It is hard to undermine the role of cleanliness in disease prevention, both internally and externally. Within our body, the lymphatic system plays an important role in clearing the intercellular passages of large and potentially harmful toxic molecules and recirculate back into the blood stream. This enables the transport of these molecules to liver for inactivation and subsequent removal from the body. Therefore, lymphatic system prevents build-up of soluble proteins in the interstitial space. Typically, more metabolically active a cell is, more intricate is the lymphatic vasculature around it. This observation was in contrast to our scientific knowledge a few years ago, when we believed that due to the presence of the blood-brain barrier, there was no lymphatic system active in the brain. The brain, as we know, is highly active metabolically and the removal of harmful solutes and proteins from the neuronal vicinity is of utmost urgency. For a long time it was believed that cerebrospinal fluid (CSF), while coursing through the brain also removed cellular metabolite by products, apart from carrying nutrients to brain tissue, through a process known as diffusion. This is a rather slow process and it did not very well explain how large molecules such as proteins were removed from the interstitial place.

Recently, using two-photon imaging technique in live mice, scientists at Rochester discovered (1) that there is another vasculature functioning in the brain which circulates CSF to every corner of the brain much more efficiently, through bulk flow or convection. While the diffusion process works more like a trickle, percolating CSF through brain tissue, the new system is under pressure, pushing large volumes of CSF through the brain to carry waste away more forcefully. This glia-lymphatic system, called the glymphatic system is like a layer of piping that surrounds the brain’s existing blood vessels. This system consists of 3 elements- the para- arterial CSF influx, which brings in CSF into the para-arterial space that surrounds the arteries, the para-venous ISF clearance route and an intracellular astrocyte network that couples the two paravascular routes. CSF is pumped into the brain along the channels that surround arteries, which then washes through brain tissue before collecting in channels around veins and draining from the brain. The astrocytes contain “end feet” like network of conduits comprising of water channels called aquaporin-4 (AQP4) that facilitate the vectorial bulk flow of CSF from para-arterial space into the interstitial space containing the interstitial fluid (ISF). As CSF-ISF exchange occurs, convective fluxes drive the waste products away from the arteries to the para-venous space, and reaching systemic circulation and eventually liver as the final destination for inactivation and degradation.

What would happen if this bulk flow system is impaired and interstitial proteins were not removed? One of the foremost thoughts that come to mind is the accumulation of proteins such as amyloid –beta (Aβ) which is a hallmark of Alzheimer’s disease and one could speculate that insufficient and delayed removal might possibly contribute to amyloid plaque deposition and AD progression. Using fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer disease, was transported along this route. The team found that when the AQP4 channels were deleted, the clearance of exogenous Aβ reduced by 65%. This suggests that the convective flow of CSF is responsible for removal of interstitial waste products and other products of cellular activity including amyloid β from the central nervous system. Interestingly, the research group also observed that the concentration of amyloid-beta is higher during wakefulness than during sleep and so they tested the hypothesis that sleep removes Aβ from brain and sleep-wake cycle regulates glymphatic clearance (2). Using fluorescent tracers in awake, sleep and anaesthetized mice, the researchers found that CSF influx was sharply reduced in awake mice as compared to mice that were naturally sleeping or were anaesthetized. Further investigation indicated that a reduction in interstitial volume during wakefulness causes increased resistance and therefore reduced flow. So, what might regulate interstitial volume? One of the theories proposed is that during waking, norepinephrine from noradrenergic neurons reduce interstitial volume decreasing CSF flow, but during sleep, since the noradrenergic neurons are silent, the interstitial volume and therefore, the convective flow is restored. This just makes perfect sense since “clean-up” or maintenance work in the brain happens when it is “offline” or not actually involved in processing sensory information. Although factors regulating this mechanism need to be worked out, the idea of sleeping our way to a clean and healthy brain is extremely appealing.

1. Iliff, J. et al. (2012) A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β.Science Translational Medicine , 147ra111.
2. Xie, L. et al. (2013) Sleep Drives Metabolite Clearance from the Adult Brain. Science 342, 373–377.