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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.

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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
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    Date
    2022-04-22
    Journal
    GeroScience
    Publisher
    Springer Nature
    Type
    Article
    
    Metadata
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    See at
    https://doi.org/10.1007/s11357-022-00562-y
    Abstract
    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. © 2022, The Author(s).
    Rights/Terms
    © 2022. The Author(s).
    Keyword
    Aging
    Autophagy
    Microglia
    Neurodegeneration
    Neuroinflammation
    Traumatic brain injury
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/18745
    ae974a485f413a2113503eed53cd6c53
    10.1007/s11357-022-00562-y
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