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

Cerebrospinal fluid flows through channels around brain blood vessels that are bounded by astrocytic endfeet, mediated by water transport through aquaporin-4. 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. Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer’s disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.