Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada.
The Hospital for Sick Children, Toronto, Canada.
Acta Neuropathol Commun. 2021 May 8;9(1):82. doi: 10.1186/s40478-021-01190-x.
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.
轻度创伤性脑损伤（mTBI）会导致广泛的神经症状，并增加日后被诊断为神经退行性疾病的风险。虽然受伤大脑的即时氧化应激反应和死后病理学已得到充分研究，但尚不清楚早期的致病变化如何导致持续的症状，并易患神经退行性变。在这项研究中，我们使用了一种重复轻度创伤性脑损伤（rmTBI）的小鼠模型，以在受伤后 24 小时或 7 天（7 dpi）时鉴定早期基因表达变化。在受伤后 24 小时，rmTBI 小鼠的基因表达显示出对双链 DNA 断裂的 DNA 损伤反应（DDR）的激活、钙和细胞-细胞信号的改变以及细胞死亡途径的抑制。在 7 dpi 时，rmTBI 小鼠的基因表达特征与诱导细胞衰老、激活神经退行性过程和抑制 DDR 一致。在两个时间点，胶质增生、小胶质细胞增生和轴突损伤在没有任何大损伤的情况下都很明显，并且在 7 dpi 时，rmTBI 小鼠的 IL1β、p21、53BP1、DNA2 和 p53 水平升高，支持 DNA 损伤诱导的细胞衰老。这些基因表达变化反映了通常与大脑衰老相关的过程的建立，并表明细胞衰老发生得很早，而且很可能早于毒性蛋白的积累。这些分子变化伴随着 Morris 水迷宫中的空间学习和记忆缺陷。总之，我们已经确定了 DNA 损伤诱导的细胞衰老作为反复轻度创伤性脑损伤的后果，这与认知障碍相关。衰老过程中涉及的途径可能代表着创伤后综合征的可行治疗靶点。衰老已被提议促进神经退行性变，并且似乎是预防 mTBI 长期并发症（如慢性创伤性脑病和其他相关神经退行性病变）的有效靶标。
