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Cited by 39Traumatic Brain Injury ResearchTraumatic Brain Injury and Neurovascular DisturbancesTelomeres, Telomerase, and Senescence

Early onset senescence and cognitive impairment in a murine model of repeated mTBI

Open access
Schwab, Nicole, Ju, YoungJun, Hazrati, Lili-Naz·2021·Acta Neuropathologica Communications
DOI 10.1186/s40478-021-01190-xPMC PMC8106230
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Abstract

Mild traumatic brain injury (mTBI) results in broad neurological symptoms and an increased risk of being diagnosed with a neurodegenerative disease later in life. While the immediate oxidative stress response and post-mortem pathology of the injured brain has been well studied, it remains unclear how early pathogenic changes may drive persistent symptoms and confer susceptibility to neurodegeneration. In this study we have used a mouse model of repeated mTBI (rmTBI) to identify early gene expression changes at 24 h or 7 days post-injury (7 dpi). At 24 h post-injury, gene expression of rmTBI mice shows activation of the DNA damage response (DDR) towards double strand DNA breaks, altered calcium and cell–cell signalling, and inhibition of cell death pathways. By 7 dpi, rmTBI mice had a gene expression signature consistent with induction of cellular senescence, activation of neurodegenerative processes, and inhibition of the DDR. At both timepoints gliosis, microgliosis, and axonal damage were evident in the absence of any gross lesion, and by 7 dpi rmTBI also mice had elevated levels of IL1β, p21, 53BP1, DNA2, and p53, supportive of DNA damage-induced cellular senescence. These gene expression changes reflect establishment of processes usually linked to brain aging and suggests that cellular senescence occurs early and most likely prior to the accumulation of toxic proteins. These molecular changes were accompanied by spatial learning and memory deficits in the Morris water maze. To conclude, we have identified DNA damage-induced cellular senescence as a repercussion of repeated mild traumatic brain injury which correlates with cognitive impairment. Pathways involved in senescence may represent viable treatment targets of post-concussive syndrome. Senescence has been proposed to promote neurodegeneration and appears as an effective target to prevent long-term complications of mTBI, such as chronic traumatic encephalopathy and other related neurodegenerative pathologies.

AI snapshot

Written from the paper’s full text.

TL;DR

In a mouse model of repeated mild traumatic brain injury, gene expression at 24 h indicated DNA damage response and inhibited cell death, progressing by 7 days to cellular senescence, impaired DNA damage response, and neurodegenerative signatures, with spatial learning and memory deficits. The authors propose early DNA damage-induced senescence as a potential treatment target for post-concussive syndrome and long-term neurodegeneration.

Key findings

  • rmTBI mice had longer righting reflex after each impact: 186.0 s longer after the first impact (p = 0.001), 61.7 s after the second (p = 0.02), and 63.1 s after the third (p = 0.01); all righting reflexes remained under 15 min, supporting a mild injury.
  • At 1 week post-injury, rmTBI mice showed spatial learning and memory impairment in the Morris water maze: longer latency to the hidden platform (main effect of injury p = 0.0001; interaction p = 0.001), less time in the goal zone in the probe test (p = 0.55), and different search strategies on training day 2 (χ2 = 6.2, df = 2, p = 0.05) and day 3 (χ2 = 33.9, df = 2, p < 0.0001), with rmTBI mice increasing allocentric strategies by only 4.2% versus 36.9% in shams.
  • NanoString analysis found 15 significantly changed genes at 24 h post-injury (4 upregulated, 11 downregulated), including DSB repair genes ATG7 (FC = 1.09, p = 0.03), DNA2 (FC = 1.11, p = 0.04), NBN (FC = 1.09, p = 0.02), and CD163 (FC = 1.22, p = 0.04); by 7 days, 32 genes were changed (19 upregulated, 13 downregulated), with senescence and neurodegeneration signatures such as BCL2L2 (FC = 1.11, p = 0.04), BNIP3 (FC = 1.17, p = 0.04), RAD51 (FC = 1.2, p = 0.05), EXO1 (FC = −1.81, p = 0.04), and MPG (FC = −1.34, p = 0.04).
  • Histology showed gliosis and microgliosis at 1 and 7 days, APP-positive axonal damage at 7 days, and no gross lesion; qPCR/Western blot validated elevated IL1β (p = 0.04), IL10 (p = 0.05), p21, 53BP1, DNA2 (p = 0.01), and p53 (p = 0.03), and reduced EXO1.

Methods

  • Adult male C57BL/6 mice (7–9 weeks old) were randomized to rmTBI or sham; the closed-skull controlled impact model delivered three impacts 24 h apart over the right somatosensory cortex. Separate groups were used for behavior (n = 8 per group), NanoString/histology (n = 3 per group), and qPCR/Western blot (n = 3 per group).
  • Neurobehavioral testing included righting reflex after each impact and Morris water maze one week after the final injury over 4 days, analyzed with Ethovision and Rtrack for latency to platform, time in goal zone, and search strategy classification.
  • Molecular and histological analyses used ipsilateral hemisphere tissue: NanoString nCounter 770-gene panel with GO/KEGG/Reactome/WikiPathways enrichment, qPCR and Western blot for DNA damage/senescence markers, and immunohistochemistry for H&E, GFAP, IBA1, APP, and Lamin A/C.

Limitations

  • Stated by the paper: not all individuals with repetitive brain injury develop long-term symptoms or neurodegenerative disease; mTBI presentation is heterogeneous between individuals and between sexes, with women tending to experience more severe symptoms, and more research is needed into inter-individual and sex heterogeneity of the DNA damage response.
  • Evident from the text: the study used only male mice, so sex differences cannot be assessed; molecular and histology groups were small (n = 3); only 24 h and 7 days post-injury were examined, so longer-term progression and causality are not tested; and the findings are largely correlational gene expression and histological changes without direct manipulation of senescence pathways.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/s40478-021-01190-x

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 70 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    rmTBI mice increased their use of allocentric strategies by only 4.2% by the end of training, whereas shams increased by 36.9%.

    “Across the trials from training day one to training day three rmTBI mice only increased the use of allocentric strategies by 4.2% by the end of training, whereas shams had increased the use of allocentric strategies by 36.9%.”
    Quote in the paperSubstantial claim
  • Findingcitation

    The longest righting reflex recorded in rmTBI mice remained under 15 min (900 s).

    “The longest righting reflex recorded remained under 15 min (900 s), which is indicative of a mild injury [106].”
    Quote in the paperSubstantial claim
  • Findingown data

    Evidence of axonal damage after injury by increased APP staining was present at 7 days after injury.

    “evidence of axonal damage after injury by increased APP staining was present at 7 days (Fig. 5b) after injury.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Histology revealed increased expression of GFAP and Iba1 at 1 day and 1 week post-injury on the side receiving the impact compared to shams.

    “Histology revealed increased expression of GFAP and Iba1 at 1 day post-injury (Fig. 4b, e) and 1 week post-injury (Fig. 4c, f) on the side receiving the impact compared to shams”
    Quote in the paperSubstantial claim
  • Findingown data

    H&E staining showed absence of structural damage such as contusion or hemorrhage in ipsilateral cortex and underlying structures.

    “Parasagittal histological section of the brain stained with Hematoxylin and eosin show absence of structural damage such as contusion or hemorrhage in ipsilateral cortex and underlying structures.”
    Quote in the paperSubstantial claim
  • May combine two claims. 53
  • Classified as probably not a substantial claim. 35
  • The quote only partly states this claim. 2

  • May combine two claims.

    Findingown data

    rmTBI brains showed normal gross morphology, with absence of any visible lesion at the region of impact, and did not visibly differ from sham brains.

    “rmTBI brains showed normal gross morphology, with an absence of any visible lesion at the region of impact and did not visibly differ from sham brains”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Lamin A/C immunohistochemistry shows loss of expression on the nuclear membrane of a subset of glial cells in the cortex and decreased expression in the dentate nucleus of the hippocampus.

    “Lamin A/C (Fig. 5) immunohistochemistry shows loss of expression on the nuclear membrane of a subset of glial cells in the cortex and decreased expression in the dentate nucleus of the hippocampus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    rmTBI mice took longer to right than shams after each impact: 186.0 s longer after the first impact, 61.7 s longer after the second, and 63.1 s longer after the third.

    “rmTBI mice took an average of 186.0 s longer to right after the first impact (p = 0.001), 61.7 s longer after the second impact (p = 0.02), and 63.1 s longer after the third impact (p = 0.01).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    rmTBI mice swam an average of 1.8 cm/s faster than sham mice.

    “rmTBI mice and sham mice differed slightly in their average swim speed, with rmTBI mice swimming 1.8 cm/s faster compared to shams on average”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    rmTBI mice used 65.6% non-goal oriented and procedural strategies by training day three, whereas shams used these strategies 26.2% of the time.

    “rmTBI mice remained stagnant using 65.6% non-goal oriented and procedural strategies by training day three, whereas shams only used these strategies 26.2% of the time.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    In the probe test, rmTBI mice spent less time in the goal zone compared to shams, but the difference was not significant (p = 0.55).

    “In the probe test rmTBI mice spent less time in the goal zone compared to shams, which was almost significant (p = 0.55, Mann–Whitney U Test)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Across three training days, rmTBI mice spent significantly longer searching for the hidden platform compared to shams at 1 week post-injury, with shams improving over time while rmTBI mice did not.

    “Across three training days, rmTBI mice spent significantly longer searching for the hidden platform (latency to goal) compared to shams at 1 week post-injury with a main effect of injury (p = 0.0001, repeated measures ANOVA), a main effect of training day (p = 0.047, repeated measures ANOVA) and a significant interaction between injury status and training day (p = 0.001, repeated measures ANOVA)”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    ECM-receptor interaction was enriched from the KEGG database among downregulated genes at 7 days post-injury.

    “Lastly, ECM-receptor interaction was enriched from the KEGG database.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Pathway analysis of downregulated genes at 7 days post-injury revealed enrichment of 12 terms.

    “Pathway analysis at 7d post-injury revealed enrichment of 12 terms (Fig. 15b).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At 1 week post-injury, qPCR revealed elevation of the senescence marker p21, the DNA damage marker 53BP1, and EXO1.

    “At 1 week post-injury qPCR also revealed elevation of the senescence marker p21, the DNA damage marker 53BP1, and EXO1, a DNA repair gene for which expression is reduced in senescent cells [27].”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    By 1 week post-injury, qPCR revealed significant elevation of senescence-associated interleukins IL1β (p = 0.04) and IL10 (p = 0.05).

    “By 1 week post-injury, qPCR revealed significant elevation of senescence-associated interleukins IL1β (p = 0.04) and IL10 (p = 0.05), which promote senescence-mediated inflammation [77] and senescence induction through p53 and p21 [134], respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Western blot analysis showed elevation of the DNA damage-induced cellular senescence markers 53BP1 (p = 0.03), DNA2 (p = 0.01), and p53 (p = 0.03).

    “WB analysis supported these findings (Fig. 16b), showing elevation of the DNA damage-induced cellular senescence markers 53BP1 (p = 0.03), DNA2 (p = 0.01), and p53 (p = 0.03).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 24 hours post-injury, rmTBI mice showed decreased expression of several cell death pathways including the membrane attack complex (C6), TNF-associated cell death (CASP9, TRADD, TRAF3), autophagy-mediated cell death (EPG5, MAPILC3A), and DNA methylation patterns (AGO4).

    “At this timepoint rmTBI mice showed decreased expression of several cell death pathways including the membrane attack complex (C6), TNF-associated cell death (CASP9, TRADD, TRAF3), autophagy-mediated cell death (EPG5, MAPILC3A), and DNA methylation patterns (AGO4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    By 7 days post-injury, many components of the DDR were significantly reduced (EXO1, MPG) with additional downregulation of cholesterol metabolizing enzymes (CYP27A1, CYP7B1), loss of toxic protein clearance and other protective mechanisms (MERTK, RELN, TTR, CD44, DAB2) and reduction of apoptosis (BAX, CIDEA).

    “By 7d post-injury, many components of the DDR were significantly reduced (EXO1, MPG) with additional downregulation of cholesterol metabolizing enzymes (CUP27A, CYP7B1), loss of toxic protein clearance and other protective mechanisms against neurodegenerative mechanisms (MERTK, RELN, TTR, CD44, DAB2) and reduction of apoptosis (BAX, CIDEA).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisereasoning

    If the DNA damage response becomes persistently activated in the face of persistent DNA damage, cellular senescence pathways may be activated.

    “If the DDR becomes persistently activated in the face of persistent DNA damage, cellular senescence pathways may be activated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    rmTBI mice have significant deficits in spatial learning and memory retention, specifically in the ability to learn and use spatial cues, and rely instead on mostly egocentric measures to complete the task.

    “These results suggest that rmTBI mice have significant deficits in their spatial learning and memory retention, specifically for the ability to learn and use spatial cues and rely instead on mostly egocentric measures to complete the task.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Accumulation of DNA damage has been reported in various models of mTBI.

    “accumulation of DNA damage has been reported in various models of mTBI [3, 123, 151]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Arun P, Rossetti F, Wilder DM, Sajja S, Van Albert SA, Wang Y et al (2020) Blast exposure leads to accelerated cellular senescence in the rat brain. Front Neurol 11:438 source

      Not checked in the free run.

    • cites [123] Ritzel RM, Doran SJ, Glaser EP, Meadows VE, Faden AI, Stoica BA et al (2019) Old age increases microglial senescence, exacerbates secondary neuroinflammation, and worsens neurological outcomes after acute traumatic brain injury in mice. Neurobiol Aging 77:194–206 source

      Not checked in the free run.

    • cites [151] Tominaga T, Shimada R, Okada Y, Kawamata T, Kibayashi K (2019) Senescence-associated-β-galactosidase staining following traumatic brain injury in the mouse cerebrum. PLoS ONE 14(3):e0213673 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The findings of lack of gross morphology, loss of righting reflex, gliosis, microgliosis, and axonal damage are supportive of eliciting a mild injury.

    “These findings, along with a lack of gross morphology and the loss of righting reflex in injured animals, are supportive of eliciting a mild injury.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Senescent cells accumulate with age, neurodegenerative disease and cognitive decline, neuropsychiatric disorders, and after TBI.

    “Senescent cells accumulate with age [23, 157, 175], neurodegenerative disease and cognitive decline [15], neuropsychiatric disorders [33], and have recently been discovered to accumulate after TBI [3, 123, 131, 132, 151].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [23] Chinta SJ, Woods G, Rane A, Demaria M, Campisi J, Andersen JK (2015) Cellular senescence and the ageing brain. Exp Gerontol 68:3–7 source

      Not checked in the free run.

    • cites [157] van Deursen JM (2014) The role of senescent cells in ageing. Nature 509(7501):439–446 source

      Not checked in the free run.

    • cites [175] Yousefzadeh MJ, Zhao J, Bukata C, Wade EA, McGowan SJ, Angelini LA, Bank MP et al (2020) Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice. Aging Cell 19(3):e13094 source

      Not checked in the free run.

    • cites [15] Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ (2018) Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562(7728):578 source

      Not checked in the free run.

    • cites [33] Diniz BS, Reynolds CF, Sibille E, Lin CW, Tseng G, Lotrich F et al (2017) Enhanced molecular aging in late-life depression: the senescent associated secretory phenotype. Am J Geriatr Psychiatry 25(1):64–72 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Some individuals recover within days to weeks after mTBI, while others have persistent long-term effects.

    “While some individuals recover within days to weeks after injury, others go on to have persistent long-term effects [147].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Tator CH, Davis HS, Duford PA, Tartaglia MC, Davis KD, Ebraheem A et al (2016) Postconcussion syndrome: demographics and predictors in 221 patients. J Neurosurg 125(5):1206 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mild traumatic brain injury (mTBI) is common and can cause a broad range of debilitating symptoms, including headaches, fatigue, irritability, sleep disturbances, depression and anxiety, and attention deficits.

    “Mild traumatic brain injury (mTBI) is common and can cause a broad range of debilitating symptoms, including headaches, fatigue, irritability, sleep disturbances, depression and anxiety, and attention deficits [61, 94, 101].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [61] Hiploylee C, Dufort PA, Davis HS, Wennberg RA, Tartaglia MC, Mikulis D, Hazrati LN, Tator CH (2017) Longitudinal study of postconcussion syndrome: Not everyone recovers. J Neurotrauma 34(8):1511–1523 source

      Not checked in the free run.

    • cites [94] McInnes K, Friesen CL, MacKenzie DE, Westwood DA, Boe SG (2017) Mild traumatic brain injury and chronic cognitive impairment: a scoping review. PLoS ONE 12(4):e0174847 source

      Not checked in the free run.

    • cites [101] Mounce LT, Williams WH, Jones JM, Harris A, Haslam SA, Jetten J (2013) Neurogenic and psychogenic acute postconcussion symptoms can be identified after mild traumatic brain injury. J Head Trauma Rehabil 28(5):397–405 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The authors' lab has previously shown evidence of double-strand breaks in human brains with mTBI history.

    “our lab has previously shown evidence of double-strand breaks (DSBs) in human brains with mTBI history [131, 132].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [131] Schwab N, Grenier K, Hazrati LN (2019) DNA repair deficiency and senescence in concussed professional athletes involved in contact sports. Acta Neuropathol Commun 7(1):182 source

      Not checked in the free run.

    • cites [132] Schwab N, Tator C, Hazrati LN (2019) DNA damage as a marker of brain damage in individuals with history of concussions. Lab Invest 99(7):1008 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    HAT1 is a cytoplasmic histone deacetylase whose loss is associated with early onset ageing and mitochondrial defects, and whose expression is reduced under treatment with hypoxic agents.

    “HAT1 (FC = −1.12, p = 0.05) is a cytoplasmic histone deacetylase, for which loss is associated with early onset ageing and mitochondrial defects [105], and for which expression is reduced under treatment with hypoxic agents [159].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [105] Nagarajan P, Agudelo Garcia PA, Iyer CC, Popova LV, Arnold WD, Parthun MR (2019) Early-onset aging and mitochondrial defects associated with loss of histone acetyltransferase 1 (Hat1). Aging Cell 18(5):e12992 source

      Not checked in the free run.

    • cites [159] Vrtacnik P, Zupan J, Mlakar V, Kranjc T, Marc J, Kerm B et al (2018) Epigenetic enzymes influenced by oxidative stress and hypoxia mimetic in osteoblasts are differentially expressed in patients with osteoporosis and osteoarthritis. Sci Rep 8:16215 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    CASP3 encodes caspase 3, an executioner in the apoptosis pathway when it is proteolytically cleaved from its pro-form.

    “CASP3 (FC = 1.11, p = 0.04) encodes caspase 3, an executioner in the apoptosis pathway when it is proteolytically cleaved from its pro- form.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The significant upregulation of ATG7, DNA2, and NBN in rmTBI mice compared to shams indicates the presence of double-strand breaks and activation of the DNA damage response at 24 h post-injury.

    “Together, the significant upregulation of these three genes in rmTBI mice compared to shams indicates the presence of DSBs at this timepoint and the activation of the DDR.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    CASP9 downregulation is anti-apoptotic and protective against TNF-receptor-activated apoptosis.

    “CASP9 (FC = −1.28, p = 0.026) is an initiator in the apoptotic pathway, and so its downregulation is both anti-apoptotic and protective against TNF-receptor-activated apoptosis [93].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] McDonnell MA, Wang D, Khan SM, Vander Heiden MG, Kelekar A (2003) Caspase-9 is activated in a cytochrome c-independent manner early during TNFalpha-induced apoptosis in murine cells. Cell Death Differ 10(9):1005 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TRADD encodes TNFRSF1A-associated death domain and mediates TNF-receptor-activated apoptosis.

    “TRADD (FC = −1.26, p = 0.02) encodes TNFRSF1A-associated death domain and is a mediator of the TNF-receptor-activated apoptosis [20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Chang X, Wang L, Wang Z, Wu S, Zhu X, Hu S et al (2017) TRADD mediates the tumor necrosis factor-induced apoptosis of L929 cells in the absence of RIP3. Sci Rep 7:16111 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    EPG5 is an autophagy-related gene essential for the formation of degradative autolysosomes.

    “EPG5 (FC = −1.12, p = 0.05) is an autophagy-related gene which is essential for the formation of degradative autolysosomes [162].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Wang Z, Miao G, Xue X, Guo X, Yuan C, Wang Z et al (2016) The Vici syndrome protein EPG5 is a Rab7 effector that determines the fusion specificity of autophagosomes with late endosomes/lysosomes. Mol Cell 63(5):781 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    AGO4 is a member of the Argonaute family that plays a role in DNA methylation and miRNA maintenance.

    “AGO4 (FC = 1.33, p = 0.04) is a member of the Argonaute family which plays a role in DNA methylation and miRNA maintenance [19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Chalertpet K, Pin-on P, Aporntewan C, Patchsung M, Ingrungruanglert P, Israsena N et al (2019) Argonaute 4 as an effector protein in RNA-directed DNA methylation in human cells. Front Genet 10:645 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Deficiency in complement factor 6 in small mammals causes a progressive neurological syndrome characterized by multifocal motor neuropathy and severe axonal degeneration.

    “Deficiency in this component in small mammals has been shown to cause a progressive neurological syndrome characterized by multifocal motor neuropathy and severe axonal degeneration [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Giannini C, Monaco S, Kirschfink M, Rother KO, Lorbacher de Ruiz H, Nardelli E et al (1992) Inherited neuroaxonal dystrophy in C6 deficient rabbits. J Neuropathol Exp Neruol 51(5):514 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TRAF3 expression reduces with age.

    “TRAF3 has been shown to reduce expression with age [82].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Li J, Ayoub A, Xiu Y, Yin X, Sanders JO, Mesfin A et al (2019) (2019) TGFβ-induced degradation of TRAF3 in mesenchymal progenitor cells causes age-related osteoporosis. Nat Commun 10(1):2795 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The 24 h post-injury expression profile suggests a significant reduction in expression of major cell death signalling pathways, possibly conferring vulnerability to subsequent brain damage and future neurodegenerative pathologies.

    “Taken together, this expression profile suggests that 24 h post-injury there is significant reduction in expression of major cell death signalling pathways, possibly conferring vulnerability to subsequent brain damage and future neurodegenerative pathologies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Seven SNPs in EPG5 have been associated with Alzheimer's disease, and eight SNPs have been associated with an earlier age of onset of Alzheimer's disease.

    “7 single-nucleotide polymorphisms (SNPs) in EPG5 have been associated with AD, and 8 SNPs have been associated with an earlier age of onset of AD [161]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [161] Wang KS, Liu X, Xie C, Liu Y, Xu C (2016) Non-parametric survival analysis of EPG5 gene with age at onset of Alzheimer’s disease. J Mol Neurosci 60(4):436 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    CD163 encodes a cell surface marker of activated M2 phenotype macrophages.

    “The fourth gene found to be upregulated 24 h post-injury was CD163 (FC = 1.22, p = 0.04), which encodes a cell surface marker of activated M2 phenotype macrophages [71], suggesting an increase in the presence and activation of macrophages 24 h post-injury.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Kim WK, Alvarez X, Fisher J, Bronfin B, Westmoreland S, McLaurin J et al (2006) CD163 identifies perivascular macrophages in normal and viral encephalitic brains and potential precursors to perivascular macrophages in blood. Am J Pathol 168(3):822 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Calcineurin subunit 2 expression decreases following TBI, and its decrease may confer susceptibility to Alzheimer's disease.

    “It has been previously reported that calcineurin subunit 2 expression decreases following TBI [165, 166] and its decrease may confer susceptibility to AD [120, 156].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [165] Wu P, Zhao Y, Haidacher SJ, Wang E, Parsley MO, Gao J et al (2013) Detection of structural and metabolic changes in traumatically injured hippocampus by quantitative differential proteomics. J Neurotrauma 30(9):775 source

      Not checked in the free run.

    • cites [166] Xiong G, Elkind JA, Kundu S, Smith CJ, Antunes MC, Tamashiro E et al (2014) Traumatic brain injury-induced ependymal ciliary loss decreases cerebral spinal fluid flow. J Neurotrauma 31(16):1396 source

      Not checked in the free run.

    • cites [120] Peterson D, Munger C, Crowley J, Corcoran C, Cruchaga C, Goate AM et al (2014) Variants in PPP3R1 and MAPT are associated with more rapid functional decline in Alzheimer’s disease: the Cache County Dementia Progression Study. Alzheimers Dement 10(3):366 source

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    • cites [156] Vacher M, Porter T, Villemagne VL, Milicic L, Peretti M, Fowler C et al (2019) Validation of a priori candidate Alzheimer’s disease SNPs with brain amyloid-beta deposition. Sci Rep 9(1):17069 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    AGO4 plays a critical role in the RNA-directed DNA methylation complex.

    “AGO4 (FC = −1.63, p = 0.04) plays a critical role in the RNA-directed DNA methylation complex [19], supporting altered DNA methylation patterns 24 h post-injury.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Chalertpet K, Pin-on P, Aporntewan C, Patchsung M, Ingrungruanglert P, Israsena N et al (2019) Argonaute 4 as an effector protein in RNA-directed DNA methylation in human cells. Front Genet 10:645 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Deficiency of TRADD results in the accumulation of double-strand break foci.

    “deficiency of TRADD has been shown to result in the accumulation of DSB foci [75].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Koo GB, Ji JH, Cho H, Morgan MJ, Kim YS (2017) Nuclear TRADD prevents DNA damage-mediated death by facilitating non-homologous end-joining repair. Sci Rep 7(1):3332 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The 7-day upregulated gene expression suggests induction of cellular senescence, activation of neurodegenerative pathways, and changes in large signalling pathways, particularly cell death, mitophagy, autophagy, metabolism, and oxidation-reduction reactions.

    “19 genes had significantly increased expression levels (Fig. 12), suggesting the induction of cellular senescence, activation of neurodegenerative pathways, and changes in large signalling pathways, particularly to cell death pathways, mitophagy, autophagy, metabolism, and oxidation and reduction reactions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    MAP1LC3A is a microtubule associated protein that mediates the interaction between microtubules and the cytoskeleton and is a key protein in the autophagy pathway.

    “MAP1LC3A (FC = −1.34, p = 0.04) is a microtubule associated protein which mediates the interaction between microtubules and the cytoskeleton [22] and is a key protein in the autophagy pathway.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Cheng X, Wang Y, Gong Y, Li F, Guo Y, Hu S et al (2016) Structural basis of FYCO1 and MAP1LC3A interaction reveals a novel binding mode for Atg8-family proteins. Autophagy 12(8):1330 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    This analysis suggests inhibition of cell death and major energy-dependent signalling pathways 24 h post-injury, consistent with activation of the DNA damage response.

    “This analysis suggests inhibition of cell death and major energy-dependent signalling pathways 24 h post-injury, consistent with analyses of up-regulated genes at this timepoint showing activation of the DNA damage response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ATG7, DNA2, and NBN encode DNA damage repair proteins in the DNA damage response, including homology-directed repair and non-homologous end joining for double-strand breaks.

    “ATG7 is an autophagy-related protein [136] which can modulate p53-dependent cell cycle pathways during prolonged stress [78] and plays a critical role in homology-directed repair (HDR) of DSBs [46]. Similarly, DNA2 encodes a HDR DNA repair protein for repair of DSBs [62] and NBN encodes a non-homologous end joining (NHEJ) DNA repair protein for repair of DSBs [158].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [136] Shi W, Liu W, Ma J, Lu J, Yang X, Wang J et al (2020) The role of Atg7-mediated autophagy in ionizing radiation-induced neural stem cell damage. Gene 738:144485 source

      Not checked in the free run.

    • cites [62] Hoa NN, Kobayashi J, Omura M, Hirakawa M, Yang SH, Komatsu K et al (2015) BRCA1 and CtIP are both required to recruit DNA2 at double-strand breaks in homologous recombination. PLoS ONE 10(4):e0124495 source

      Not checked in the free run.

    • cites [158] Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K et al (1998) Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93(3):467 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    C6 encodes complement factor 6, a late complement component that forms the membrane attack complex.

    “C6 (FC = −1.84, p = 0.04) encodes complement factor 6, a late complement component which forms the membrane attack complex.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TRAF3 is a TNF-receptor-associated factor critical for NF-kappaB activation and cell death pathways.

    “TRAF3 (FC = −1.12, p = 0.03) is a TNF-receptor-associated factor which is critical for NF-kappaB activation and cell death pathways [60].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Hildebrand JM, Yi Z, Buchta CM, Poovassery J, Stunz LL, Bishop GA (2011) Roles of tumor necrosis factor receptor associated factor 3 (TRAF3) and TRAF5 in immune cell functions. Immunol Rev 244(1):55 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Loss of lamin A/C is associated with the induction of cellular senescence through DNA-damage sensing pathways.

    “Loss of lamin A/C is associated with the induction of cellular senescence through DNA-damage sensing pathways [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Gibbs-Seymour I, Markiewicz E, Bekker-Jensen S, Mailand N, Hutchison CJ (2015) Lamin A/C-dependent interaction with 53BP1 promotes cellular responses to DNA damage. Aging Cell 14:162–169 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    This analysis indicates a significant impairment of the DNA damage response, particularly the reduction of DNA damage repair enzymes, and impaired hypoxia response at 7 days post-injury, which are consistent with the induction of cellular senescence.

    “This analysis indicates a significant impairment of the DNA damage response, particularly the reduction of DNA damage repair enzymes, and impaired hypoxia response at 7d post-injury, which are consistent with the induction of cellular senescence.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    BNIP3L encodes BCL2 interacting protein 3 like, is typically thought pro-apoptotic, but anti-apoptotic roles have been discovered in reactive astrocytes during ALS, and it increases in senescent cells to direct mitochondria to autophagosomes for degradation.

    “Although BNIP3L is typically thought of as pro-apoptotic [181], anti-apoptotic roles have been recently discovered, particularly in reactive astrocytes during ALS disease progression [35]. Similarly, BNIP3L has been shown to increase in senescent cells to direct mitochondria to autophagosomes for degradation [174].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [181] Zhu L, Qi B, Hou D (2019) Roles of HIF1α- and HIF2 α-regulated BNIP3 in hypoxia-induced injury of neurons. Pathol Res Pract 215(4):822 source

      Not checked in the free run.

    • cites [35] Duval N, Sumner WA, Andrianakos AG, Gray JJ, Bouchard RJ, Wilkins HM et al (2018) The bcl-2 homology-3 domain (bh3)-only proteins, bid, dp5/hrk, and bnip3l, are upregulated in reactive astrocytes of end-stage mutant sod1 mouse spinal cord. Front Cell Neurosci 12:15 source

      Not checked in the free run.

    • cites [174] Young ARJ, Narita M, Ferreira M, Kirschner K, Sadaie M, Darot JFJ et al (2009) Autophagy mediates the mitotic senescence transition. Genes Dev 23(7):798 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    GO enrichment analysis indicates that at 7 days post-injury the stress-response remains activated and significant regulation (both positive and negative) of cell death pathways is occurring.

    “This GO enrichment analysis indicates that 7d post-injury the stress-response remains activated, and that significant regulation (both positive and negative) of cell death pathways is occurring.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    BNIP3 encodes BCL2 interacting protein 3, which is increased in hypoxic-ischemic-encephalopathy and physiological ageing, and increases in association with cellular senescence especially in cells over-expressing p21 and p16.

    “BNIP3 (FC = 1.17, p = 0.04) encodes BCL2 interacting protein 3, which is increased in hypoxic-ischemic-encephalopathy [18] and physiological ageing [31], and has been shown to increase in association with cellular senescence especially in cells over-expressing p21 and p16 [16].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Castranio EL, Wolfe CM, Nam KN, Letronne F, Fitz NF, Lefterov I et al (2018) ABCA1 haplodeficiency affects the brain transcriptome following traumatic brain injury in mice expressing human APOE isoforms. Acta Neuropathol Commun 6(1):69 source

      Not checked in the free run.

    • cites [31] Dethlefsen MM, Halling JF, Moller HD, Plomgaard P, Regenberg B, Ringhold S et al (2018) Regulation of apoptosis and autophagy in mouse and human skeletal muscle with aging and lifelong exercise training. Exp Gerontol 111:141 source

      Not checked in the free run.

    • cites [16] Capparelli C, Chiavarina B, Whitaker-Menezes D, Pestell TG, Pestell RG, Hulit J et al (2012) CDK inhibitors (p16/p19/p21) induce senescence and autophagy in cancer-associated fibroblasts, “fueling” tumolir growth via paracrine interactions, without an increase in neo-angiogenesis. Cell Cycle 11(19):3599 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CLEC7A is a disease-associated microglia gene that increases after TBI in mice, in a mouse model of Alzheimer's disease, and in aged microglia associated with neurodegenerative disease.

    “CLEC7A (FC = 2.02, p = 0.02) is a disease-associated microglia gene which has been shown to increase after TBI in mice [19], in a mouse model of AD [38, 56], and in aged microglia associated with neurodegenerative disease [135].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [19] Chalertpet K, Pin-on P, Aporntewan C, Patchsung M, Ingrungruanglert P, Israsena N et al (2019) Argonaute 4 as an effector protein in RNA-directed DNA methylation in human cells. Front Genet 10:645 source

      Not checked in the free run.

    • cites [38] Fitz NF, Wolfe CM, Playso BE, Biedrzycki RJ, Lu Y, Nam KN et al (2020) Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice. Mol Neurodegen 15(1):41 source

      Not checked in the free run.

    • cites [56] Haure-Mirande JV, Wang M, Audrain M, Fanutza T, Kim SH, Heja S et al (2018) Integrative approach to sporadic Alzheimer’s disease: deficiency of TYROBP in cerebral Aβ amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Aβ burden. Mol Psychiatry 24(3):431 source

      Not checked in the free run.

    • cites [135] Shi L, Rocha M, Zhang W, Jian M, Li S, Ye Q et al (2020) Genome-wide transcriptomic analysis of microglia reveals impaired responses in aged mice after cerebral ischemia. J Cereb Blood Flor Metab 40(1_suppl):S49 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These pathway changes support the roles of individual genes detailed above and suggest the induction of cellular senescence and neurodegenerative changes at 7 days post-injury.

    “These pathway changes support the roles of individual genes detailed above and suggests the induction of cellular senescence and neurodegenerative changes 7d post-injury.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    BCL2L2 encodes the anti-apoptotic and pro-senescence BCL-W protein.

    “BCL2L2 (FC = 1.11, p = 0.04) encodes the anti-apoptotic and pro-senescence BCL-W protein [173].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] Yosef R, Pilpel N, Tokarsky-Amiel R, Biran A, Ovadya Y, Cohen S et al (2016) Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun 7:11190 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CHST8 encodes carbohydrate sulfotransferase 8, which has been suggested to be enriched in Alzheimer's disease pathology progression and increased in the hippocampus of Alzheimer's disease brains.

    “This enzyme has been suggested to be enriched in AD pathology progression [144] and increased in the hippocampus of AD brains [64].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [144] Stefanova NA, Ershov NI, Kolosova NG (2019) Suppression of Alzheimer’s disease-like pathology progression by mitochondria-targeted antioxidant SkQ1: a transcriptome profiling study. Oxid Med Cell Longev 2019:3984906 source

      Not checked in the free run.

    • cites [64] Huynh MB, Ouidja MO, Chantepie S, Carpentier G, Maiza A, Zhang G et al (2019) Glycosaminoglycans from Alzheimer’s disease hippocampus have altered capacities to bind and regulate growth factors activities and to bind tau. PLoS ONE 14(1):e0209573 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Pathway analysis suggests activation of the hypoxia-induced AGE-RAGE pathway, and increased TNF, mitophagy, and autophagy signalling at 7 days post-injury.

    “Furthermore, this analysis suggests activation of the hypoxia-induced AGE-RAGE pathway (related to multiple age-related pathologies), and increased TNF, mitophagy, and autophagy signalling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Pathway analysis at 7 days post-injury supports reduction of the DNA damage response, impaired oxidation reduction reactions, and impeded metabolism.

    “Together, the pathway analysis at this timepoint supports reduction of the DDR, impaired oxidation reduction reactions, and impeded metabolism at this timepoint.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    GPR34 encodes an inhibitory G-protein coupled receptor found on microglia that is overexpressed in regions of the brain affected by neurodegeneration in both humans and mice.

    “GPR34 (FC = 1.36, p = 0.002) encodes an inhibitory G-protein coupled receptor found on microglia which is overexpressed in regions of the brain affected by neurodegeneration in both humans and mice [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Bonham LW, Sirkis DW, Yokoyama JS (2019) The transcriptional landscape of microglial genes in aging and neurodegenerative disease. Front Immunol 10:1170 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Two downregulated genes suggest the presence of astrogliosis and possible dysfunction of critical brain barriers including the blood-brain barrier and the ependymal epithelial lining of the ventricles.

    “Consistent with some of the above changes, two downregulated genes suggest the presence of astrogliosis and possible dysfunction of critical brain barriers including the blood–brain barrier and the ependymal epithelial lining of the ventricles.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    RAD51 encodes a DNA repair enzyme that associates with gH2AX foci.

    “RAD51 (FC = 1.2, p = 0.05) encodes a DNA repair enzyme which associate with gH2AX foci [103].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Munch S, Weidtkamp-Peters S, Klement K, Grigaravicius P, Monajembashi S, Salomoni P et al (2014) The tumor suppressor PML specifically accumulates at RPA/RAD51-containing DNA damage repair foci but is nonessential for DNA damage-induced fibroblast senescence. Mol Cell Biol 34(10):1733 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DAPK1 is a calcium-dependent serine/threonine kinase highly expressed in the cortex in Alzheimer's disease, after ischemic damage, and in physiological ageing where it may play a role in the decay of learning and memory.

    “DAPK1 (FC = 1.08, p = 0.05) is a calcium-dependent serine/threonine kinase that is highly expressed in the cortex in AD [167], after ischemic damage [154], and in physiological ageing where it has been suggested to play a role in the decay of learning and memory with age [51].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [167] Xu LZ, Li BQ, Jia JP (2019) DAPK1: A novel pathology and treatment target for Alzheimer’s disease. Mol Neurobiol 56(4):2838 source

      Not checked in the free run.

    • cites [154] Tu W, Xu X, Peng L, Zhong X, Zhang W, Soundarapandian MM et al (2010) DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell 140(2):222 source

      Not checked in the free run.

    • cites [51] Guo Y, Li H, Ke X, Deng M, Qu Z, Cai Y et al (2019) Degradation of caytaxin causes learning and memory deficits via activation of DAPK1 in aging. Mol Neurobiol 56(5):3368 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Pathway analysis supports dysregulation of cell death at 7 days post-injury, with negative regulation suggested by apoptosis modulation by HSP70 and positive regulation suggested by apoptosis.

    “This pathway analysis supports the dysregulation of cell death at this timepoint, with negative regulation suggested by apoptosis modulation by HSP70 and positive regulation suggested by apoptosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Enriched biological process terms for downregulated genes at 7 days post-injury encompassed regulation of cell death pathways, locomotion and metabolism, cell motility and migration, and the response to stress, suggesting significant changes in basic biological processes of the cell.

    “The enriched biological process terms encompassed regulation of cell death pathways, locomotion and metabolism, cell motility and migration, and the response to stress, suggesting significant changes in basic biological processes of the cell, perhaps due to the morphological changes associated with cellular senescence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These findings were supported with qPCR and Western blots, directly showing elevation of IL1β, IL10, p21, 53BP1, DNA2, and reduction in EXO1-all molecular signatures of cellular senescence induced by genotoxic stress.

    “These findings were supported with qPCR and WBs, directly showing elevation of IL1β, IL10, p21, 53BP1, DNA2, and reduction in EXO1—all of which are molecular signatures of cellular senescence induced by genotoxic stress.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The DDR is lost in ageing in association with the accumulation of senescent cells and 'inflammaging'.

    “Concomitantly, the DDR is lost in ageing in association with the accumulation of senescent cells and “inflammaging” [111, 150].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [111] Olivieri F, Albertini MC, Orciani M, Ceka A, Cricca M, Procopio AD et al (2015) DNA damage response (DDR) and senescence: shuttled inflamma-miRNAs on the stage of inflamm-aging. Oncotarget 6(34):35509 source

      Not checked in the free run.

    • cites [150] Tiwari V, Wilson DM (2019) DNA damage and associated DNA repair defects in disease and premature aging. Am J Hum Genet 105(2):237 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    In this study, using a murine model of rmTBI, the authors have shown evidence of a response to DNA damage in the brain 24 hours following repeated brain injury, and progression to cellular senescence, impaired DNA damage responses, and brain ageing by 7 days.

    “In this study, using a murine model of rmTBI we have shown evidence of a response to DNA damage in the brain 24 h following repeated brain injury, and progression to cellular senescence, impaired DNA damage responses, and brain ageing by 7 days.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Several significantly changed genes at 7 days post-injury play roles in the maintenance of critical brain barriers including the blood-brain barrier and synapse maintenance in neuronal networks, and associate with neurodegenerative disease pathogenesis in early stages prior to protein accumulation.

    “In addition, several significantly changed genes at this timepoint play roles in the maintenance of critical brain barriers including the blood–brain barrier (CYP7B1, MERTK, CD44) and synapse maintenance in neuronal networks (MERTK, RELN), and associate with neurodegenerative disease pathogenesis in early stages prior to protein accumulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    At 24 hours post-injury, the DDR and inhibition of cell death are evident, suggesting that cells are attempting to repair damage inflicted by the mTBI.

    “At 24 h post-injury, therefore, the DDR and inhibition of cell death are evident, suggesting that cells are attempting to repair damage inflicted by the mTBI.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Up-regulated pathways at 7 days post-injury include cellular senescence (AGO4, BCL2L2, BNIP3, BNIP3L, RAD51, RB1CC1), PKA and JNK signalling pathways (MAPK10, RAB6B, PIK3CD), and early neurodegenerative processes (CHST8, CLEC7A, DAPK1, GPR34, MAFB, MSR1, OLFML3, SUMO1, TYROBP).

    “Up-regulated pathways at this timepoint include cellular senescence (AGO4, BCL2L2, BNIP3, BNIP3L, RAD51, RB1CC1), PKA and JNK signalling pathways (MAPK10, RAB6B, PIK3CD), and early neurodegenerative processes (CHST8, CLEC7A, DAPK1, GPR34, MAFB, MSR1, OLFML3, SUMO1, TYROBP).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Activation of the DDR in response to DNA damage is essential for the maintenance of genome integrity.

    “Activation of the DDR in response to DNA damage is essential for the maintenance of genome integrity [67].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Jackson SP, Bartek J (2009) The DNA-damage response in human biology and disease. Nature 461(7267):1071 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    IL1α was elevated 1 day post-injury, returned to baseline by 1 week post-injury, and signatures of senescence (elevated p21, p53, and reduced EXO1) were evident.

    “IL1α was found to be elevated 1 day post-injury, an interleukin which senses DNA damage and is a regulator of the cellular senescence response to such genotoxic stress—yet by 1 week post-injury IL1α returns to baseline and signatures of senescence (namely elevated p21, p53, and reduced EXO1) are evident.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Personalized medicine approaches may be foreseeable due to naturally occurring polymorphisms and alterations in the DDR or hypoxia response which may underlie individual and sex differences.

    “Within this strategy, personalized medicine approaches may be foreseeable due to naturally occurring polymorphisms and alterations in the DDR or hypoxia response which may underlie individual and sex differences.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Reduced expression of Lamin A/C in glial cells following rmTBI is suggestive of DNA damage-associated cellular senescence, perhaps contributing to neurological dysfunction.

    “Reduced expression of Lamin A/C in glial cells following rmTBI is therefore concerning, and suggestive of DNA damage-associated cellular senescence, perhaps contributing to neurological dysfunction.”
    Quote in the paperSubstantial claim
70 of 70

  • The paper relies on this without support.

    The murine rmTBI model recapitulates key features of human repeated mTBI and can be used to infer human pathophysiological mechanisms.

    “Here we have presented a murine model of repeated mTBI.”
    “In this study, using a murine model of rmTBI we have shown evidence of a response to DNA damage in the brain 24 h following repeated brain injury, and progression to cellular senescence, impaired DNA damage responses, and brain ageing by 7 days.”

  • The paper relies on this without support.

    The 7-day post-injury timepoint in mice corresponds to the acute period in humans and is relevant to early human mTBI.

    “These results suggest that by 7d post-injury signs of brain senescence and neurodegeneration are detectable.”
    “We suggest that these pathogenic processes are critical early events which may drive early symptoms as well as late onset neurodegenerative processes after mTBI they represent viable treatment targets for early intervention strategies.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Putative senescent states have been suggested in microglia, neurons, astrocytes, and oligodendrocyte progenitor cells with aging and in various disease contexts.

    “Putative senescent states have been suggested in a variety of neural subpopulations with aging and in various disease contexts, including microglia [26–30], neurons [31–33], astrocytes [26,34,35], and oligodendrocyte progenitor cells [36].”

    From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [28]

  • Two recent publications identified a possible senescence signature following TBI in adult mice.

    “Two recent publications identified a possible senescence signature following TBI in adult mice [28,29].”

    From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [28]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • qPCR EXO1 result reverses in the discussion

    Major

    The results report elevated EXO1 by qPCR at one week, while the discussion says the qPCR and Western blot findings directly showed reduced EXO1. This reverses the direction of a result used to support the senescence conclusion.

  • Upregulated 24-hour pathway categories total 19, not 20

    Minor

    The reported categories contain two WikiPathways terms, sixteen Reactome terms, and one KEGG term. These sum to 19, not the stated 20.

    Reported 20 · recomputed 19

  • Downregulated 24-hour pathway categories total 20, not 19

    Minor

    The reported seven WikiPathways, three Reactome, and ten KEGG terms sum to 20, rather than the stated 19.

    Reported 19 · recomputed 20

  • Figure 10 caption gives the wrong expression direction

    Minor

    The caption calls Figure 10 an analysis of upregulated genes, but the results identify Figure 10 as the analysis of downregulated genes.

  • Upregulated pathway analysis points to a downregulated-gene figure

    Minor

    The text cites Figure 15b for pathways enriched among upregulated genes, whereas the Figure 15 caption identifies panel b as an analysis of downregulated genes.

  • The 24-hour pathway analysis cites the gene-expression figure

    Minor

    The text cites Figure 7b for pathway enrichment, while the Figure 8 caption identifies its panel b as the upregulated-gene pathway analysis.

  • APP staining is assigned to a Lamin A/C panel

    Minor

    The results cite Figure 5b for increased APP staining at seven days, but the Figure 5 caption identifies panel b as Lamin A/C staining at one day.

7 of 7

The citation lists haven’t been fetched yet

References 187 · Cited by 39

Research works printed but not linked: 1

  1. Matsuzaki S, Lee L, Knock E, Srikumar T, Sakurai M, Hazrati LN et al (2015) SUMO1 affects synaptic function. Spine Density Mem Sci Rep 5:10730

Authors
Schwab, N., Ju, Y., & Hazrati, L.-N.
Affiliations
  • University of Toronto (CA)
  • Hospital for Sick Children (CA)
Corresponding author
Hazrati, Lili-Naz
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2021-05-08
Volume
9
Issue
1
Pages
82-82
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-021-01190-x
PMC
PMC8106230
OpenAlex
W3160781037
Semantic Scholar
47c48f07e0be809e82ea1aa84c2556642d610c4d
Cited by
39
References
187
Citations by year
2026: 3 · 2025: 11 · 2024: 8 · 2023: 6 · 2022: 7 · 2021: 4
FWCI
4.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • TSpace (University of Toronto) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship@McGill (McGill) (submittedVersion, cc-by)
Funders
Canadian Institutes of Health Research
Topics
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
repetitive mild traumatic brain injury, cellular senescence, DNA damage response, cognitive impairment, post-concussion syndrome, neurodegeneration, gene expression changes, DNA double-strand breaks, microglial activation, gliosis, axonal injury, spatial learning and memory deficits, chronic traumatic encephalopathy, p53, 53BP1, p21, IL-1β, brain aging
MeSH terms
Aging, Animals, Brain Concussion, Disease Models, Animal, DNA Damage, Male, Mice, Inbred C57BL, Age of Onset, Maze Learning, Mice, Cognitive Dysfunction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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