Transglutaminase 2 Deletion Enhances Astrocyte-to-Neuron Metabolic Support and Attenuates Subacute Pathology Following Repetitive Mild Traumatic Brain Injury
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE337851 | GEO | 2026/07/16
REPOSITORIES: GEO
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Project description:While traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of mild cortical injury that does not directly damage subcortical structures (mTBI), we found a chronic increase in C1q expression specifically in the corticothalamic circuit. Increased C1q expression co-localized with neuron loss and chronic inflammation, and correlated with disruption in sleep spindles and emergence of epileptic activities. Blocking C1q counteracted these outcomes, suggesting that C1q is a disease modifier in mTBI. Single-nucleus RNA sequencing demonstrated that microglia are the source of thalamic C1q. Since the corticothalamic circuit is important for cognition and sleep, which can be impaired by TBI, this circuit could thus be a new target for treating TBI-related disabilities.
2021-09-14 | GSE179541 | GEO
Project description:The etiology of mild traumatic brain injury (mTBI) remains elusive due to the tissue and cellular heterogeneity of the affected brain regions that underlie cognitive impairments and subsequent neurological disorders. This complexity is further exacerbated by disrupted circuits within and between cell populations across brain regions and the periphery, which occur at different timescales and in spatial domains. We profiled three tissues (hippocampus, frontal cortex, and blood leukocytes) at the acute (24hr) and chronic (7days) phases of mTBI at single cell resolution and demonstrated that the coordinated gene expression patterns across cell types were disrupted and re-organized by TBI at different timescales with distinct regional and cellular patterns. Gene expression-based network modeling identified astrocytes as a key regulator of the cell-cell coordination following mTBI in both hippocampus and frontal cortex across timepoints, and mt-Rnr2, which encodes the mitochondrial peptide humanin, as a potential target for intervention based on its broad regional and dynamic dysregulation following mTBI. Treatment of a murine mTBI model with humanin reversed cognitive impairment caused by mTBI through the restoration of metabolic pathways within astrocytes. Our results offer a systems-level understanding of the dynamic and spatial regulation of gene programs by mTBI and pinpoint key target genes, pathways, and cell circuits that are amenable to therapeutics.
2022-08-17 | GSE180862 | GEO
Project description:The relationship between repetitive mild traumatic brain injury (r-mTBI) and Alzheimer’s disease (AD) is well-recognized. However, the precise nature of how r-mTBI leads to or precipitates AD pathogenesis is currently not understood. Part A: Plasma biomarkers potentially provide non-invasive tools for detecting neurological changes in the brain, and can reveal overlaps between long-term consequences of r-mTBI and AD. In this study we address this by generating time-dependent molecular profiles of response to r-mTBI and AD pathogenesis in mouse models using unbiased proteomic analyses. To model AD, we used the well-validated hTau and PSAPP(APP/PS1) mouse models that develop age-related tau and amyloid pathological features respectively, and our well-established model of r-mTBI in C57BL/6 mice. Plasma were collected at different ages (3, 9, and 15 months-old for hTau and PSAPP mice), encompassing pre-, peri- and post-“onset” of the cognitive and neuropathological phenotypes, or at different timepoints after r-mTBI (24hrs, 3, 6, 9 and 12 months post-injury). Liquid chromatography/mass spectrometry (LC-MS) approaches coupled with Tandem Mass Tag labeling technology were applied to develop molecular profiles of protein species that were significantly differentially expressed as a consequence of mTBI or AD. Mixed model ANOVA after Benjamini-Hochberg correction, and a stringent cut-off identified 31 proteins significantly changing in r-mTBI groups over time and, when compared with changes over time in sham mice, 13 of these were unique to the injured mice. The canonical pathways predicted to be modulated by these changes were LXR/RXR activation, production of nitric oxide and reactive oxygen species and complement systems. We identified 18 proteins significantly changing in PSAPP mice and 19 proteins in hTau mice compared to their wildtype littermates with ageing. Six proteins were found to be significantly regulated in all three models i.e. r-mTBI, hTau and PSAPP mice compared to their controls. The top canonical pathways coincidently changing in all three models were LXR/RXR activation, and production of nitric oxide and reactive oxygen species. This work suggests potential biomarkers for TBI and AD pathogenesis and for the overlap between these two, and warrant targeted investigation in human populations. Part B: In this study we also address the aformention gap in the field by utilizing our unbiased proteomic approach to generate detailed time-dependent brain molecular profiles of response to repetitive mTBI and AD pathogenesis in established mouse models. Methods: We used the well-validated hTau and PSAPP(APP/PS1) mouse models that develops age-related tau and amyloid pathological features respectively, and our well-established model of repetitive-mTBI in C57BL/6 mice. Brain tissue from these animals were collected at different time points after repetitive mTBI (24hrs -12 months post-injury) and at different ages (3-15 months-old for hTau and PSAPP mice), encompassing pre-, peri- and post-“onset” of the cognitive and neuropathological phenotypes previously described in all models. Liquid chromatography/mass spectrometry (LC-MS) approach coupled with Tandem Mass Tag labeling technology were applied to reveal molecular profiles of proteins and pathways that are significantly altered as a consequence of AD or repetitive mTBI. Results: Mixed model ANOVA after Benjamin Hochberg correction identified 30 and 47 proteins that were specifically unique and changing in the hippocampus and cortex, respectively, within the r-mTBI group alone when compared with changes overtime in sham mice. PI3K/AKT signaling, Protein Kinase A signaling and PPAR/RXR activation in the hippocampus, and Protein Kinase A signaling, GNRH signaling and B cell receptor signaling in the cortex were the top canonical systems significantly altered in injury groups compared to sham mice. Mixed model AONVA identified 19 proteins significantly changing in the cortex of PSAPP mice and 7 proteins in hTau mice compared to their relative wildtype littermates respectively. In addition to the heterogeneous changes observed in the TBI and AD mouse models, there was a notable convergence and coincidental change in 6 unique proteins identified in the repetitive mTBI model and the hTau and PSAPP model. These proteins ostensibly indicate significant common pathobiological responses involving alterations in mitochondrial bioenergetics and energy metabolism, aberrant cytoskeletal reorganization and alterations in intracellular signaling transduction cascades. Conclusion: We believe that this work could help identify the common molecular substrates responsible for the precipitation of AD pathogenesis following repetitive mTBI, and also help to identify novel biological targets for therapeutic modulation in mTBI and AD.
2022-02-22 | PXD010602 | Pride
Project description:The relationship between repetitive mild traumatic brain injury (r-mTBI) and Alzheimer’s disease (AD) is well-recognized. However, the precise nature of how r-mTBI leads to or precipitates AD pathogenesis is currently not understood. Part A: Plasma biomarkers potentially provide non-invasive tools for detecting neurological changes in the brain, and can reveal overlaps between long-term consequences of r-mTBI and AD. In this study we address this by generating time-dependent molecular profiles of response to r-mTBI and AD pathogenesis in mouse models using unbiased proteomic analyses. To model AD, we used the well-validated hTau and PSAPP(APP/PS1) mouse models that develop age-related tau and amyloid pathological features respectively, and our well-established model of r-mTBI in C57BL/6 mice. Plasma were collected at different ages (3, 9, and 15 months-old for hTau and PSAPP mice), encompassing pre-, peri- and post-“onset” of the cognitive and neuropathological phenotypes, or at different timepoints after r-mTBI (24hrs, 3, 6, 9 and 12 months post-injury). Liquid chromatography/mass spectrometry (LC-MS) approaches coupled with Tandem Mass Tag labeling technology were applied to develop molecular profiles of protein species that were significantly differentially expressed as a consequence of mTBI or AD. Mixed model ANOVA after Benjamini-Hochberg correction, and a stringent cut-off identified 31 proteins significantly changing in r-mTBI groups over time and, when compared with changes over time in sham mice, 13 of these were unique to the injured mice. The canonical pathways predicted to be modulated by these changes were LXR/RXR activation, production of nitric oxide and reactive oxygen species and complement systems. We identified 18 proteins significantly changing in PSAPP mice and 19 proteins in hTau mice compared to their wildtype littermates with ageing. Six proteins were found to be significantly regulated in all three models i.e. r-mTBI, hTau and PSAPP mice compared to their controls. The top canonical pathways coincidently changing in all three models were LXR/RXR activation, and production of nitric oxide and reactive oxygen species. This work suggests potential biomarkers for TBI and AD pathogenesis and for the overlap between these two, and warrant targeted investigation in human populations. Part B: In this part of the study we address the above problem by utilizing our unbiased proteomic approach to generate detailed time-dependent brain molecular profiles of response to repetitive mTBI and AD pathogenesis in established mouse models. The same animal models described above were used herein. A LC/MS approach coupled with TMT labeling was also employed. Results: Mixed model ANOVA after Benjamin Hochberg correction identified 30 and 47 proteins that were specifically unique and changing in the hippocampus and cortex, respectively, within the r-mTBI group alone when compared with changes overtime in sham mice. PI3K/AKT signaling, Protein Kinase A signaling and PPAR/RXR activation in the hippocampus, and Protein Kinase A signaling, GNRH signaling and B cell receptor signaling in the cortex were the top canonical systems significantly altered in injury groups compared to sham mice. Mixed model AONVA identified 19 proteins significantly changing in the cortex of PSAPP mice and 7 proteins in hTau mice compared to their relative wildtype littermates respectively. In addition to the heterogeneous changes observed in the TBI and AD mouse models, there was a notable convergence and coincidental change in 6 unique proteins identified in the repetitive mTBI model and the hTau and PSAPP model. These proteins ostensibly indicate significant common pathobiological responses involving alterations in mitochondrial bioenergetics and energy metabolism, aberrant cytoskeletal reorganization and alterations in intracellular signaling transduction cascades. Conclusion: We believe that this work could help identify the common molecular substrates responsible for the precipitation of AD pathogenesis following repetitive mTBI, and also help to identify novel biological targets for therapeutic modulation in mTBI and AD.
2019-01-11 | PXD010664 | Pride
Project description:Primary blast-induced mild traumatic brain injury (mTBI) represents a common injury experienced during modern warfare. With virtually no apparent physical damage or symptoms presented, an effective source with minimum-invasion for mTBI biomarker discovery is required. In this study, we measure the transcriptomic sensitivity of the hair follicles in relation to the severity of primary blast-derived TBI.
2016-05-07 | GSE80371 | GEO
Project description:Background: Mild head injury associated with long-term functional impairments (i.e., depression, anxiety) is frequently observed among patients who experienced mild traumatic brain injury (mTBI). Moreover, repetitive injuries within a window of vulnerability can lead to exacerbated consequences compared to a single mTBI. However, current interventions for mTBI focus on alleviating symptoms, rather than targeting underlying mechanisms. Following the initial mechanical impact, increasing evidence suggests that the brain undergoes an inflammatory cascade consisting of pro-inflammatory intracellular signaling pathways and production of cytokines, ultimately leading to chronic neuroinflammation and persistent neurological deficits, such as depression. Specifically, in the context of severe brain injury, the p38 MAPK signaling pathway has been identified as a key driver to the inflammatory response, associated with increased microglial activation, proinflammatory cytokines, and synaptic dysfunctions, but its role in the context of mild brain injury remains unclear. As such, this study aimed to investigate whether p38 MAPK drives the inflammatory responses and longer-term deficits following a weight-drop mouse model of repetitive mTBI (rmTBI). Methods: We injected C57/BL6 mice with SB239063, a small molecule p38 MAPK inhibitor, after each of the 5 once-daily weight-drop closed head injuries (CHIs) or sham. We evaluated functional outcomes within 4-weeks after the final CHI and quantified cytokine expressions, microglia reactivity, and transcriptional profiles at 4hr and 4-weeks post final injury. Results: We found that in females, acute inhibition of p38 MAPK attenuated acute inflammatory response comprised of increased cytokine/chemokine expression and microglial activation at 4-hours post injury and longer-term anti-depressive-like behavioral at 4-weeks post injury. However, such effects of p38 inhibition were less obvious in males. On the transcript level, we found that p38 inhibition not only normalized the effects of the brain injury but also upregulated protective genes and pathways associated with recovery and the maintenance of brain homeostasis. Together, these findings support the therapeutic potential of p38 MAPK inhibition following (r)mTBI, indicating the role of p38 MAPK in driving the acute and longer-term consequences post brain injury in a sex dependent manner.
2026-03-18 | GSE298240 | GEO
Project description:Traumatic brain injury (TBI) is a global problem reaching near epidemic numbers that manifests clinically with cognitive problems that decades later may result in dementias like Alzheimer’s disease (AD). Presently, little can be done to prevent ensuing neurological dysfunctions by pharmacological means. Recently, it has become apparent that several CNS diseases share common terminal features of neuronal cell death. The effects of exendin-4 (Ex-4), a neuroprotective agent delivered via a subcutaneous micro-osmotic pump, were examined in the setting of mild TBI (mTBI). Utilizing a model of mTBI, where cognitive disturbances occur over time, animals were subjected to four treatments: sham; Ex-4; mTBI and Ex-4/mTBI. mTBI mice displayed deficits in novel object recognition, while Ex-4/mTBI mice performed similar to sham. Hippocampal gene expression, assessed by gene array methods, showed significant differences with little overlap in co-regulated genes between groups. Importantly, changes in gene expression induced by mTBI, including genes associated with AD were largely prevented by Ex-4. These data suggest a strong beneficial action of Ex-4 in managing secondary events induced by a traumatic brain injury.
2012-10-17 | GSE41345 | GEO
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:Traumatic brain injury (TBI) pathologies are caused by primary and secondary injuries. Primary injuries result from physical damage to the brain, and secondary injuries arise from cellular responses to primary injuries. A characteristic cellular response is sustained activation of inflammatory pathways commonly mediated by NF-B transcription factors. Using a Drosophila melanogaster TBI model, we previously found that the main proximal transcriptional response to primary injuries is triggered by activation of Toll and Imd innate immune response pathways that engage NF-B factors Dif and Relish (Rel), respectively. Here, we monitor the abundance of Rel protein by mass spectrometry (MS) and observe that Rel increases in fly heads at 4-8 h after TBI. To investigate the necessity of Rel for secondary injuries, we generated a null allele, Reldel, by CRISPR/Cas9 editing. Heterozygous but not homozygous Reldel mutation reduced mortality at 24 h after TBI and increased the lifespan of injured flies. Additionally, the effect of heterozygous Reldel mutation on mortality was modulated by genetic background and diet. To identify genes that facilitate effects of heterozygous Reldel mutation on TBI outcomes, we compared genome-wide mRNA expression profiles of uninjured and injured +/+, +/Reldel, and Reldel/Reldel flies at 4 h following TBI. Only a few genes changed expression more than two-fold in +/Reldel flies relative to +/+ and Reldel/Reldel flies, and they were not canonical innate immune response genes. Therefore, Rel is necessary for TBI-induced secondary injuries but in complex ways involving Rel gene dose, genetic background, diet, and possibly small changes in expression of innate immune response genes.
2020-12-04 | PXD021869 | Pride
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.
2021-05-01 | GSE167942 | GEO