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

Published on Aug 15, 2012in Science Translational Medicine17.16
· DOI :10.1126/scitranslmed.3003748
Jeffrey J. Iliff24
Estimated H-index: 24
(URMC: University of Rochester Medical Center),
Minghuan Wang6
Estimated H-index: 6
(URMC: University of Rochester Medical Center)
+ 8 AuthorsErlend A. Nagelhus32
Estimated H-index: 32
(University of Oslo)
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Abstract
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.
  • References (56)
  • Citations (1126)
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References56
Newest
Published on May 4, 2012in Journal of Alzheimer's Disease3.70
Jean-Marie Serot6
Estimated H-index: 6
,
Jadwiga Zmudka4
Estimated H-index: 4
,
P. Jouanny13
Estimated H-index: 13
According to the amyloid theory, the appearance of amyloid- (A) deposits represents a pivotal event in late onset Alzheimer's disease (LOAD). Physiologically, A42 monomers are cleaned by capillary resorption, enzymatic catabolism, and cerebrospinal fluid (CSF) transport. Factors that promote the oligomerization of A42 must be specified. In vitro, these monomers spontaneously form neurotoxic oligomers whose rate increases with time suggesting that the stasis of CSF favors the oligomerization. In ...
Published on Mar 1, 2012in Glia5.83
Martine Eilert-Olsen3
Estimated H-index: 3
(University of Oslo),
Nadia Nabil Haj-Yasein8
Estimated H-index: 8
(University of Oslo)
+ 11 AuthorsMarvin E. Adams32
Estimated H-index: 32
(UW: University of Washington)
Expression of the water channel aquaporin-4 (AQP4) at the blood–brain interface is dependent upon the dystrophin associated protein complex. Here we investigated whether deletion of the Aqp4 gene affects the molecular composition of this protein scaffold and the integrity of the blood–brain barrier. High-resolution immunogold cytochemistry revealed that perivascular expression of α-syntrophin was reduced by 60% in Aqp4−/− mice. Additionally, perivascular AQP4 expression was reduced by 88% in α-s...
Published on Nov 1, 2011in Nature Neuroscience21.13
Steven A. Goldman88
Estimated H-index: 88
(UR: University of Rochester),
Zhuoxun Chen3
Estimated H-index: 3
(UR: University of Rochester)
Abstract Abstract• References• Author information The perivascular niche for neurogenesis was first reported as the co-association of newly generated neurons and their progenitors with both dividing and mitotically quiescent endothelial cells in restricted regions of the brain in adult birds and mammals alike. This review attempts to summarize our present understanding of the interaction of blood vessels with neural stem and progenitor cells, addressing both glial and neuronal progenitor cell in...
Nadia Nabil Haj-Yasein8
Estimated H-index: 8
,
Gry Fluge Vindedal8
Estimated H-index: 8
+ 8 AuthorsOle Petter Ottersen84
Estimated H-index: 84
Tissue- and cell-specific deletion of the Aqp4 gene is required to differentiate between the numerous pools of aquaporin-4 (AQP4) water channels. A glial-conditional Aqp4 knockout mouse line was generated to resolve whether astroglial AQP4 controls water exchange across the blood–brain interface. The conditional knockout was driven by the glial fibrillary acidic protein promoter. Brains from conditional Aqp4 knockouts were devoid of AQP4 as assessed by Western blots, ruling out the presence of a...
Published on Jun 1, 2011in Nature Neuroscience21.13
Adam W. Bero6
Estimated H-index: 6
(WashU: Washington University in St. Louis),
Ping Yan15
Estimated H-index: 15
(WashU: Washington University in St. Louis)
+ 5 AuthorsDavid M. Holtzman2
Estimated H-index: 2
(WashU: Washington University in St. Louis)
Using a mouse model of Alzheimer's disease and in vivo microdialysis, this study shows that neuronal activity drives the level of interstitial fluid amyloid-β and subsequent amyloid-β plaque deposition.
Published on May 1, 2011in The FASEB Journal5.39
Lihua Li7
Estimated H-index: 7
,
Hua Zhang20
Estimated H-index: 20
+ 2 AuthorsA. S. Verkman125
Estimated H-index: 125
Aquaporin-4 (AQP4) deficiency in mice reduces neuroinflammation in experimental autoimmune encephalomyelitis (EAE) produced by active immunization with myelin oligodendrocyte glycoprotein peptide (MOG). Potential mechanisms for the protective effect of AQP4 deficiency were investigated, including AQP4-dependent leukocyte and microglia cell function, immune cell entry in the central nervous system (CNS), intrinsic neuroinflammation, and humoral immune response. As we found with active-immunizatio...
Alexander S. Thrane10
Estimated H-index: 10
(URMC: University of Rochester Medical Center),
Phillip M. Rappold4
Estimated H-index: 4
(URMC: University of Rochester Medical Center)
+ 13 AuthorsRune Enger8
Estimated H-index: 8
(University of Oslo)
Aquaporin-4 (AQP4) is a primary influx route for water during brain edema formation. Here, we provide evidence that brain swelling triggers Ca2+ signaling in astrocytes and that deletion of the Aqp4 gene markedly interferes with these events. Using in vivo two-photon imaging, we show that hypoosmotic stress (20% reduction in osmolarity) initiates astrocytic Ca2+ spikes and that deletion of Aqp4 reduces these signals. The Ca2+ signals are partly dependent on activation of P2 purinergic receptors,...
Published on Dec 1, 2010in Journal of Neurochemistry4.87
Berislav V. Zlokovic87
Estimated H-index: 87
(URMC: University of Rochester Medical Center),
Rashid Deane45
Estimated H-index: 45
(URMC: University of Rochester Medical Center)
+ 2 AuthorsEthan A. Winkler19
Estimated H-index: 19
(URMC: University of Rochester Medical Center)
Low-density lipoprotein receptor-related protein-1 (LRP1), a member of the LDL receptor family, has major roles in the cellular transport of cholesterol, endocytosis of forty structurally diverse ligands, transcytosis of ligands across the blood-brain barrier, and transmembrane and nuclear signaling. Recent evidence indicates that LRP1 regulates brain and systemic clearance of Alzheimer's disease (AD) amyloid β-peptide (Aβ). According to the two hit vascular hypothesis for AD, vascular damage pr...
Published on Oct 1, 2010in Neurotherapeutics5.55
Mary E. Hamby5
Estimated H-index: 5
(UCLA: University of California, Los Angeles),
Michael V. Sofroniew68
Estimated H-index: 68
(UCLA: University of California, Los Angeles)
Reactive astrogliosis has long been recognized as a ubiquitous feature of CNS pathologies. Although its roles in CNS pathology are only beginning to be defined, genetic tools are enabling molecular dissection of the functions and mechanisms of reactive astrogliosis in vivo. It is now clear that reactive astrogliosis is not simply an all-or-nothing phenomenon but, rather, is a finely gradated continuum of molecular, cellular, and functional changes that range from subtle alterations in gene expre...
Cited By1126
Newest
Published on May 8, 2019in Acta neuropathologica communications
Alex J. Smith18
Estimated H-index: 18
(UCSF: University of California, San Francisco),
Tianjiao Duan (UCSF: University of California, San Francisco), A. S. Verkman125
Estimated H-index: 125
(UCSF: University of California, San Francisco)
Redistribution of the water channel aquaporin-4 (AQP4) away from astrocyte endfeet and into parenchymal processes is a striking histological feature in mouse models of Alzheimer’s disease (AD) and other neurological conditions with prominent astrogliosis. AQP4 redistribution has been proposed to impair bulk Aβ clearance in AD, resulting in increased amyloid deposition in the brain; however, this finding is controversial. Here, we provide evidence in support of a different and novel role of AQP4 ...
Published on Feb 22, 2019in Scientific Reports4.01
Jeffrey J. Lochhead11
Estimated H-index: 11
(UA: University of Arizona),
Kathryn L. Kellohen1
Estimated H-index: 1
(UA: University of Arizona)
+ 1 AuthorsThomas P. Davis52
Estimated H-index: 52
(UA: University of Arizona)
In the brain, insulin acts as a growth factor, regulates energy homeostasis, and is involved in learning and memory acquisition. Many central nervous system (CNS) diseases are characterized by deficits in insulin signaling. Pre-clinical studies have shown that intranasal insulin is neuroprotective in models of Alzheimer’s disease, Parkinson’s disease, and traumatic brain injury. Clinical trials have also shown that intranasal insulin elicits beneficial cognitive effects in patients with Alzheime...
Published on Dec 1, 2019in Scientific Reports4.01
Farshid Sepehrband7
Estimated H-index: 7
(SC: University of Southern California),
Giuseppe Barisano2
Estimated H-index: 2
(SC: University of Southern California)
+ 4 AuthorsArthur W. Toga131
Estimated H-index: 131
(SC: University of Southern California)
Imaging the perivascular spaces (PVS), also known as Virchow-Robin space, has significant clinical value, but there remains a need for neuroimaging techniques to improve mapping and quantification of the PVS. Current technique for PVS evaluation is a scoring system based on visual reading of visible PVS in regions of interest, and often limited to large caliber PVS. Enhancing the visibility of the PVS could support medical diagnosis and enable novel neuroscientific investigations. Increasing the...
Published on Dec 1, 2019in Fluids and Barriers of the CNS
Jeffrey Tithof (UR: University of Rochester), Douglas H. Kelley12
Estimated H-index: 12
(UR: University of Rochester)
+ 1 AuthorsJohn H. Thomas30
Estimated H-index: 30
(UR: University of Rochester)
Background Periarterial spaces (PASs) are annular channels that surround arteries in the brain and contain cerebrospinal fluid (CSF): a flow of CSF in these channels is thought to be an important part of the brain’s system for clearing metabolic wastes. In vivo observations reveal that they are not concentric, circular annuli, however: the outer boundaries are often oblate, and the arteries that form the inner boundaries are often offset from the central axis.
Published on Feb 26, 2019in Scientific Reports4.01
Taro Bannai3
Estimated H-index: 3
(UTokyo: University of Tokyo),
Tatsuo Mano4
Estimated H-index: 4
(UTokyo: University of Tokyo)
+ 10 AuthorsTakeshi Iwatsubo91
Estimated H-index: 91
(UTokyo: University of Tokyo)
Epidemiological studies have shown that atherosclerotic risk factors accelerate the pathological process underlying Alzheimer’s disease (AD) via chronic cerebral hypoperfusion. In this study, we aimed to clarify the mechanisms by which cerebral hypoperfusion may exacerbate AD pathology. We applied bilateral common carotid artery stenosis (BCAS) to a mice model of AD and evaluated how the equilibrium of amyloid β oligomers respond to hypoperfusion. BCAS accelerated amyloid β (Aβ) convergence to t...
Published on 2019in Scientific Reports4.01
Kulam Najmudeen Magdoom2
Estimated H-index: 2
(UF: University of Florida),
Alec C. Brown (UF: University of Florida)+ 3 AuthorsMalisa Sarntinoranont19
Estimated H-index: 19
(UF: University of Florida)
Investigating the mechanisms by which metabolic wastes are cleared from nervous tissue is important for understanding natural function and the pathophysiology of several neurological disorders including Alzheimer’s disease. Recent evidence suggests clearance may be the function of annular spaces around cerebral blood vessels, called perivascular spaces (PVS), through which cerebrospinal fluid (CSF) is transported from the subarachnoid space into brain parenchyma to exchange with interstitial flu...
Published on Mar 29, 2019in Fluids and Barriers of the CNS
Tetsuya Akaishi9
Estimated H-index: 9
(Tohoku University),
Eiko Onishi1
Estimated H-index: 1
(Tohoku University)
+ 8 AuthorsMasanori Yamauchi11
Estimated H-index: 11
(Tohoku University)
Background The central nervous system was previously thought to draw oxygen and nutrition from the arteries and discharge carbon dioxide and other metabolic wastes into the venous system. At present, the functional role of cerebrospinal fluid in brain metabolism is not fully known.
Published on Apr 12, 2019in Scientific Reports4.01
Liam M. Koehn1
Estimated H-index: 1
(University of Melbourne),
Katarzyna M. Dziegielewska36
Estimated H-index: 36
(University of Melbourne)
+ 5 AuthorsMark D. Habgood26
Estimated H-index: 26
(University of Melbourne)
Many pregnant women and prematurely born infants require medication for clinical conditions including cancer, cardiac defects and psychiatric disorders. In adults drug transfer from blood into brain is mostly restricted by efflux mechanisms (ATP-binding cassette, ABC transporters). These mechanisms have been little studied during brain development. Here expression of eight ABC transporters (abcb1a, abcb1b, abcg2, abcc1, abcc2, abcc3, abcc4, abcc5) and activity of conjugating enzyme glutathione-s...
Published on Dec 1, 2019in Fluids and Barriers of the CNS
M. Keith Sharp11
Estimated H-index: 11
(University of Louisville),
Roxana O. Carare20
Estimated H-index: 20
(Southampton General Hospital),
Bryn A. Martin14
Estimated H-index: 14
(UIdaho: University of Idaho)
Background As an alternative to advection, solute transport by shear-augmented dispersion within oscillatory cerebrospinal fluid flow was investigated in small channels representing the basement membranes located between cerebral arterial smooth muscle cells, the paraarterial space surrounding the vessel wall and in large channels modeling the spinal subarachnoid space (SSS).