Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice.
AuthorRitzel, Rodney M
Choi, Harry M C
Lipinski, Marta M
Faden, Alan I
MetadataShow full item record
AbstractElderly 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).
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/18745
- Microglial Depletion with CSF1R Inhibitor During Chronic Phase of Experimental Traumatic Brain Injury Reduces Neurodegeneration and Neurological Deficits.
- Authors: Henry RJ, Ritzel RM, Barrett JP, Doran SJ, Jiao Y, Leach JB, Szeto GL, Wu J, Stoica BA, Faden AI, Loane DJ
- Issue date: 2020 Apr 1
- Interferon-β Plays a Detrimental Role in Experimental Traumatic Brain Injury by Enhancing Neuroinflammation That Drives Chronic Neurodegeneration.
- Authors: Barrett JP, Henry RJ, Shirey KA, Doran SJ, Makarevich OD, Ritzel RM, Meadows VA, Vogel SN, Faden AI, Stoica BA, Loane DJ
- Issue date: 2020 Mar 11
- Old age increases microglial senescence, exacerbates secondary neuroinflammation, and worsens neurological outcomes after acute traumatic brain injury in mice.
- Authors: Ritzel RM, Doran SJ, Glaser EP, Meadows VE, Faden AI, Stoica BA, Loane DJ
- Issue date: 2019 May
- Valproic acid affects neuronal fate and microglial function via enhancing autophagic flux in mice after traumatic brain injury.
- Authors: Zheng Z, Wu Y, Li Z, Ye L, Lu Q, Zhou Y, Yuan Y, Jiang T, Xie L, Liu Y, Chen D, Ye J, Nimlamool W, Zhang H, Xiao J
- Issue date: 2020 Aug
- Sustained neuronal and microglial alterations are associated with diverse neurobehavioral dysfunction long after experimental brain injury.
- Authors: Ritzel RM, Li Y, He J, Khan N, Doran SJ, Faden AI, Wu J
- Issue date: 2020 Mar