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

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.

SUBMITTER: Schwab N

PROVIDER: S-EPMC8106230 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesTo examine whether physical frailty onset before, after, or in concert with cognitive impairment is differentially associated with fall incidence in community-dwelling older adults.DesignA longitudinal observational study.Setting and participantsData from 1337 older adults age ≥65 years and free of physical frailty or cognitive impairment at baseline were obtained from the National Health Aging Trends Study (2011‒2017), a nationally representative cohort study of US older adult Medicare beneficiaries.MethodsParticipants were assessed annually for frailty (physical frailty phenotype) and cognitive impairment (bottom quintile of clock drawing test or immediate and delayed recall; or proxy-report of diagnosis of dementia or AD8 score of ≥2). Incident falls were ascertained annually via self-report. Multinomial logistic regression was performed to estimate the association between order of first onset of cognitive impairment and/or frailty and incident single or repeated falls in the 1-year interval following their first onset.ResultsOf the 1,337, 832 developed cognitive impairment first (termed "CI first"), 286 developed frailty first (termed "frailty first") and 219 had co-occurrence of cognitive impairment and frailty within one year (termed "CI-frailty co-occurrence") over 5 years. Overall, 491 (34.5%) had at least 1 fall during the 1-year interval following the onset of physical frailty and/or cognitive impairment. After adjustment, "CI-frailty co-occurrence" was associated with a more than 2-fold increased risk of repeated falls than "CI first" (odds ratio 2.35, 95% confidence interval 1.51‒3.67; P < .001). No significant difference was found between participants with "frailty first" and "CI first" (P = .07). In addition, the order of onset was not associated with risk of a single fall.Conclusions and implicationsOlder adults experiencing "CI-frailty co-occurrence" had the greatest risk of repeated falls compared with those with "CI first" and "frailty first". Fall risk screening should consider the order and timing of onset of physical frailty and cognitive impairment.

Project description:Neurogenesis continues throughout the lifetime in the hippocampus, while the rate declines with brain aging. It has been hypothesized that reduced neurogenesis may contribute to age-related cognitive impairment. Ginsenoside Rg1 is an active ingredient of Panax ginseng in traditional Chinese medicine, which exerts anti-oxidative and anti-aging effects. This study explores the neuroprotective effect of ginsenoside Rg1 on the hippocampus of the D-gal (D-galactose) induced aging rat model. Sub-acute aging was induced in male SD rats by subcutaneous injection of D-gal (120 mg/kg·d) for 42 days, and the rats were treated with ginsenoside Rg1 (20 mg/kg·d, intraperitoneally) or normal saline for 28 days after 14 days of D-gal injection. In another group, normal male SD rats were treated with ginsenoside Rg1 alone (20 mg/kg·d, intraperitoneally) for 28 days. It showed that administration of ginsenoside Rg1 significantly attenuated all the D-gal-induced changes in the hippocampus, including cognitive capacity, senescence-related markers and hippocampal neurogenesis, compared with the D-gal-treated rats. Further investigation showed that ginsenoside Rg1 protected NSCs/NPCs (neural stem cells/progenitor cells) shown by increased level of SOX-2 expression; reduced astrocytes activation shown by decrease level of Aeg-1 expression; increased the hippocampal cell proliferation; enhanced the activity of the antioxidant enzymes GSH-Px (glutathione peroxidase) and SOD (Superoxide Dismutase); decreased the levels of IL-1?, IL-6 and TNF-?, which are the proinflammatory cytokines; increased the telomere lengths and telomerase activity; and down-regulated the mRNA expression of cellular senescence associated genes p53, p21Cip1/Waf1 and p19Arf in the hippocampus of aged rats. Our data provides evidence that ginsenoside Rg1 can improve cognitive ability, protect NSCs/NPCs and promote neurogenesis by enhancing the antioxidant and anti-inflammatory capacity in the hippocampus.

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

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