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Updated: Oct 4, 2025
A Repetitive Concussive Head Injury Model in Mice
Published on: October 12, 2016
Repetitive Mild Closed Head Injury in Adolescent Mice Is Associated with Impaired Proteostasis, Neuroinflammation,
Limin Wu1, Brian T Kalish2,3,4,5, Benjamin Finander2,3
1Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
Abstract:
Repetitive mild traumatic brain injury (mTBI) in children and adolescents leads to acute and chronic neurologic sequelae and is linked to later life neurodegenerative disease. However, the biological mechanisms connecting early life mTBI to neurodegeneration remain unknown. Using an adolescent mouse repetitive closed head injury model that induces progressive cognitive impairment in males and anxiety in females in the absence of overt histopathology, we examined transcriptional and translational changes in neurons isolated from sham and injured brain in the chronic phase after injury. At 14 months, single-nuclei RNA sequencing of cortical brain tissue identified disruption of genes associated with neuronal proteostasis and evidence for disrupted ligand-receptor signaling networks in injured mice. Western blot analysis of isolated neurons showed evidence of inflammasome activation and downstream IL-1β processing, as previously demonstrated in acute CNS injury models, and accumulation of misfolded, hyperphosphorylated tau, and changes in expression of proteins suggestive of impaired translation in males but not in females. At 6 months, injured IL-1 receptor 1 (IL-1R1) KO mice, which are protected from postinjury cognitive deficits, had decreased accumulation of pro-IL-1β and misfolded tau in cortex and cerebellum, suggesting that IL-1R1 is upstream of inflammasome priming (defined as increase in pro-IL-1β) and abnormal tau phosphorylation. Together, our findings provide evidence for neuronal inflammasome activation and impaired proteostasis as key mechanisms linking repetitive mTBI in adolescence to later life neurologic dysfunction and neurodegeneration.SIGNIFICANCE STATEMENT Repetitive mild closed head injury in adolescent male mice leads to impaired proteostasis, tau phosphorylation, and inflammasome activation in neurons later in adulthood through mechanisms involving IL-1 receptor 1. The data are the first to link repetitive mild traumatic brain injury in adolescence to neurodegeneration and suggest molecular targets and pathways to prevent neurologic sequelae in the chronic period after injuries.
Insights
Repetitive mild traumatic brain injury in adolescents can cause long-term brain damage. This study reveals neuronal inflammasome activation and impaired proteostasis as key mechanisms linking early injury to later neurodegeneration.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Repetitive mild traumatic brain injury (mTBI) in youth is linked to later neurodegenerative diseases, but underlying mechanisms are unclear.
- Understanding these mechanisms is crucial for developing preventative strategies against chronic neurological sequelae.
Purpose of the Study:
- To investigate the biological mechanisms connecting adolescent repetitive mTBI to chronic neurodegenerative changes.
- To identify molecular pathways involved in the long-term consequences of early-life head injuries.
Main Methods:
- Utilized an adolescent mouse model of repetitive closed head injury.
- Employed single-nuclei RNA sequencing and Western blot analysis on isolated neurons from injured and sham brains.
- Examined gene expression, protein accumulation, and inflammasome activation in the chronic phase post-injury.
Main Results:
- Disrupted genes related to neuronal proteostasis and altered ligand-receptor signaling networks were identified in injured mice.
- Evidence of inflammasome activation, increased misfolded tau, and impaired translation was observed.
- IL-1 receptor 1 (IL-1R1) knockout mice showed protection from cognitive deficits and reduced pathological markers, indicating IL-1R1's role in disease progression.
Conclusions:
- Neuronal inflammasome activation and impaired proteostasis are critical mechanisms linking adolescent mTBI to later-life neurological dysfunction and neurodegeneration.
- IL-1R1 signaling is upstream of inflammasome activation and abnormal tau phosphorylation, suggesting it as a potential therapeutic target.
- These findings provide the first molecular link between adolescent repetitive mTBI and neurodegeneration, offering targets for prevention.
