Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma
A pathological characteristic of repetitive traumatic brain injury (TBI) is the deposition of hyperphosphorylated and aggregated tau species in the brain and increased levels of extracellular monomeric tau are believed to play a role in the pathogenesis of neurodegenerative tauopathies. The pathways...
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doaj-3637edde966242adb0ffcb73e4b2ca7e2021-03-22T08:43:02ZengElsevierNeurobiology of Disease1095-953X2021-03-01150105237Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head traumaJoseph Ojo0Max Eisenbaum1Ben Shackleton2Cillian Lynch3Utsav Joshi4Nicole Saltiel5Andrew Pearson6Charis Ringland7Daniel Paris8Benoit Mouzon9Michael Mullan10Fiona Crawford11Corbin Bachmeier12The Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UKThe Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UKThe Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UKThe Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UKThe Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UKThe Roskamp Institute, Sarasota, FL, USAThe Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UKThe Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UKThe Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UKThe Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UKThe Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UKThe Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UK; James A. Haley Veterans' Hospital, Tampa, FL, USAThe Roskamp Institute, Sarasota, FL, USA; The Open University, Milton Keynes, UK; Bay Pines VA Healthcare System, Bay Pines, FL, USA; Corresponding author at: 2040 Whitfield Avenue, Sarasota, FL 34243, USA.A pathological characteristic of repetitive traumatic brain injury (TBI) is the deposition of hyperphosphorylated and aggregated tau species in the brain and increased levels of extracellular monomeric tau are believed to play a role in the pathogenesis of neurodegenerative tauopathies. The pathways by which extracellular tau is eliminated from the brain, however, remains elusive. The purpose of this study was to examine tau uptake by cerebrovascular cells and the effect of TBI on these processes. We found monomeric tau interacts with brain vascular mural cells (pericytes and smooth muscle cells) to a greater extent than other cerebrovascular cells, indicating mural cells may contribute to the elimination of extracellular tau, as previously described for other solutes such as beta-amyloid. Consistent with other neurodegenerative disorders, we observed a progressive decline in cerebrovascular mural cell markers up to 12 months post-injury in a mouse model of repetitive mild TBI (r-mTBI) and human TBI brain specimens, when compared to control. These changes appear to reflect mural cell degeneration and not cellular loss as no difference in the mural cell population was observed between r-mTBI and r-sham animals as determined through flow cytometry. Moreover, freshly isolated r-mTBI cerebrovessels showed reduced tau uptake at 6 and 12 months post-injury compared to r-sham animals, which may be the result of diminished cerebrovascular endocytosis, as caveolin-1 levels were significantly decreased in mouse r-mTBI and human TBI cerebrovessels compared to their respective controls. Further emphasizing the interaction between mural cells and tau, similar reductions in mural cell markers, tau uptake, and caveolin-1 were observed in cerebrovessels from transgenic mural cell-depleted animals. In conclusion, our studies indicate repeated injuries to the brain causes chronic mural cell degeneration, reducing the caveolar-mediated uptake of tau by these cells. Alterations in tau uptake by vascular mural cells may contribute to tau deposition in the brain following head trauma and could represent a novel therapeutic target for TBI or other neurodegenerative disorders.http://www.sciencedirect.com/science/article/pii/S0969996120305131Mural cellsTauPericytesSmooth muscle cellsTraumatic brain injuryAlzheimer's disease |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Joseph Ojo Max Eisenbaum Ben Shackleton Cillian Lynch Utsav Joshi Nicole Saltiel Andrew Pearson Charis Ringland Daniel Paris Benoit Mouzon Michael Mullan Fiona Crawford Corbin Bachmeier |
spellingShingle |
Joseph Ojo Max Eisenbaum Ben Shackleton Cillian Lynch Utsav Joshi Nicole Saltiel Andrew Pearson Charis Ringland Daniel Paris Benoit Mouzon Michael Mullan Fiona Crawford Corbin Bachmeier Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma Neurobiology of Disease Mural cells Tau Pericytes Smooth muscle cells Traumatic brain injury Alzheimer's disease |
author_facet |
Joseph Ojo Max Eisenbaum Ben Shackleton Cillian Lynch Utsav Joshi Nicole Saltiel Andrew Pearson Charis Ringland Daniel Paris Benoit Mouzon Michael Mullan Fiona Crawford Corbin Bachmeier |
author_sort |
Joseph Ojo |
title |
Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma |
title_short |
Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma |
title_full |
Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma |
title_fullStr |
Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma |
title_full_unstemmed |
Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma |
title_sort |
mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2021-03-01 |
description |
A pathological characteristic of repetitive traumatic brain injury (TBI) is the deposition of hyperphosphorylated and aggregated tau species in the brain and increased levels of extracellular monomeric tau are believed to play a role in the pathogenesis of neurodegenerative tauopathies. The pathways by which extracellular tau is eliminated from the brain, however, remains elusive. The purpose of this study was to examine tau uptake by cerebrovascular cells and the effect of TBI on these processes. We found monomeric tau interacts with brain vascular mural cells (pericytes and smooth muscle cells) to a greater extent than other cerebrovascular cells, indicating mural cells may contribute to the elimination of extracellular tau, as previously described for other solutes such as beta-amyloid. Consistent with other neurodegenerative disorders, we observed a progressive decline in cerebrovascular mural cell markers up to 12 months post-injury in a mouse model of repetitive mild TBI (r-mTBI) and human TBI brain specimens, when compared to control. These changes appear to reflect mural cell degeneration and not cellular loss as no difference in the mural cell population was observed between r-mTBI and r-sham animals as determined through flow cytometry. Moreover, freshly isolated r-mTBI cerebrovessels showed reduced tau uptake at 6 and 12 months post-injury compared to r-sham animals, which may be the result of diminished cerebrovascular endocytosis, as caveolin-1 levels were significantly decreased in mouse r-mTBI and human TBI cerebrovessels compared to their respective controls. Further emphasizing the interaction between mural cells and tau, similar reductions in mural cell markers, tau uptake, and caveolin-1 were observed in cerebrovessels from transgenic mural cell-depleted animals. In conclusion, our studies indicate repeated injuries to the brain causes chronic mural cell degeneration, reducing the caveolar-mediated uptake of tau by these cells. Alterations in tau uptake by vascular mural cells may contribute to tau deposition in the brain following head trauma and could represent a novel therapeutic target for TBI or other neurodegenerative disorders. |
topic |
Mural cells Tau Pericytes Smooth muscle cells Traumatic brain injury Alzheimer's disease |
url |
http://www.sciencedirect.com/science/article/pii/S0969996120305131 |
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