Neurons and glial cells acquire a senescent signature after repeated mild traumatic brain injury in a sex-dependent manner.
Neurons and glial cells acquire a senescent signature after repeated mild traumatic brain injury in a sex-dependent manner.
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DOI：
10.3389/fnins.2022.1027116
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发表时间：
2022
影响因子：
4.3
通讯作者：
Hazrati, Lili-Naz
中科院分区：
文献类型：
--
作者：
Schwab, Nicole;Taskina, Daria;Leung, Emily;Innes, Brendan T.;Bader, Gary D.;Hazrati, Lili-Naz
轻度创伤性脑损伤（mTBI）是一个重要的公共卫生问题，因为它可能导致长期的神经系统症状和神经退行性疾病的风险。驱动这一现象的病理生理机制尚不清楚，目前尚无有效的 mTBI 治疗方法。在这项关于重复 mTBI (rmTBI) 的研究中，我们在 C57BL/6 小鼠中诱导了 3 次轻度闭合性颅骨损伤或假手术，间隔 24 小时。我们发现 rmTBI 小鼠具有长时间的翻正反射和星形胶质细胞增生，在莫里斯水迷宫 (MWM) 和明暗测试中存在神经损伤。皮质和海马组织分析揭示了双链断裂、氧化损伤和 R 环形式的 DNA 损伤、细胞衰老的标志物（包括 p16 和 p21）以及 cGAS-STING 通路介导的信号传导。这项研究发现了小鼠 rmTBI 后新的性别差异。尽管这些标记物在男女中均因 rmTBI 而增加，但与男性相比，女性的 DNA 损伤水平较高，衰老蛋白 p16 水平较低，cGAS-STING 信号蛋白水平较低。雄性 rmTBI 小鼠大脑的单细胞 RNA 测序揭示了 DNA 损伤反应的激活、细胞衰老的证据以及让人想起神经元和神经胶质细胞中衰老相关分泌表型 (SASP) 的促炎标记。细胞类型特异性变化还存在脑免疫激活、兴奋性和抑制性神经元神经传递改变以及血管功能障碍的证据。用抗衰老药物 ABT263 治疗受伤小鼠，仅显着降低雄性小鼠的衰老标志物，但对雌性小鼠没有治疗作用。 ABT263 在雄性小鼠中减少衰老的同时，还显着改善了 MWM 的表现。这项研究提供了令人信服的证据，证明衰老会导致 rmTBI 后的大脑功能障碍，但可能以性别依赖性的方式发生。
Mild traumatic brain injury (mTBI) is an important public health issue, as it can lead to long-term neurological symptoms and risk of neurodegenerative disease. The pathophysiological mechanisms driving this remain unclear, and currently there are no effective therapies for mTBI. In this study on repeated mTBI (rmTBI), we have induced three mild closed-skull injuries or sham procedures, separated by 24 h, in C57BL/6 mice. We show that rmTBI mice have prolonged righting reflexes and astrogliosis, with neurological impairment in the Morris water maze (MWM) and the light dark test. Cortical and hippocampal tissue analysis revealed DNA damage in the form of double-strand breaks, oxidative damage, and R-loops, markers of cellular senescence including p16 and p21, and signaling mediated by the cGAS-STING pathway. This study identified novel sex differences after rmTBI in mice. Although these markers were all increased by rmTBI in both sexes, females had higher levels of DNA damage, lower levels of the senescence protein p16, and lower levels of cGAS-STING signaling proteins compared to their male counterparts. Single-cell RNA sequencing of the male rmTBI mouse brain revealed activation of the DNA damage response, evidence of cellular senescence, and pro-inflammatory markers reminiscent of the senescence-associated secretory phenotype (SASP) in neurons and glial cells. Cell-type specific changes were also present with evidence of brain immune activation, neurotransmission alterations in both excitatory and inhibitory neurons, and vascular dysfunction. Treatment of injured mice with the senolytic drug ABT263 significantly reduced markers of senescence only in males, but was not therapeutic in females. The reduction of senescence by ABT263 in male mice was accompanied by significantly improved performance in the MWM. This study provides compelling evidence that senescence contributes to brain dysfunction after rmTBI, but may do so in a sex-dependent manner.
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影响因子：
13.5
作者：
Harry, G. Jean
通讯作者：
Harry, G. Jean
影响因子：
3.2
作者：
Bieniek KF;Cairns NJ;Crary JF;Dickson DW;Folkerth RD;Keene CD;Litvan I;Perl DP;Stein TD;Vonsattel JP;Stewart W;Dams-O'Connor K;Gordon WA;Tripodis Y;Alvarez VE;Mez J;Alosco ML;McKee AC;TBI/CTE Research Group
通讯作者：
TBI/CTE Research Group
影响因子：
1.9
作者：
Andrews, TK;Rose, FD;Johnson, DA
通讯作者：
Johnson, DA
影响因子：
4.3
作者：
Cha, Jeeyeon M.;Aronoff, David M.
通讯作者：
Aronoff, David M.
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J