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Influence of traumatic brain injury on extracellular tau elimination at the blood–brain barrier
Repetitive head trauma has been associated with the accumulation of tau species in the brain. Our prior work showed brain vascular mural cells contribute to tau processing in the brain, and that these cells progressively degenerate following repetitive mild traumatic brain injury (r-mTBI). The curre...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549249/ https://www.ncbi.nlm.nih.gov/pubmed/34702292 http://dx.doi.org/10.1186/s12987-021-00283-y |
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author | Eisenbaum, Maxwell Pearson, Andrew Gratkowski, Arissa Mouzon, Benoit Mullan, Michael Crawford, Fiona Ojo, Joseph Bachmeier, Corbin |
author_facet | Eisenbaum, Maxwell Pearson, Andrew Gratkowski, Arissa Mouzon, Benoit Mullan, Michael Crawford, Fiona Ojo, Joseph Bachmeier, Corbin |
author_sort | Eisenbaum, Maxwell |
collection | PubMed |
description | Repetitive head trauma has been associated with the accumulation of tau species in the brain. Our prior work showed brain vascular mural cells contribute to tau processing in the brain, and that these cells progressively degenerate following repetitive mild traumatic brain injury (r-mTBI). The current studies investigated the role of the cerebrovasculature in the elimination of extracellular tau from the brain, and the influence of r-mTBI on these processes. Following intracranial injection of biotin-labeled tau, the levels of exogenous labeled tau residing in the brain were elevated in a mouse model of r-mTBI at 12 months post-injury compared to r-sham mice, indicating reduced tau elimination from the brain following head trauma. This may be the result of decreased caveolin-1 mediated tau efflux at the blood–brain barrier (BBB), as the caveolin inhibitor, methyl-β-cyclodextrin, significantly reduced tau uptake in isolated cerebrovessels and significantly decreased the basolateral-to-apical transit of tau across an in vitro model of the BBB. Moreover, we found that the upstream regulator of endothelial caveolin-1, Mfsd2a, was elevated in r-mTBI cerebrovessels compared to r-sham, which coincided with a decreased expression of cerebrovascular caveolin-1 in the chronic phase following r-mTBI (> 3 months post-injury). Lastly, angiopoietin-1, a mural cell-derived protein governing endothelial Mfsd2a expression, was secreted from r-mTBI cerebrovessels to a greater extent than r-sham animals. Altogether, in the chronic phase post-injury, release of angiopoietin-1 from degenerating mural cells downregulates caveolin-1 expression in brain endothelia, resulting in decreased tau elimination across the BBB, which may describe the accumulation of tau species in the brain following head trauma. |
format | Online Article Text |
id | pubmed-8549249 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-85492492021-10-27 Influence of traumatic brain injury on extracellular tau elimination at the blood–brain barrier Eisenbaum, Maxwell Pearson, Andrew Gratkowski, Arissa Mouzon, Benoit Mullan, Michael Crawford, Fiona Ojo, Joseph Bachmeier, Corbin Fluids Barriers CNS Research Repetitive head trauma has been associated with the accumulation of tau species in the brain. Our prior work showed brain vascular mural cells contribute to tau processing in the brain, and that these cells progressively degenerate following repetitive mild traumatic brain injury (r-mTBI). The current studies investigated the role of the cerebrovasculature in the elimination of extracellular tau from the brain, and the influence of r-mTBI on these processes. Following intracranial injection of biotin-labeled tau, the levels of exogenous labeled tau residing in the brain were elevated in a mouse model of r-mTBI at 12 months post-injury compared to r-sham mice, indicating reduced tau elimination from the brain following head trauma. This may be the result of decreased caveolin-1 mediated tau efflux at the blood–brain barrier (BBB), as the caveolin inhibitor, methyl-β-cyclodextrin, significantly reduced tau uptake in isolated cerebrovessels and significantly decreased the basolateral-to-apical transit of tau across an in vitro model of the BBB. Moreover, we found that the upstream regulator of endothelial caveolin-1, Mfsd2a, was elevated in r-mTBI cerebrovessels compared to r-sham, which coincided with a decreased expression of cerebrovascular caveolin-1 in the chronic phase following r-mTBI (> 3 months post-injury). Lastly, angiopoietin-1, a mural cell-derived protein governing endothelial Mfsd2a expression, was secreted from r-mTBI cerebrovessels to a greater extent than r-sham animals. Altogether, in the chronic phase post-injury, release of angiopoietin-1 from degenerating mural cells downregulates caveolin-1 expression in brain endothelia, resulting in decreased tau elimination across the BBB, which may describe the accumulation of tau species in the brain following head trauma. BioMed Central 2021-10-26 /pmc/articles/PMC8549249/ /pubmed/34702292 http://dx.doi.org/10.1186/s12987-021-00283-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Eisenbaum, Maxwell Pearson, Andrew Gratkowski, Arissa Mouzon, Benoit Mullan, Michael Crawford, Fiona Ojo, Joseph Bachmeier, Corbin Influence of traumatic brain injury on extracellular tau elimination at the blood–brain barrier |
title | Influence of traumatic brain injury on extracellular tau elimination at the blood–brain barrier |
title_full | Influence of traumatic brain injury on extracellular tau elimination at the blood–brain barrier |
title_fullStr | Influence of traumatic brain injury on extracellular tau elimination at the blood–brain barrier |
title_full_unstemmed | Influence of traumatic brain injury on extracellular tau elimination at the blood–brain barrier |
title_short | Influence of traumatic brain injury on extracellular tau elimination at the blood–brain barrier |
title_sort | influence of traumatic brain injury on extracellular tau elimination at the blood–brain barrier |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549249/ https://www.ncbi.nlm.nih.gov/pubmed/34702292 http://dx.doi.org/10.1186/s12987-021-00283-y |
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