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Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation

BACKGROUND: Apolipoprotein E (apoE) is a major carrier of cholesterol and essential for synaptic plasticity. In brain, it’s expressed by many cells but highly expressed by the choroid plexus and the predominant apolipoprotein in cerebrospinal fluid (CSF). The role of apoE in the CSF is unclear. Rece...

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Autores principales: Achariyar, Thiyagaragan M., Li, Baoman, Peng, Weiguo, Verghese, Philip B., Shi, Yang, McConnell, Evan, Benraiss, Abdellatif, Kasper, Tristan, Song, Wei, Takana, Takahiro, Holtzman, David M., Nedergaard, Maiken, Deane, Rashid
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5146863/
https://www.ncbi.nlm.nih.gov/pubmed/27931262
http://dx.doi.org/10.1186/s13024-016-0138-8
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author Achariyar, Thiyagaragan M.
Li, Baoman
Peng, Weiguo
Verghese, Philip B.
Shi, Yang
McConnell, Evan
Benraiss, Abdellatif
Kasper, Tristan
Song, Wei
Takana, Takahiro
Holtzman, David M.
Nedergaard, Maiken
Deane, Rashid
author_facet Achariyar, Thiyagaragan M.
Li, Baoman
Peng, Weiguo
Verghese, Philip B.
Shi, Yang
McConnell, Evan
Benraiss, Abdellatif
Kasper, Tristan
Song, Wei
Takana, Takahiro
Holtzman, David M.
Nedergaard, Maiken
Deane, Rashid
author_sort Achariyar, Thiyagaragan M.
collection PubMed
description BACKGROUND: Apolipoprotein E (apoE) is a major carrier of cholesterol and essential for synaptic plasticity. In brain, it’s expressed by many cells but highly expressed by the choroid plexus and the predominant apolipoprotein in cerebrospinal fluid (CSF). The role of apoE in the CSF is unclear. Recently, the glymphatic system was described as a clearance system whereby CSF and ISF (interstitial fluid) is exchanged via the peri-arterial space and convective flow of ISF clearance is mediated by aquaporin 4 (AQP4), a water channel. We reasoned that this system also serves to distribute essential molecules in CSF into brain. The aim was to establish whether apoE in CSF, secreted by the choroid plexus, is distributed into brain, and whether this distribution pattern was altered by sleep deprivation. METHODS: We used fluorescently labeled lipidated apoE isoforms, lenti-apoE3 delivered to the choroid plexus, immunohistochemistry to map apoE brain distribution, immunolabeled cells and proteins in brain, Western blot analysis and ELISA to determine apoE levels and radiolabeled molecules to quantify CSF inflow into brain and brain clearance in mice. Data were statistically analyzed using ANOVA or Student’s t- test. RESULTS: We show that the glymphatic fluid transporting system contributes to the delivery of choroid plexus/CSF-derived human apoE to neurons. CSF-delivered human apoE entered brain via the perivascular space of penetrating arteries and flows radially around arteries, but not veins, in an isoform specific manner (apoE2 > apoE3 > apoE4). Flow of apoE around arteries was facilitated by AQP4, a characteristic feature of the glymphatic system. ApoE3, delivered by lentivirus to the choroid plexus and ependymal layer but not to the parenchymal cells, was present in the CSF, penetrating arteries and neurons. The inflow of CSF, which contains apoE, into brain and its clearance from the interstitium were severely suppressed by sleep deprivation compared to the sleep state. CONCLUSIONS: Thus, choroid plexus/CSF provides an additional source of apoE and the glymphatic fluid transporting system delivers it to brain via the periarterial space. By implication, failure in this essential physiological role of the glymphatic fluid flow and ISF clearance may also contribute to apoE isoform-specific disorders in the long term. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-016-0138-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-51468632016-12-15 Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation Achariyar, Thiyagaragan M. Li, Baoman Peng, Weiguo Verghese, Philip B. Shi, Yang McConnell, Evan Benraiss, Abdellatif Kasper, Tristan Song, Wei Takana, Takahiro Holtzman, David M. Nedergaard, Maiken Deane, Rashid Mol Neurodegener Research Article BACKGROUND: Apolipoprotein E (apoE) is a major carrier of cholesterol and essential for synaptic plasticity. In brain, it’s expressed by many cells but highly expressed by the choroid plexus and the predominant apolipoprotein in cerebrospinal fluid (CSF). The role of apoE in the CSF is unclear. Recently, the glymphatic system was described as a clearance system whereby CSF and ISF (interstitial fluid) is exchanged via the peri-arterial space and convective flow of ISF clearance is mediated by aquaporin 4 (AQP4), a water channel. We reasoned that this system also serves to distribute essential molecules in CSF into brain. The aim was to establish whether apoE in CSF, secreted by the choroid plexus, is distributed into brain, and whether this distribution pattern was altered by sleep deprivation. METHODS: We used fluorescently labeled lipidated apoE isoforms, lenti-apoE3 delivered to the choroid plexus, immunohistochemistry to map apoE brain distribution, immunolabeled cells and proteins in brain, Western blot analysis and ELISA to determine apoE levels and radiolabeled molecules to quantify CSF inflow into brain and brain clearance in mice. Data were statistically analyzed using ANOVA or Student’s t- test. RESULTS: We show that the glymphatic fluid transporting system contributes to the delivery of choroid plexus/CSF-derived human apoE to neurons. CSF-delivered human apoE entered brain via the perivascular space of penetrating arteries and flows radially around arteries, but not veins, in an isoform specific manner (apoE2 > apoE3 > apoE4). Flow of apoE around arteries was facilitated by AQP4, a characteristic feature of the glymphatic system. ApoE3, delivered by lentivirus to the choroid plexus and ependymal layer but not to the parenchymal cells, was present in the CSF, penetrating arteries and neurons. The inflow of CSF, which contains apoE, into brain and its clearance from the interstitium were severely suppressed by sleep deprivation compared to the sleep state. CONCLUSIONS: Thus, choroid plexus/CSF provides an additional source of apoE and the glymphatic fluid transporting system delivers it to brain via the periarterial space. By implication, failure in this essential physiological role of the glymphatic fluid flow and ISF clearance may also contribute to apoE isoform-specific disorders in the long term. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-016-0138-8) contains supplementary material, which is available to authorized users. BioMed Central 2016-12-08 /pmc/articles/PMC5146863/ /pubmed/27931262 http://dx.doi.org/10.1186/s13024-016-0138-8 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Achariyar, Thiyagaragan M.
Li, Baoman
Peng, Weiguo
Verghese, Philip B.
Shi, Yang
McConnell, Evan
Benraiss, Abdellatif
Kasper, Tristan
Song, Wei
Takana, Takahiro
Holtzman, David M.
Nedergaard, Maiken
Deane, Rashid
Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation
title Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation
title_full Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation
title_fullStr Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation
title_full_unstemmed Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation
title_short Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation
title_sort glymphatic distribution of csf-derived apoe into brain is isoform specific and suppressed during sleep deprivation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5146863/
https://www.ncbi.nlm.nih.gov/pubmed/27931262
http://dx.doi.org/10.1186/s13024-016-0138-8
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