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Vascular senescence and leak are features of the early breakdown of the blood–brain barrier in Alzheimer’s disease models

Alzheimer’s disease (AD) is an age-related disease, with loss of integrity of the blood–brain barrier (BBB) being an early feature. Cellular senescence is one of the reported nine hallmarks of aging. Here, we show for the first time the presence of senescent cells in the vasculature in AD patients a...

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Autores principales: Ting, Ka Ka, Coleman, Paul, Kim, Hani Jieun, Zhao, Yang, Mulangala, Jocelyne, Cheng, Ngan Ching, Li, Wan, Gunatilake, Dilini, Johnstone, Daniel M., Loo, Lipin, Neely, G. Gregory, Yang, Pengyi, Götz, Jürgen, Vadas, Mathew A., Gamble, Jennifer R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643714/
https://www.ncbi.nlm.nih.gov/pubmed/37782439
http://dx.doi.org/10.1007/s11357-023-00927-x
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author Ting, Ka Ka
Coleman, Paul
Kim, Hani Jieun
Zhao, Yang
Mulangala, Jocelyne
Cheng, Ngan Ching
Li, Wan
Gunatilake, Dilini
Johnstone, Daniel M.
Loo, Lipin
Neely, G. Gregory
Yang, Pengyi
Götz, Jürgen
Vadas, Mathew A.
Gamble, Jennifer R.
author_facet Ting, Ka Ka
Coleman, Paul
Kim, Hani Jieun
Zhao, Yang
Mulangala, Jocelyne
Cheng, Ngan Ching
Li, Wan
Gunatilake, Dilini
Johnstone, Daniel M.
Loo, Lipin
Neely, G. Gregory
Yang, Pengyi
Götz, Jürgen
Vadas, Mathew A.
Gamble, Jennifer R.
author_sort Ting, Ka Ka
collection PubMed
description Alzheimer’s disease (AD) is an age-related disease, with loss of integrity of the blood–brain barrier (BBB) being an early feature. Cellular senescence is one of the reported nine hallmarks of aging. Here, we show for the first time the presence of senescent cells in the vasculature in AD patients and mouse models of AD. Senescent endothelial cells and pericytes are present in APP/PS1 transgenic mice but not in wild-type littermates at the time of amyloid deposition. In vitro, senescent endothelial cells display altered VE-cadherin expression and loss of cell junction formation and increased permeability. Consistent with this, senescent endothelial cells in APP/PS1 mice are present at areas of vascular leak that have decreased claudin-5 and VE-cadherin expression confirming BBB breakdown. Furthermore, single cell sequencing of endothelial cells from APP/PS1 transgenic mice confirms that adhesion molecule pathways are among the most highly altered pathways in these cells. At the pre-plaque stage, the vasculature shows significant signs of breakdown, with a general loss of VE-cadherin, leakage within the microcirculation, and obvious pericyte perturbation. Although senescent vascular cells were not directly observed at sites of vascular leak, senescent cells were close to the leak area. Thus, we would suggest in AD that there is a progressive induction of senescence in constituents of the neurovascular unit contributing to an increasing loss of vascular integrity. Targeting the vasculature early in AD, either with senolytics or with drugs that improve the integrity of the BBB may be valid therapeutic strategies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-023-00927-x.
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spelling pubmed-106437142023-11-15 Vascular senescence and leak are features of the early breakdown of the blood–brain barrier in Alzheimer’s disease models Ting, Ka Ka Coleman, Paul Kim, Hani Jieun Zhao, Yang Mulangala, Jocelyne Cheng, Ngan Ching Li, Wan Gunatilake, Dilini Johnstone, Daniel M. Loo, Lipin Neely, G. Gregory Yang, Pengyi Götz, Jürgen Vadas, Mathew A. Gamble, Jennifer R. GeroScience Original Article Alzheimer’s disease (AD) is an age-related disease, with loss of integrity of the blood–brain barrier (BBB) being an early feature. Cellular senescence is one of the reported nine hallmarks of aging. Here, we show for the first time the presence of senescent cells in the vasculature in AD patients and mouse models of AD. Senescent endothelial cells and pericytes are present in APP/PS1 transgenic mice but not in wild-type littermates at the time of amyloid deposition. In vitro, senescent endothelial cells display altered VE-cadherin expression and loss of cell junction formation and increased permeability. Consistent with this, senescent endothelial cells in APP/PS1 mice are present at areas of vascular leak that have decreased claudin-5 and VE-cadherin expression confirming BBB breakdown. Furthermore, single cell sequencing of endothelial cells from APP/PS1 transgenic mice confirms that adhesion molecule pathways are among the most highly altered pathways in these cells. At the pre-plaque stage, the vasculature shows significant signs of breakdown, with a general loss of VE-cadherin, leakage within the microcirculation, and obvious pericyte perturbation. Although senescent vascular cells were not directly observed at sites of vascular leak, senescent cells were close to the leak area. Thus, we would suggest in AD that there is a progressive induction of senescence in constituents of the neurovascular unit contributing to an increasing loss of vascular integrity. Targeting the vasculature early in AD, either with senolytics or with drugs that improve the integrity of the BBB may be valid therapeutic strategies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-023-00927-x. Springer International Publishing 2023-10-02 /pmc/articles/PMC10643714/ /pubmed/37782439 http://dx.doi.org/10.1007/s11357-023-00927-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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 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/) .
spellingShingle Original Article
Ting, Ka Ka
Coleman, Paul
Kim, Hani Jieun
Zhao, Yang
Mulangala, Jocelyne
Cheng, Ngan Ching
Li, Wan
Gunatilake, Dilini
Johnstone, Daniel M.
Loo, Lipin
Neely, G. Gregory
Yang, Pengyi
Götz, Jürgen
Vadas, Mathew A.
Gamble, Jennifer R.
Vascular senescence and leak are features of the early breakdown of the blood–brain barrier in Alzheimer’s disease models
title Vascular senescence and leak are features of the early breakdown of the blood–brain barrier in Alzheimer’s disease models
title_full Vascular senescence and leak are features of the early breakdown of the blood–brain barrier in Alzheimer’s disease models
title_fullStr Vascular senescence and leak are features of the early breakdown of the blood–brain barrier in Alzheimer’s disease models
title_full_unstemmed Vascular senescence and leak are features of the early breakdown of the blood–brain barrier in Alzheimer’s disease models
title_short Vascular senescence and leak are features of the early breakdown of the blood–brain barrier in Alzheimer’s disease models
title_sort vascular senescence and leak are features of the early breakdown of the blood–brain barrier in alzheimer’s disease models
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643714/
https://www.ncbi.nlm.nih.gov/pubmed/37782439
http://dx.doi.org/10.1007/s11357-023-00927-x
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