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Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology

The deposition of misfolded proteins, including amyloid beta plaques and neurofibrillary tangles is the histopathological hallmark of Alzheimer’s disease (AD). The glymphatic system, a brain-wide network of perivascular pathways that supports interstitial solute clearance, is dependent upon expressi...

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Autores principales: Simon, Matthew J., Wang, Marie X., Murchison, Charles F., Roese, Natalie E., Boespflug, Erin L., Woltjer, Randall L., Iliff, Jeffrey J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098119/
https://www.ncbi.nlm.nih.gov/pubmed/30120299
http://dx.doi.org/10.1038/s41598-018-30779-x
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author Simon, Matthew J.
Wang, Marie X.
Murchison, Charles F.
Roese, Natalie E.
Boespflug, Erin L.
Woltjer, Randall L.
Iliff, Jeffrey J.
author_facet Simon, Matthew J.
Wang, Marie X.
Murchison, Charles F.
Roese, Natalie E.
Boespflug, Erin L.
Woltjer, Randall L.
Iliff, Jeffrey J.
author_sort Simon, Matthew J.
collection PubMed
description The deposition of misfolded proteins, including amyloid beta plaques and neurofibrillary tangles is the histopathological hallmark of Alzheimer’s disease (AD). The glymphatic system, a brain-wide network of perivascular pathways that supports interstitial solute clearance, is dependent upon expression of the perivascular astroglial water channel aquaporin-4 (AQP4). Impairment of glymphatic function in the aging rodent brain is associated with reduced perivascular AQP4 localization, and in human subjects, reduced perivascular AQP4 localization is associated with AD diagnosis and pathology. Using human transcriptomic data, we demonstrate that expression of perivascular astroglial gene products dystroglycan (DAG1), dystrobrevin (DTNA) and alpha-syntrophin (SNTA1), are associated with dementia status and phosphorylated tau (P-tau) levels in temporal cortex. Gene correlation analysis reveals altered expression of a cluster of potential astrocytic endfoot components in human subjects with dementia, with increased expression associated with temporal cortical P-tau levels. The association between perivascular astroglial gene products, including DTNA and megalencephalic leukoencephalopathy with subcortical cysts 1 (MLC1) with AD status was confirmed in a second human transcriptomic dataset and in human autopsy tissue by Western blot. This suggests changes in the astroglial endfoot domain may underlie vulnerability to protein aggregation in AD.
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spelling pubmed-60981192018-08-23 Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology Simon, Matthew J. Wang, Marie X. Murchison, Charles F. Roese, Natalie E. Boespflug, Erin L. Woltjer, Randall L. Iliff, Jeffrey J. Sci Rep Article The deposition of misfolded proteins, including amyloid beta plaques and neurofibrillary tangles is the histopathological hallmark of Alzheimer’s disease (AD). The glymphatic system, a brain-wide network of perivascular pathways that supports interstitial solute clearance, is dependent upon expression of the perivascular astroglial water channel aquaporin-4 (AQP4). Impairment of glymphatic function in the aging rodent brain is associated with reduced perivascular AQP4 localization, and in human subjects, reduced perivascular AQP4 localization is associated with AD diagnosis and pathology. Using human transcriptomic data, we demonstrate that expression of perivascular astroglial gene products dystroglycan (DAG1), dystrobrevin (DTNA) and alpha-syntrophin (SNTA1), are associated with dementia status and phosphorylated tau (P-tau) levels in temporal cortex. Gene correlation analysis reveals altered expression of a cluster of potential astrocytic endfoot components in human subjects with dementia, with increased expression associated with temporal cortical P-tau levels. The association between perivascular astroglial gene products, including DTNA and megalencephalic leukoencephalopathy with subcortical cysts 1 (MLC1) with AD status was confirmed in a second human transcriptomic dataset and in human autopsy tissue by Western blot. This suggests changes in the astroglial endfoot domain may underlie vulnerability to protein aggregation in AD. Nature Publishing Group UK 2018-08-17 /pmc/articles/PMC6098119/ /pubmed/30120299 http://dx.doi.org/10.1038/s41598-018-30779-x Text en © The Author(s) 2018 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Simon, Matthew J.
Wang, Marie X.
Murchison, Charles F.
Roese, Natalie E.
Boespflug, Erin L.
Woltjer, Randall L.
Iliff, Jeffrey J.
Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology
title Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology
title_full Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology
title_fullStr Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology
title_full_unstemmed Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology
title_short Transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology
title_sort transcriptional network analysis of human astrocytic endfoot genes reveals region-specific associations with dementia status and tau pathology
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098119/
https://www.ncbi.nlm.nih.gov/pubmed/30120299
http://dx.doi.org/10.1038/s41598-018-30779-x
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