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Glymphatic Failure as a Pathway to Dementia Science 02 Oct 2020: Glymphatic failure as a final common pathway to dementia Maiken Nedergaard, et.al. Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA. [paraphrase] Sleep is evolutionarily conserved across all species, and impaired sleep is a common trait of the diseased brain. Sleep quality decreases as we age, and disruption of the regular sleep architecture is a frequent antecedent to the onset of dementia in neurodegenerative diseases. The glymphatic system, which clears the brain of protein waste products, is mostly active during sleep. Yet the glymphatic system degrades with age, suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias. The ties that bind sleep, aging, glymphatic clearance, and protein aggregation have shed new light on the pathogenesis of a broad range of neurodegenerative diseases, for which glymphatic failure may constitute a therapeutically targetable final common pathway. A fundamental tenet of brain homeostasis is that protein clearance must approximate protein synthesis. Is removal of protein waste also controlled by the sleep-wake cycle? Until 2012 it was believed that the brain, singular among organs, was recycling all of its own protein waste. Only a small number of proteins were known to be transported across the blood-brain barrier, and these did not include most of the primary proteins made or shed by brain cells. In the absence of lymphatic vessels or any overt pathways for fluid export, it was unclear how protein waste might exit the mature brain parenchyma. The default conclusion was that the classical cellular protein degradation pathways—autophagy and ubiquitination—must be responsible for all central nervous system (CNS) protein recycling. This supposition, that the brain must recycle its own waste, was questioned after the discovery of the glymphatic system. The glymphatic system is a highly organized cerebrospinal fluid (CSF) transport system that shares several key functions, including the export of excess interstitial fluid and proteins, with the lymphatic vessels of peripheral tissues. Indeed, both the brain’s CSF and peripheral lymph are drained together into the venous system, from which protein waste is removed and recycled by the liver. Yet brain tissue itself lacks histologically distinct lymphatic vessels. Rather, fluid clearance from the brain proceeds via the glymphatic pathway, a structurally distinct system of fluid transport that uses the perivascular spaces created by the vascular endfeet of astrocytes. The endfeet surround arteries, capillaries, and veins, serving as a second wall that covers the entire cerebral vascular bed. The perivascular spaces are open, fluid-filled tunnels that offer little resistance to flow. This is in sharp contrast to the disorientingly crowded and compact architecture of adult brain tissue, the neuropil, through which interstitial fluid flow is necessarily slow and restricted—akin to a marsh, flowing to the glymphatic system’s creeks and then rivers. The glymphatic system’s perivascular tunnels are directly connected to the subarachnoid spaces surrounding the brain, from which CSF is rapidly driven into deep regions of the brain by the cardiac rhythm–linked pulsations of the arterial wall. The vascular endfeet of astrocytes, a primary subtype of glial cells, surround the perivascular spaces and can be regarded as open gates for fluid influx into the neuropil. The astrocytic endfeet are connected by gap junctions, and almost 50% of their plasma membrane facing the vessel wall is occupied by square arrays composed of the water channel protein aquaporin-4 (AQP4). Deletion of AQP4 channels in mice reduces both the influx of CSF tracers and the efflux of solutes from the neuropil. Given this pathway’s functional similarities to the peripheral lymphatic system, we termed this astrocyte-regulated mechanism of brain fluid transport the “glymphatic (glial-lymphatic) system.” Notably, fluid transport through the glymphatic system is directionally polarized, with influx along penetrating arteries, fluid entry into the neuropil supported by AQP4, and efflux along the perivenous spaces, as well as along the cranial and spinal nerves. In addition to its vectorial nature, glymphatic clearance is temporally regulated, and cyclically so, whereby fluid transport is enabled by sleep and suppressed during wakefulness. Brain fluid transport initiates and proceeds during NREM sleep, and CSF tracer influx correlates with the prevalence of EEG slow-wave activity. Fluid flow through the glymphatic system is thus inextricably linked with sleep, to the extent that flow appears to stop with the onset of wakefulness. In this regard, slow-wave activity predominates in the early hours of sleep and is a direct measure of sleep pressure, increasing with antecedent sleep deprivation. As such, waste removal is likely most efficient in the early hours of sleep and especially during recovery sleep after prolonged wakefulness. Yet it is easy to imagine why the awake state might be incompatible with active parenchymal fluid flow. Wakefulness relies on the precision of synaptic transmission in both time and space. Active flow might be expected to increase glutamate spillover during synaptic activity, resulting in bystander activation of local synapses and hence a loss of both the temporal and spatial fidelity of synaptic transmission. A recent analysis showed that glymphatic flow is also regulated by circadian rhythmicity, such that fluid transport peaks during the sleep phase of diurnal activity and falls during the active phase, independent of the light cycle. This rhythm is supported by the temporally regulated localization of AQP4 via the dystrophin-associated complex, providing a dynamic link to the molecular circadian clock. The most substantial risk factor for developing protein aggregation, as for developing dementia, is age. With the glymphatic system in mind, it is notable that sleep quality decreases as a function of normal aging. Insomnia is more frequent with increasing age, and total sleep duration becomes shorter and more interrupted. Perhaps more critically, older individuals rarely enter deep NREM (stage 3) sleep. Most NREM sleep in people older than 60 years of age is light, consisting of the more superficial stages 1 and 2. Thus, the aged brain spends less time in NREM sleep, potentially causing a catastrophic decline in clearance of brain waste, as the efficacy of glymphatic fluid transport correlates directly with the prevalence of slow-wave activity. The age-related impairment in sleep quality may thus be causally related to the increased incidence and accelerated course of neurodegenerative disease in older people, whose disrupted sleep architecture may sharply diminish the clearance of brain fluid and its attendant export of protein waste, thus leading to the stagnant interstitial flow that favors aggregate formation. In addition to the deterioration of sleep architecture in aging, the neurodegenerative diseases—including AD, Parkinson’s disease, Huntington’s disease, the multisystem atrophies, and the FTDs—are all associated with sleep disturbances. The best characterized among these are the sleep pathologies associated with Parkinson’s disease, in which REM sleep disturbances often precede the onset of motor symptoms by several years or even decades. Future work should define whether sleep disturbances that preceded the clinical diagnosis contribute to aggregate seeding and whether sleep disturbances during disease progression accelerate aggregate spread. It would seem axiomatic that a stronger focus on age-related impairment of sleep quality should benefit the aging population. The polarized expression of AQP4 in the vascular endfeet of astrocytes facilitates glymphatic fluid transport and amyloid-β export in rodents. In humans, genetic variation in AQP4 affects both sleep and amyloid-β burden. A recent study established a link between AQP4, sleep, and the effects of prolonged wakefulness on cognitive function. The study demonstrated that a common single-nucleotide polymorphism (SNP) of AQP4 was linked to changes in slow-wave activity during NREM sleep that were mirrored by changes in daytime sleepiness as well as in altered reaction times during extended wakefulness. [end of paraphrase] |