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.
Mild traumatic brain injury (mTBI) can lead to long-term neurological dysfunction and increase one's risk of neurodegenerative disease. Several repercussions of mTBI have been identified and well-studied, including neuroinflammation, gliosis, microgliosis, excitotoxicity, and proteinopathy – however the pathophysiological mechanisms activating these pathways after mTBI remains controversial and unclear. Emerging research suggests DNA damage-induced cellular senescence as a possible driver of mTBI-related sequalae. Cellular senescence is a state of chronic cell-cycle arrest and inflammation associated with physiological aging, mood disorders, dementia, and various neurodegenerative pathologies. This narrative review evaluates the existing studies which identify DNA damage or cellular senescence after TBI (including mild, moderate, and severe TBI) in both experimental animal models and human studies, and outlines how cellular senescence may functionally explain both the molecular and clinical manifestations of TBI. Studies on this subject clearly show accumulation of various forms of DNA damage (including oxidative damage, single-strand breaks, and double-strand breaks) and senescent cells after TBI, and indicate that cellular senescence may be an early event after TBI. Further studies are required to understand the role of sex, cell-type specific mechanisms, and temporal patterns, as senescence may be a pathway of interest to target for therapeutic purposes including prognosis and treatment.
Numerous cellular processes including toxic protein aggregation and oxidative stress have been studied extensively as potential mechanisms underlying neurodegeneration. However, limited therapeutic efficacy targeting these processes has prompted other mechanisms to be explored. Previous research has emphasized a link between cellular senescence and neurodegeneration, where senescence induced by excess DNA damage and deficient DNA repair results in structural and functional changes that ultimately contribute to brain dysfunction and increased vulnerability for neurodegeneration. Specific DNA repair proteins, such as BRCA1, have been associated with both stress-induced senescence and neurodegenerative diseases, however specific mechanisms remain unclear. Therefore, this review explores DNA damage-induced senescence in the brain as a driver of neurodegeneration, with particular focus on BRCA1, and its potential contribution to sex-specific differences associated with neurodegenerative disease.
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