Contributions of astrocyte RelA signaling in aging-related neurodegenerative sequelae following TBI

摘要 创伤性脑损伤（TBI）与发生几种脑损伤的风险增加显著相关。 神经退行性疾病，包括阿尔茨海默病（AD）和AD相关痴呆（ADRD）， 这是AD/ADRD最重要的环境风险因素之一。综合这些相关因素 老龄化是TBI发病率和易感性的重要因素。由于周围环境的复杂性 TBI作为一种进行性神经退行性疾病导致AD/ADRD，其细胞机制可能是 衰老大脑易发生退行性反应的潜在原因仍然难以捉摸。迄今为止， 已发表的与TBI相关的阿尔茨海默氏症样损害相关的研究结果已使用年轻人进行了检查 主要是雄性啮齿动物，这并不能准确地模拟人类中最大的风险人群。 然而，我们的老化TBI模型概括了阿尔茨海默病样损伤的几个相关性，包括慢性TBI。 记忆障碍、神经炎症加重、神经胶质增生、磷酸化tau蛋白以及小胶质细胞 这些表型先前在阿尔茨海默病的人类和小鼠模型中均有记载。指导 根据初步研究结果，我们的总体假设是，在TBI后老化的大脑中，RelA驱动加剧了 星形胶质细胞的反应，潜在的老化大脑的易感性持续递减的结果有关， 稳态星形胶质细胞易感性、神经炎症和神经网络功能障碍。我们相信这些 由TBI在老化大脑中引发的改变的反应最终表现为进行性脑损伤的相关特征。 与AD/ADRD相关的神经变性。我们将追求三个目标，以测试这一假设使用新的 用于靶向年轻和老年小鼠中的星形胶质细胞的遗传模型以确定1.）老年人的易感性 星形胶质细胞在TBI后失去关键的稳态特征，2.）星形胶质细胞调节细胞增殖的能力 TBI后小胶质细胞向递减的AD相关炎性表型的转化，和3.）的 星形胶质细胞在突触回路脆弱性和记忆受损中的作用，这是一个重要的标志， TBI/ADRD累积起来，这些研究将有助于阐明细胞和分子底物 通过这种方式，老化的大脑对TBI的反应促进了进行性神经退行性后遗症， 最终导致AD/ADRD。我们的显著发现将最终决定RelA在多大程度上是一个关键因素。 这些AD相关后遗症中的介质，有可能阐明新的治疗靶点， 预防

ABSTRACT Traumatic brain injury (TBI) is significantly correlated with increased risk for developing several neurodegenerative disorders, including Alzheimer’s Disease (AD) and AD-related dementia (ADRD), representing one of the most powerful environmental risk factors for AD/ADRD. Compounding these correlates is that aging is a substantial factor in the incidence and vulnerability to TBI. Owing to the complexities surrounding TBI as a progressive neurodegenerative disorder leading to AD/ADRD, the cellular mechanisms potentially underlying the aging brain’s susceptibility to acquire degenerative responses remains elusive. To date, the bulk of published findings related to TBI-related Alzheimer’s-like impairments have been examined using young adult and predominantly male rodents, which does not accurately model the greatest at-risk population in humans. However, our aging TBI model recapitulates several correlates of Alzheimer’s like impairments including chronic memory impairment, exacerbated neuroinflammation, gliosis, phosphorylated tau, as well as microglial phenotypes previously documented in both human’s and mouse models of Alzheimer’s disease. Guided by preliminary findings, our overarching hypothesis is that in the aging brain following TBI, RelA drives exacerbated astrocyte responses, underlying the aging brain’s susceptibility for persistent decremental outcomes related to homeostatic astrocyte susceptibility, neuroinflammation, and neural network dysfunction. We believe these altered responses, initiated by TBI in the aging brain ultimately manifest in correlates characteristic of progressive neurodegeneration associated with AD/ADRD. We will pursue three aims to test this hypothesis using novel genetic models for targeting astrocytes in young and aged mice to determine 1.) The susceptibility of aged astrocytes to lose critical homeostatic features following TBI, 2.) The ability of astrocytes to regulate the conversion of microglia towards decremental AD-associated inflammatory phenotypes following TBI, and 3.) The role of astrocytes in the vulnerability of synaptic circuitry and impaired memory, a critical hallmark associated with TBI/ADRD. Cumulatively, these studies will help to elucidate both the cellular and molecular substrates through which the aging brain’s response to TBI facilitates progressive neurodegenerative sequelae that can eventually lead to AD/ADRD. Our salient findings will ultimately determine the extent to which RelA is a critical mediator in these AD-associated sequelae with the potential to elucidate new therapeutic targets toward their prevention.