Glymphatic system

The glymphatic system (or glymphatic clearance pathway, or paravascular system) is a functional waste clearance pathway for the vertebrate central nervous system (CNS). The pathway consists of a para-arterial influx route for cerebrospinal fluid (CSF) to enter the brain parenchyma, coupled to a clearance mechanism for the removal of interstitial fluid (ISF) and extracellular solutes from the interstitial compartments of the brain and spinal cord. Exchange of solutes between CSF and ISF is driven primarily by arterial pulsation and regulated during sleep by the expansion and contraction of brain extracellular space. Clearance of soluble proteins, waste products, and excess extracellular fluid is accomplished through convective bulk flow of ISF, facilitated by astrocytic aquaporin 4 (AQP4) water channels. The glymphatic system (or glymphatic clearance pathway, or paravascular system) is a functional waste clearance pathway for the vertebrate central nervous system (CNS). The pathway consists of a para-arterial influx route for cerebrospinal fluid (CSF) to enter the brain parenchyma, coupled to a clearance mechanism for the removal of interstitial fluid (ISF) and extracellular solutes from the interstitial compartments of the brain and spinal cord. Exchange of solutes between CSF and ISF is driven primarily by arterial pulsation and regulated during sleep by the expansion and contraction of brain extracellular space. Clearance of soluble proteins, waste products, and excess extracellular fluid is accomplished through convective bulk flow of ISF, facilitated by astrocytic aquaporin 4 (AQP4) water channels. The name 'glymphatic system' was coined by the Danish neuroscientist Maiken Nedergaard in recognition of its dependence upon glial cells and the similarity of its functions to those of the peripheral lymphatic system. While glymphatic flow was initially believed to be the complete answer to the long-standing question of how the sensitive neural tissue of the CNS functions in the perceived absence of a lymphatic drainage pathway for extracellular proteins, excess fluid, and metabolic waste products, two subsequent articles by Louveau et al. from the University of Virginia School of Medicine and Aspelund et al. from the University of Helsinki reported independently the discovery that the dural sinuses and meningeal arteries are in fact lined with conventional lymphatic vessels, and that this long-elusive vasculature forms a connecting pathway to the glymphatic system. In a study published in 2012, a group of researchers from the University of Rochester headed by M. Nedergaard used in-vivo two-photon imaging of small fluorescent tracers to monitor the flow of subarachnoid CSF into and through the brain parenchyma. The two-photon microscopy allowed the Rochester team to visualize the flux of CSF in living mice, in real time, without needing to puncture the CSF compartment (imaging was performed through a closed cranial window). According to findings of that study, subarachnoid CSF enters the brain rapidly, along the paravascular spaces surrounding the penetrating arteries, then exchanges with the surrounding interstitial fluid. Similarly, interstitial fluid was cleared from the brain parenchyma via the paravascular spaces surrounding large draining veins. Paravascular spaces are CSF-filled channels formed between the brain blood vessels and leptomeningeal sheathes that surround cerebral surface vessels and proximal penetrating vessels. Around these penetrating vessels, paravascular spaces take the form of Virchow-Robin spaces. Where the Virchow-Robin spaces terminate within the brain parenchyma, paravascular CSF can continue traveling along the basement membranes surrounding arterial vascular smooth muscle, to reach the basal lamina surrounding brain capillaries. CSF movement along these paravascular pathways is rapid and arterial pulsation has long been suspected as an important driving force for paravascular fluid movement. In a study published in 2013, J. Iliff and colleagues demonstrated this directly. Using in vivo 2-photon microscopy, the authors reported that when cerebral arterial pulsation was either increased or decreased, the rate of paravacular CSF flux in turn increased or decreased, respectively. Astrocytes extend long processes that interface with neuronal synapses, as well as projections referred to as 'end-feet' that completely ensheathe the brain's entire vasculature. Although the exact mechanism is not completely understood, astrocytes are known to facilitate changes in blood flow and have long been thought to play a role in waste removal in the brain. Researchers have long known that astrocytes express water channels called aquaporins. Until recently, however, no physiological function has been identified that explains their presence in the astrocytes of the mammalian CNS. Aquaporins are membrane-bound channels that play critical roles in regulating the flux of water into and out of cells. Relative to simple diffusion, the presence of aquaporins in biological membranes facilitates a 3–10 fold increase in water permeability.Two types of aquaporins are expressed in the CNS: aquaporin-1, which is expressed by specialized epithelial cells of the choroid plexus, and aquaporin-4 (AQP4), which is expressed by astrocytes. Aquaporin-4 expression in astrocytes is highly polarized to the endfoot processes ensheathing the cerebral vasculature. Up to 50% of the vessel-facing endfoot surface that faces the vasculature is occupied by orthogonal arrays of AQP4.In 2012, it was shown that AQP4 is essential for paravascular CSF–ISF exchange. Analysis of genetically modified mice that lacked the AQP4 gene revealed that the bulk flow-dependent clearance of interstitial solutes decreases by 70% in the absence of AQP4. Based upon this role of AQP4-dependent glial water transport in the process of paravascular interstitial solute clearance, Iliff and Nedergaard termed this brain-wide glio-vascular pathway the 'glymphatic system'. A publication by L. Xie and colleagues in 2013 explored the efficiency of the glymphatic system during slow wave sleep and provided the first direct evidence that the clearance of interstitial waste products increases during the resting state. Using a combination of diffusion iontophoresis techniques pioneered by Nicholson and colleagues, in vivo 2-photon imaging, and electroencephalography to confirm the wake and sleep states, Xia and Nedergaard demonstrated that the changes in efficiency of CSF–ISF exchange between the awake and sleeping brain were caused by expansion and contraction of the extracellular space, which increased by ~60% in the sleeping brain to promote clearance of interstitial wastes such as amyloid beta. On the basis of these findings, they hypothesized that the restorative properties of sleep may be linked to increased glymphatic clearance of metabolic waste products produced by neural activity in the awake brain. Another key function of the glymphatic system was documented by Thrane et al., who in 2013 demonstrated that the brain's system of paravascular pathways plays an important role in transporting small lipophilic molecules. Led by M. Nedergaard, Thrane and colleagues also showed that the paravascular transport of lipids through the glymphatic pathway activated glial calcium signalling and that the depressurization of the cranial cavity, and thus impairment of the glymphatic circulation, led to unselective lipid diffusion, intracellular lipid accumulation and pathological signalling among astrocytes. Although further experiments are needed to parse out the physiological significance of the connection between the glymphatic circulation, calcium signalling and paravascular lipid transport in the brain, the findings point to the adoption of a function in the CNS similar to the capacity of the intestinal lymph vessels (lacteals) to carry lipids to the liver. Pathologically, neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease are all characterized by the progressive loss of neurons, cognitive decline, motor impairments, and sensory loss. Collectively these diseases fall within a broad category referred to as proteinopathies, due to the common assemblage of misfolded or aggregated intracellular or extracellular proteins. According to the prevailing amyloid hypothesis of Alzheimer's disease, the aggregation of amyloid-beta (a peptide normally produced in and cleared from the healthy young brain) into extracellular plaques drives the neuronal loss and brain atrophy that is the hallmark of Alzheimer's dementia. Although the full extent of the glymphatic system's involvement in Alzheimer's disease and other neurodegenerative disorders remains unclear, researchers have demonstrated through experiments with genetically modified mice that the proper function of the glymphatic clearance system was necessary to remove soluble amyloid-beta from the brain interstitium. In mice that lack the AQP4 gene, amyloid-beta clearance is reduced by approximately 55 percent.