The Emerging Relationship Between Interstitial Fluid–Cerebrospinal Fluid Exchange, Amyloid-β, and Sleep

Abstract

Amyloid-β (Aβ) plaques are a key histopathological hallmark of Alzheimer's disease (AD), and soluble Aβ species are believed to play an important role in the clinical development of this disease. Emerging biomarker data demonstrate that Aβ plaque deposition begins decades before the onset of clinical symptoms, suggesting that understanding the biological determinants of the earliest steps in the development of AD pathology may provide key opportunities for AD treatment and prevention. Although a clinical association between sleep disruption and AD has long been appreciated, emerging clinical studies and insights from the basic neurosciences have shed important new light on how sleep and Aβ homeostasis may be connected in the setting of AD. Aβ, like many interstitial solutes, is cleared in part through the exchange of brain interstitial fluid and cerebrospinal fluid along a brain-wide network of perivascular pathways recently termed the glymphatic system. Glymphatic function is primarily a feature of the sleeping brain, rather than the waking brain, and is slowed in the aging and posttraumatic brain. These changes may underlie the diurnal fluctuations in interstitial and cerebrospinal fluid Aβ levels observed in both the rodent and the human. These and other emerging studies suggest that age-related sleep disruption may be one key factor that renders the aging brain vulnerable to Aβ deposition and the development of AD. If this is true, sleep may represent a key modifiable risk factor or therapeutic target in the preclinical phases of AD.

Is Alzheimer’s Disease a Liver Disease of the Brain?

“…The clearance of amyloid from the brain during sleep is primarily via the glymphatic pathway [66,67]. These lymphatic vessels exit the cranium along veins and arteries associated with the middle meningeal arteries, transporting waste via the deep cervical lymph nodes to the systemic circulation (reviewed in [68]).…”

Is Sleep Disruption a Cause or Consequence of Alzheimer’s Disease? Reviewing Its Possible Role as a Biomarker

“…The glymphatic activity seemed to be an important feature of the sleeping brain, rather than of the awake brain. Therefore, these changes in the paravascular flow could underlie the circadian fluctuations in extracellular and CSF Aβ levels observed in both rodents and humans [129]. In a study comparing awake mice with mice in states of physiological sleep or sleep induced by anesthesia, Xie and colleagues [130] found that Aβ was eliminated more efficiently (at twice the speed) during physiological sleep or anesthesia, than during wakefulness.…”

“…Based on these results, many researchers are focusing their attention on this novel mechanism linking sleep, metabolite clearance and the development of AD [127,129,[132][133][134], even though it has received contrary and critical opinions [135].…”

Regional differences in the ependyma of the optic tectal ventricle of adult zebrafish with structures referring to brain hydrodynamics

“…However, it is mostly unknown how the CSF, directly or indirectly, supplies the brain parenchyma with the interstitial fluid (ISF), the required “internal milieu.” There are different and sometimes conflicting data concerning the interactions of the two fluid systems (Abbott, ; Abbott, ; Boespflug & Iliff, ; Brinker, Stopa, Morrison, & Klinge, ; Hladky & Barrand, ; Klarica, Radoš, & Orešković, ; Ma et al, ; Nakada & Kwee, ; Orešković, Radoš, & Klarica, ; Redzic, ). Whether the CSF through diffusion and/or convection may enter into the interstitial space of the neural parenchyma from the ventricular space through the ependymal lining and/or through the perivascular spaces of the larger vessels, are still under question (Boespflug & Iliff, ; Hladky & Barrand, ; Klarica et al, ). It is also not clear whether the CSF/ISF can flow within the very dense neuronal parenchyma or it is only diffusion that drives the fluid exchange (Abbott, ; Abbott, ).…”