. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012 Aug 15;4(147):147ra111. PubMed.


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  1. This study importantly adds to our knowledge that passive clearance pathways from the brain interstitial and cerebrospinal fluid could potentially play an important role in clearing toxic molecules from the brain. This is in addition to previously demonstrated vascular clearance across the blood-brain barrier, which typically requires the presence of specific transporters at the luminal side of blood vessels to eliminate toxins away from brain. Vascular clearance is more rapid than the passive clearance pathway. In addition to previously demonstrated roles of vascular smooth muscle cells in small penetrating cerebral arteries, the study sheds a new light on possible role of astrocytes in the regulation of the passive clearance route, which further cements the concept that cells of the neurovascular unit may critically determine the levels of different potential neurotoxins in brain.

  2. Iliff and colleagues use a clever approach to describe a brand-new bulk flow clearance pathway for interstitial fluid (ISF) and cerebrospinal fluid (CSF) water as well as molecules; fluids drain through paravenous spaces within parenchyma to be eliminated. Interestingly, this is specific to paravenous spaces, not other blood vessels, and is particularly reliant on spaces regulated by aquaporin 4. Aquaporin 4-null mice have reduced perivascular space, which presumably would restrict water flow, and could be responsible for the reduced clearance of molecules. If this system is active in other locales, then it is possible that other flow-regulating molecules besides Aqp4 could be active there instead.

    This “glymphatic system” affects small molecules more so than larger molecules, likely due to physical restrictions within the pathway. Determining what physical obstructions are responsible for this differential size preference will be interesting. But more than size alone determines the rate of clearance, since Aβ is cleared faster than a similarly sized dextran molecule. The relative contribution of the glymphatic system, arachnoid villi transport, and active blood-brain barrier transport should also be determined, though will likely need to be done for individual molecules.

    We generally think about bulk flow clearance pathways as an amorphous entity that clears CSF molecules through arachnoid villi, or that clears ISF into the CSF. In contrast, the glymphatic system is a new bulk flow pathway that can be linked to specific molecules and regulation. This system also takes into account physical space, which is something we don’t usually think about in terms of clearance pathways. It will be interesting to see how other molecules are handled by this clearance pathway, as well as what changes due to disease could alter it.

  3. Iliff et al. have presented a very interesting study. They observed that tracers injected into the CSF via the cisterna magna of mice extended into the brain along paravascular pathways around arteries but not around veins. The lower-molecular-weight tracers extended into the brain parenchyma and into paravenous compartments, and then into the CSF. A similar distribution of tracer was observed following intraparenchymal injections into the cerebral cortex and deep grey matter of the mouse brain. The authors suggest that homoeostasis of interstitial fluid is maintained by the flow of CSF through the brain and, from their experiments using aquaporin 4 knockout mice, they conclude that astrocytes may be involved in this pathway. This work confirms and extends the work of Rennels (Rennels et al., 1985) in a rather elegant way.

    As Iliff et al. emphasized, maintenance of the external environment for neurons and other cells is an important factor in maintaining normal function in the CNS. The absence of traditional lymphatics in the brain has led to the suggestions that solutes in the interstitial fluid are either cleared directly into the blood, into the CSF, or by perivascular lymphatic drainage along basement membranes in the walls of capillaries and arteries of the cerebral circulation into regional lymph nodes in the neck. Evidence that vascular basement membranes are a route for drainage of solutes is derived from intraparenchymal injections of tracers (Carare et al., 2008; Hawkes et al., 2011) and from the observation that amyloid-β accumulates in the basement membrane pathways in capillary and artery walls as cerebral amyloid angiopathy (CAA) (Herzig et al., 2006; Weller et al., 2009). The amyloid-β that accumulates in capillary and artery walls in transgenic APP mice is derived from neurons (Herzig et al., 2006) rather than from extraneural sources. This suggests that amyloid in CAA is deposited during perivascular drainage from the brain along basement membranes within the walls of capillaries and arteries. Although Iliff et al. are skeptical about the existence of basement membrane drainage pathways within capillary and artery walls, the interstitial fluid drainage system described by these authors does not explain the distribution of amyloid-β in the walls of cortical and leptomeningeal arteries in CAA.

    As new technologies, including two-photon imaging, are introduced further to the study of fluid and solute clearance from the CNS, the discrepancies identified above will hopefully be resolved. Whatever the final solution proves to be, facilitating elimination of amyloid-β from the aging brain will remain an important therapeutic target for Alzheimer’s disease.


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