Repetitive mild closed head injury in adolescent mice is associated with impaired proteostasis, neuroinflammation, and tauopathy
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ABSTRACT:
PROVIDER: PRJNA705646 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13811528.fastq.gz | Fastqsanger.gz | |||
| SRR13811529.fastq.gz | Fastqsanger.gz | |||
| SRR13811530.fastq.gz | Fastqsanger.gz | |||
| SRR13811531.fastq.gz | Fastqsanger.gz |
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Project description:Repetitive mild traumatic brain injury (mTBI) in children and adolescents leads to acute and chronic neurological sequelae and is linked by epidemiological data 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 (CHI) model that induces progressive cognitive impairment 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 in injured mice. Western blot analysis of neurons isolated by immunopanning showed evidence of inflammasome activation, accumulation of misfolded, hyperphosphorylated Tau, and changes in expression of proteins suggestive of impaired translation. Compared to injured wild type, injured interleukin-1 receptor 1 knockout mice, which are protected from post-injury cognitive deficits, had reduced microgliosis and decreased accumulation of pro-interleukin-1 beta and misfolded tau in cortex and cerebellum at six months. Taken together, our findings provide evidence for neuronal inflammasome activation and impaired proteostasis as key mechanisms linking repetitive mTBI in adolescence to later life neurological dysfunction and neurodegeneration.
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