As a consequence of the multiple clearance mechanisms, the kinetics of Aβ clearance in vivo is considerably more complex than that of inert membrane‐impermeant tracer molecules, such as dextrans. Aβ peptides are cleared more rapidly than comparably sized dextrans (28, 43), suggesting the potentially limited importance of the paravascular clearance pathway for Aβ clearance in the healthy brain (41). However, it is possible that Aβ proteolysis and blood‐brain barrier transcytosis become substantially impaired in AD, which might increase the relative importance of paravascular clearance mechanisms under certain conditions (44).…”

“…Limitations of existing models include failure to account for distortion of brain structure in response to pressure pulsation (compliance) and effects of activity‐dependent solute transport between the endfoot and paravascular space. We also note that existing models do not include the extracellular matrix, which will reduce the cross‐sectional area available for convective fluid flow and increase hydraulic resistance (41) so that model results provide an upper limit on convective rates, making it even less likely that convection can occur.…”

Sex‐specific incident dementia in patients with central nervous system trauma

“…It is crucial that this evidence is acknowledged in research and practice. Sleep has been shown to play a protective role in warding off toxic protein accumulation [55] , and scientific evidence is rapidly developing, suggesting that the “glymphatic” system of the CNS, the interstitial spaces surrounding glia, and neurons, has substantially higher clearance of amyloid beta during sleep as compared with wakefulness, potentially reducing evolution of neurodegeneration in those with healthy sleep [56] . Future research on this topic is greatly needed.…”

This was the year that was: brain barriers and brain fluid research in 2019

“…There has been much interest in the effects of the sleep/ wake cycle on the clearance of metabolic waste products from the brain, particularly potentially toxic metabolites including β-amyloid (Aβ) and tau and this was reviewed in-depth by Hladky and Barrand [99]. Recently, Holth et al [100] have examined the effects of the sleep/wake cycle on brain interstitial fluid and CSF tau and found high levels during wakefulness and sleep deprivation.…”