A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.
Jeffrey J. Iliff,Minghuan Wang,Minghuan Wang,Yonghong Liao,Benjamin A. Plogg,Weiguo Peng,Georg Andreas Gundersen,Helene Benveniste,G. Edward Vates,Rashid Deane,Steven A. Goldman,Erlend A. Nagelhus +11 more
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TLDR
An anatomically distinct clearing system in the brain that serves a lymphatic-like function is described and 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.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.read more
Citations
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Neuroinflammation in Alzheimer's disease
Michael T. Heneka,Monica J. Carson,Joseph El Khoury,Gary E. Landreth,Frederic Brosseron,Douglas L. Feinstein,Andreas H. Jacobs,Tony Wyss-Coray,Tony Wyss-Coray,Javier Vitorica,Richard M. Ransohoff,Karl Herrup,Sally A. Frautschy,Bente Finsen,Guy C. Brown,Alexei Verkhratsky,Alexei Verkhratsky,Alexei Verkhratsky,Koji Yamanaka,Jari Koistinaho,Eicke Latz,Eicke Latz,Annett Halle,Gabor C. Petzold,Terrence Town,Dave Morgan,Mari L. Shinohara,V. Hugh Perry,Clive Holmes,Clive Holmes,Nicolas G. Bazan,David J. Brooks,Stéphane Hunot,Bertrand Joseph,Nikolaus Deigendesch,Olga Garaschuk,Erik Boddeke,Charles A. Dinarello,John C.S. Breitner,Greg M. Cole,Douglas T. Golenbock,Markus P. Kummer +41 more
TL;DR: Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction.
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Sleep Drives Metabolite Clearance From the Adult Brain
Lulu Xie,Hongyi Kang,Qiwu Xu,Michael Chen,Yonghong Liao,Meenakshisundaram Thiyagarajan,John O’Donnell,Daniel J. Christensen,Charles Nicholson,Jeffrey J. Iliff,Takahiro Takano,Rashid Deane +11 more
TL;DR: It is reported that sleep has a critical function in ensuring metabolic homeostasis and convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep, suggesting the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.
Journal ArticleDOI
The spectrum of disease in chronic traumatic encephalopathy
Ann C. McKee,Thor D. Stein,Thor D. Stein,Christopher J. Nowinski,Robert S. Stern,Daniel H. Daneshvar,Victor E. Alvarez,H. J. Lee,Garth F. Hall,Sydney M. Wojtowicz,Sydney M. Wojtowicz,Christine M. Baugh,David O. Riley,Caroline A. Kubilus,Kerry Cormier,Matthew A. Jacobs,Brett Martin,Carmela R. Abraham,Tsuneya Ikezu,Robert Ross Reichard,Benjamin Wolozin,Andrew E. Budson,Andrew E. Budson,Lee E. Goldstein,Neil W. Kowall,Robert C. Cantu +25 more
TL;DR: The frequent association of chronic traumatic encephalopathy with other neurodegenerative disorders suggests that repetitive brain trauma and hyperphosphorylated tau protein deposition promote the accumulation of other abnormally aggregated proteins including TAR DNA-binding protein 43, amyloid beta protein and alpha-synuclein.
Journal ArticleDOI
Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders
TL;DR: This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy.
Journal ArticleDOI
A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules
Aleksanteri Aspelund,Salli Antila,Steven T. Proulx,Tine V. Karlsen,Sinem Karaman,Michael Detmar,Helge Wiig,Kari Alitalo +7 more
TL;DR: The presence of a lymphatic vessel network in the dura mater of the mouse brain is discovered and it is shown that these dural lymphatic vessels are important for the clearance of macromolecules from the brain.
References
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