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Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice
Elderly patients with traumatic brain injury (TBI) have greater mortality and poorer outcomes than younger individuals. The extent to which old age alters long-term recovery and chronic microglial activation after TBI is unknown, and evidence for therapeutic efficacy in aged mice is sorely lacking....
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9213636/ https://www.ncbi.nlm.nih.gov/pubmed/35451674 http://dx.doi.org/10.1007/s11357-022-00562-y |
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author | Ritzel, Rodney M. Li, Yun Lei, Zhuofan Carter, Jordan He, Junyun Choi, Harry M. C. Khan, Niaz Li, Hui Allen, Samantha Lipinski, Marta M. Faden, Alan I. Wu, Junfang |
author_facet | Ritzel, Rodney M. Li, Yun Lei, Zhuofan Carter, Jordan He, Junyun Choi, Harry M. C. Khan, Niaz Li, Hui Allen, Samantha Lipinski, Marta M. Faden, Alan I. Wu, Junfang |
author_sort | Ritzel, Rodney M. |
collection | PubMed |
description | Elderly patients with traumatic brain injury (TBI) have greater mortality and poorer outcomes than younger individuals. The extent to which old age alters long-term recovery and chronic microglial activation after TBI is unknown, and evidence for therapeutic efficacy in aged mice is sorely lacking. The present study sought to identify potential inflammatory mechanisms underlying age-related outcomes late after TBI. Controlled cortical impact was used to induce moderate TBI in young and old male C57BL/6 mice. At 12 weeks post-injury, aged mice exhibited higher mortality, poorer functional outcomes, larger lesion volumes, and increased microglial activation. Transcriptomic analysis identified age- and TBI-specific gene changes consistent with a disease-associated microglial signature in the chronically injured brain, including those involved with complement, phagocytosis, and autophagy pathways. Dysregulation of phagocytic and autophagic function in microglia was accompanied by increased neuroinflammation in old mice. As proof-of-principle that these pathways have functional importance, we administered an autophagic enhancer, trehalose, in drinking water continuously for 8 weeks after TBI. Old mice treated with trehalose showed enhanced functional recovery and reduced microglial activation late after TBI compared to the sucrose control group. Our data indicate that microglia undergo chronic changes in autophagic regulation with both normal aging and TBI that are associated with poorer functional outcome. Enhancing autophagy may therefore be a promising clinical therapeutic strategy for TBI, especially in older patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00562-y. |
format | Online Article Text |
id | pubmed-9213636 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-92136362022-06-23 Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice Ritzel, Rodney M. Li, Yun Lei, Zhuofan Carter, Jordan He, Junyun Choi, Harry M. C. Khan, Niaz Li, Hui Allen, Samantha Lipinski, Marta M. Faden, Alan I. Wu, Junfang GeroScience Original Article Elderly patients with traumatic brain injury (TBI) have greater mortality and poorer outcomes than younger individuals. The extent to which old age alters long-term recovery and chronic microglial activation after TBI is unknown, and evidence for therapeutic efficacy in aged mice is sorely lacking. The present study sought to identify potential inflammatory mechanisms underlying age-related outcomes late after TBI. Controlled cortical impact was used to induce moderate TBI in young and old male C57BL/6 mice. At 12 weeks post-injury, aged mice exhibited higher mortality, poorer functional outcomes, larger lesion volumes, and increased microglial activation. Transcriptomic analysis identified age- and TBI-specific gene changes consistent with a disease-associated microglial signature in the chronically injured brain, including those involved with complement, phagocytosis, and autophagy pathways. Dysregulation of phagocytic and autophagic function in microglia was accompanied by increased neuroinflammation in old mice. As proof-of-principle that these pathways have functional importance, we administered an autophagic enhancer, trehalose, in drinking water continuously for 8 weeks after TBI. Old mice treated with trehalose showed enhanced functional recovery and reduced microglial activation late after TBI compared to the sucrose control group. Our data indicate that microglia undergo chronic changes in autophagic regulation with both normal aging and TBI that are associated with poorer functional outcome. Enhancing autophagy may therefore be a promising clinical therapeutic strategy for TBI, especially in older patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00562-y. Springer International Publishing 2022-04-22 /pmc/articles/PMC9213636/ /pubmed/35451674 http://dx.doi.org/10.1007/s11357-022-00562-y Text en © The Author(s) 2022 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, visithttp://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Ritzel, Rodney M. Li, Yun Lei, Zhuofan Carter, Jordan He, Junyun Choi, Harry M. C. Khan, Niaz Li, Hui Allen, Samantha Lipinski, Marta M. Faden, Alan I. Wu, Junfang Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice |
title | Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice |
title_full | Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice |
title_fullStr | Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice |
title_full_unstemmed | Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice |
title_short | Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice |
title_sort | functional and transcriptional profiling of microglial activation during the chronic phase of tbi identifies an age-related driver of poor outcome in old mice |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9213636/ https://www.ncbi.nlm.nih.gov/pubmed/35451674 http://dx.doi.org/10.1007/s11357-022-00562-y |
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