Sleep Facilitates Clearance of Metabolites from the Brain: Glymphatic Function in Aging and Neurodegenerative Diseases

Abstract

Decline of cognition and increasing risk of neurodegenerative diseases are major problems associated with aging in humans. Of particular importance is how the brain removes potentially toxic biomolecules that accumulate with normal neuronal function. Recently, a biomolecule clearance system using convective flow between the cerebrospinal fluid (CSF) and interstitial fluid (ISF) to remove toxic metabolites in the brain was described. Xie and colleagues now report that in mice the clearance activity of this so-called "glymphatic system" is strongly stimulated by sleep and is associated with an increase in interstitial volume, possibly by shrinkage of astroglial cells. Moreover, anesthesia and attenuation of adrenergic signaling can activate the glymphatic system to clear potentially toxic proteins known to contribute to the pathology of Alzheimer disease (AD) such as beta-amyloid (Abeta). Clearance during sleep is as much as two-fold faster than during waking hours. These results support a new hypothesis to answer the age-old question of why sleep is necessary. Glymphatic dysfunction may pay a hitherto unsuspected role in the pathogenesis of neurodegenerative diseases as well as maintenance of cognition. Furthermore, clinical studies suggest that quality and duration of sleep may be predictive of the onset of AD, and that quality sleep may significantly reduce the risk of AD for apolipoprotein E (ApoE) ɛ4 carriers, who have significantly greater chances of developing AD. Further characterization of the glymphatic system in humans may lead to new therapies and methods of prevention of neurodegenerative diseases. A public health initiative to ensure adequate sleep among middle-aged and older people may prove useful in preventing AD, especially in apolipoprotein E (ApoE) ɛ4 carriers.

New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation

“…Aβ deposition in the preclinical stage of AD appears to be associated with worse sleep quality (Ju et al, 2013; Spira and Gottesman, 2017) and was also associated with worse cognitive and memory performance (Molano et al, 2017). An alternative mechanism linking sleep and Aβ has been recently suggested (Mendelsohn and Larrick, 2013), whereby sleep can facilitate the removal of toxic proteins and other molecules from the brain through regulation of the ‘glymphatic’ system (Jessen et al, 2015). Extracellular Aβ is vacated by this mechanism twice as fast as during NREM SWS than during awake periods (Xie et al, 2013).…”

Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion

“…20,21 Sleep is also critically involved in systemic physiology, including metabolism, [22][23][24][25][26] appetite regulation, 27,28 immune and hormone function, [29][30][31][32][33] and cardiovascular systems. [34][35][36][37] Sleep duration is associated with mortality risk [38][39][40] and with illnesses ranging from cardiovascular 41 and cerebrovascular 42 disease to obesity, 43 diabetes, 44 cancer, 45,46 and depression.…”

Significance of Understanding Function of Glymphatic System to Manage Practical Clinical Problems of the Elderly

“…Mendelsohn et al state that "clinical studies suggest that the quality and duration of sleep may be predictive of the onset of AD, and that quality sleep may significantly reduce the risk of AD" [15]. Deformation of the perivascular space is also found in vascular forms of dementia [1].…”