Research ArticleCerebrospinal Fluid Circulation

A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β

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Science Translational Medicine  15 Aug 2012:
Vol. 4, Issue 147, pp. 147ra111
DOI: 10.1126/scitranslmed.3003748

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A New Footing for Waste Clearance in the Brain

Where are the lymph vessels of the brain? The lymphatic system’s complex network of vessels extends throughout most of the body, transporting excess fluid and waste products from the interstitial spaces between cells to the blood. Such vessels are notably absent from the brain, however, leading to long-standing questions about how interstitial fluid in this organ is cleared of waste. Now, Iliff et al. describe an anatomically distinct clearing system in the brain that serves a lymphatic-like function.

The researchers first investigated the fate of tracer molecules introduced into the cerebrospinal fluid (CSF) in mice. Produced in ventricular cavities deep within the brain, the CSF fills the subarachnoid space—a gap between two of the membranes that encase the brain and spinal cord. Whereas tracers infused into the ventricle remained near that site, those injected into the subarachnoid space rapidly entered the brain itself. By visualizing fluorescent tracers through a cranial window in live mice, the authors found that CSF enters the brain in specific channels that are defined by features of small blood vessels in the brain. Such vessels are almost entirely ensheathed by astrocytic endfeet (terminal enlargements of long processes that project from astrocytes). The CSF tracers readily flow inward to the brain matter in a compartment between the outside of vessels—in this case small arteries entering the brain—and the astrocytic endfeet. At later time points, the tracer exits the brain in similar channels surrounding veins, having apparently circulated through the brain interstitium. Such CSF flux—and the clearance of tracers injected into the brain itself—were markedly reduced in mice lacking aquaporin-4, a water channel localized to astrocytic endfeet, indicating that these channels mediate this flux.

These findings may have relevance for understanding or treating neurodegenerative diseases that involve the mis-accumulation of soluble proteins, such as amyloid β in Alzheimer’s disease. Indeed, Iliff et al. found that normal clearance of amyloid β (previously injected into the brain) requires aquaporin-4.

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