Neurons and glial cells acquire a senescent signature after repeated mild traumatic brain injury in a sex-dependent manner
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE216586 | GEO | 2022/10/29
REPOSITORIES: GEO
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Project description:Mild traumatic brain injury (mTBI) is an important public health issue, as it can lead to long-term neurological symptoms and risk of neurodegenerative disease. The pathophysiological mechanisms driving this remain unclear, and currently there are no effective therapies for mTBI. In this study on repeated mTBI (rmTBI), we have induced three mild closed-skull injuries or sham procedures, separated by 24 h, in C57BL/6 mice. We show that rmTBI mice have prolonged righting reflexes and astrogliosis, with neurological impairment in the Morris water maze (MWM) and the light dark test. Cortical and hippocampal tissue analysis revealed DNA damage in the form of double-strand breaks, oxidative damage, and R-loops, markers of cellular senescence including p16 and p21, and signaling mediated by the cGAS-STING pathway. This study identified novel sex differences after rmTBI in mice. Although these markers were all increased by rmTBI in both sexes, females had higher levels of DNA damage, lower levels of the senescence protein p16, and lower levels of cGAS-STING signaling proteins compared to their male counterparts. Single-cell RNA sequencing of the male rmTBI mouse brain revealed activation of the DNA damage response, evidence of cellular senescence, and pro-inflammatory markers reminiscent of the senescence-associated secretory phenotype (SASP) in neurons and glial cells. Cell-type specific changes were also present with evidence of brain immune activation, neurotransmission alterations in both excitatory and inhibitory neurons, and vascular dysfunction. Treatment of injured mice with the senolytic drug ABT263 significantly reduced markers of senescence only in males, but was not therapeutic in females. The reduction of senescence by ABT263 in male mice was accompanied by significantly improved performance in the MWM. This study provides compelling evidence that senescence contributes to brain dysfunction after rmTBI, but may do so in a sex-dependent manner.
| S-EPMC9669743 | biostudies-literature
Project description:N6-methyladenosine (m6A), a prevalent post-transcriptional modification in eukaryotic RNA, plays a significant role in regulating sensory experiences, learning, and injury in the mammalian central nervous system. However, the pattern of lncRNA m6A methylation in the mouse cortex following repetitive mild traumatic brain injury (rmTBI) has not been explored. This study conducted a genome-wide analysis of lncRNA m6A methylation in the mouse cortex using methylated RNA immunoprecipitation sequencing (MeRIP-Seq). Our analysis revealed 43,103 peaks were significantly upregulated or downregulated. Notably, the expression of m6A peaks indicated altered methylation and expression levels of 423 lncRNAs after rmTBI. In addition, employing METTL3 inhibitor STM2457 demonstrated that functional METTL3 was essential for repairing neural damage caused by rmTBI and influenced spatial learning and memory in rmTBI-model mice. Thus, the m6A methylation pattern of lncRNA in the mouse cortex after rmTBI identifies METTL3 as a potential intervention target for epigenetic modification following such injuries.
2025-01-22 | GSE287356 | GEO
Project description:Neurons and glial cells acquire a senescent signature after repeated mild traumatic brain injury in a sex-dependent manner
| PRJNA894462 | ENA
Project description:Repetitive mild traumatic brain injuries (rmTBI) sustained within a window of vulnerability can result in long term cognitive deficits, depression, and eventual neurodegeneration associated with tau pathology, amyloid beta plaques, gliosis, and neuronal and functional loss. However, we have limited understanding of how successive injuries affect the brain to result in these devastating long-term consequences. In the current study, we addressed the question of how repeated injuries affect the brain in the acute phase of injury (<24hr) by exposing the 3xTg-AD mouse model of tau and amyloid beta pathology to successive (1x, 3x, 5x) once-daily weight drop closed-head injuries and quantifying transcription at 30min, 4hr, and 24hr after each injury.
2024-05-17 | GSE226838 | GEO
Project description:To acquire the time profiling of miRNA levels in microglial exosomes from injured brain after rmTBI, we employed a developed rmTBI mice model, and harvested the microglial exosomes at 1, 3, 7, 14, 21, 28, 35 and 42 DPI. The exosomes were first identified by TEM scanning, NTA measurement and Western Blot. miRNA microArray was performed to detect the miRNA levels in microglial exosomes after rmTBI. 3, 14 and 42 DPI were selected to respectively represents the time-point of acute phase, sub-acute phase and chronic phase after rmTBI. 10 miRNAs had an expression change of more than two-folds (up- or down-regualted) with a P value less than 0.05 at the 3 time-points. Among them, the expression changes of miR-124-3p were particularly evident. In addition, miR-124-3p was the only miRNA that up-regulated at 3 and 14 DPI, and down-regulated (reversely expressed) at 42 DPI, suggesting that its low expression in the chronic phase after rmTBI may exert a reverse impact on neural pathology, compared with that in the acute and sub-acute phase.
2019-07-10 | GSE133997 | GEO
Project description:Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts, which is susceptible in elderly people with declined mobility, athletes of full contact sports, military personnel and victims of domestic violence. It has been pathologically diagnosed in brain donors with a history of repetitive mild traumatic brain injury (rmTBI), but cannot be clinically diagnosed for a long time. By the continuous efforts by neuropathologists, neurologists and neuroscientists in recent 10 years, an expert consensus for the diagnostic framework of CTE was proposed in 2021 funded by the National Institute of Neurological Disorders and Stroke. The new consensus contributes to facilitating research in the field. However, it still needs to incorporate in-vivo biomarkers to further refine and validate the clinical diagnostic criteria. From this, a single-center, observational cohort study has been being conducted by Tianjin Medical University General Hospital since 2021. As a pilot study of this clinical trial, the present research recruited 4 pairs of gender- and age-matched rmTBI patients with healthy subjects. Their blood samples were collected for exosome isolation, and multi-omics screening to explore potential diagnostic biomarkers in blood and its exosomes.
2022-10-18 | E-MTAB-12329 | biostudies-arrayexpress
Project description:Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts, which is susceptible in elderly people with declined mobility, athletes of full contact sports, military personnel and victims of domestic violence. It has been pathologically diagnosed in brain donors with a history of repetitive mild traumatic brain injury (rmTBI), but cannot be clinically diagnosed for a long time. By the continuous efforts by neuropathologists, neurologists and neuroscientists in recent 10 years, an expert consensus for the diagnostic framework of CTE was proposed in 2021 funded by the National Institute of Neurological Disorders and Stroke. The new consensus contributes to facilitating research in the field. However, it still needs to incorporate in-vivo biomarkers to further refine and validate the clinical diagnostic criteria. From this, a single-center, observational cohort study has been being conducted by Tianjin Medical University General Hospital since 2021. As a pilot study of this clinical trial, the present research recruited 4 pairs of gender- and age-matched rmTBI patients with healthy subjects. Their blood samples were collected for exosome isolation, and multi-omics screening to explore potential diagnostic biomarkers in blood and its exosomes.
2022-10-18 | E-MTAB-12330 | biostudies-arrayexpress
Project description:Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts, which is susceptible in elderly people with declined mobility, athletes of full contact sports, military personnel and victims of domestic violence. It has been pathologically diagnosed in brain donors with a history of repetitive mild traumatic brain injury (rmTBI), but cannot be clinically diagnosed for a long time. By the continuous efforts by neuropathologists, neurologists and neuroscientists in recent 10 years, an expert consensus for the diagnostic framework of CTE was proposed in 2021 funded by the National Institute of Neurological Disorders and Stroke. The new consensus contributes to facilitating research in the field. However, it still needs to incorporate in-vivo biomarkers to further refine and validate the clinical diagnostic criteria. From this, a single-center, observational cohort study has been being conducted by Tianjin Medical University General Hospital since 2021. As a pilot study of this clinical trial, the present research recruited 4 pairs of gender- and age-matched rmTBI patients with healthy subjects. Their blood samples were collected for exosome isolation, and multi-omics screening to explore potential diagnostic biomarkers in blood and its exosomes.
2022-10-18 | E-MTAB-12331 | biostudies-arrayexpress
Project description:Repetitive mild traumatic brain injury (rmTBI) precedes chronic traumatic encephalopathy (CTE) and involves neurovascular dysfunction. Omega-3 polyunsaturated fatty acids (PUFA) are promoted as neuroprotective, but long-term effects after brain injury remain uncertain. We uncover a metabolic vulnerability associated with cerebral accumulation of eicosapentaenoic acid (EPA), a major PUFA derived from fish oil. In a fish oil diet model, EPA accumulates at baseline yet is selectively depleted after rmTBI, consistent with mobilization during injury-associated metabolic remodeling. This pattern coincides with matrix remodeling, endothelial degeneration, and impaired neurovascular function. Cortical transcriptomics indicates reduced angiogenic programs with increased fatty acid metabolism, and lipidomics links EPA to maladaptive lipid engagement. Mechanistic studies using metabolically adapted endothelial cells show that EPA selectively impairs reparative function. Analysis of postmortem CTE brain tissue reveals parallel vascular and metabolic gene expression changes, strengthening translational relevance. Together, these findings challenge the assumption of uniform omega-3 neuroprotection after brain injury.
2026-02-11 | GSE319252 | GEO
Project description:Repetitive mild traumatic brain injury (rmTBI) precedes chronic traumatic encephalopathy (CTE) and involves neurovascular dysfunction. Omega-3 polyunsaturated fatty acids (PUFA) are promoted as neuroprotective, but long-term effects after brain injury remain uncertain. We uncover a metabolic vulnerability associated with cerebral accumulation of eicosapentaenoic acid (EPA), a major PUFA derived from fish oil. In a fish oil diet model, EPA accumulates at baseline yet is selectively depleted after rmTBI, consistent with mobilization during injury-associated metabolic remodeling. This pattern coincides with matrix remodeling, endothelial degeneration, and impaired neurovascular function. Cortical transcriptomics indicates reduced angiogenic programs with increased fatty acid metabolism, and lipidomics links EPA to maladaptive lipid engagement. Mechanistic studies using metabolically adapted endothelial cells show that EPA selectively impairs reparative function. Analysis of postmortem CTE brain tissue reveals parallel vascular and metabolic gene expression changes, strengthening translational relevance. Together, these findings challenge the assumption of uniform omega-3 neuroprotection after brain injury.
2026-02-11 | GSE319253 | GEO