A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.
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.
Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA. jeffrey_iliff@urmc.rochester.edu
Jeffrey J
JJ
Iliff
Minghuan
M
Wang
Yonghong
Y
Liao
Benjamin A
BA
Plogg
Weiguo
W
Peng
Georg A
GA
Gundersen
Helene
H
Benveniste
G Edward
GE
Vates
Rashid
R
Deane
Steven A
SA
Goldman
Erlend A
EA
Nagelhus
Maiken
M
Nedergaard
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D002552:Cerebral Ventricles / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism*; D021621:Imaging, Three-Dimensional; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D036641:Microscopy, Fluorescence, Multiphoton; D014867:Water / Q000378:metabolism
D016229:Amyloid beta-Peptides; D051401:Aquaporin 4; D014867:Water