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

摘要 创伤性脑损伤(TBI)与发生以下疾病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)， 是AD/ADRD最强大的环境风险因素之一。将这些关联复合在一起 老龄化是脑外伤发病率和易感性的重要因素。由于周围环境的复杂性 脑外伤作为一种导致AD/ADRD的进行性神经退行性疾病，其细胞机制可能 在老化的大脑中，获得退行性反应的敏感性仍然难以捉摸。到目前为止，大部分 已发表的与脑外伤相关的阿尔茨海默氏样损害的发现中，有一半是通过年轻成年人进行检查的 以雄性啮齿动物为主，这并不能准确地模拟人类中最危险的种群。 然而，我们的老化脑损伤模型概括了阿尔茨海默氏样损害的几个相关因素，包括慢性 记忆障碍，加重神经炎症，神经胶质细胞增生，磷酸化tau，以及小胶质细胞 先前在人类和小鼠阿尔茨海默病模型中都记录了表型。指导原则 初步发现，我们的首要假设是，在脑损伤后老化的大脑中，rela驱动加剧 星形胶质细胞的反应，潜在的老化的大脑的易感性持续递减的结果与 动态平衡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 在老化的大脑中，由脑外伤引发的反应改变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来使用小说来验证这一假设 在年轻和老年小鼠中靶向星形胶质细胞的遗传模型以确定1。)老年人的易感性 脑外伤后星形胶质细胞失去关键的动态平衡特征，2.)星形胶质细胞调节血管紧张素转换酶 脑外伤后小胶质细胞向AD相关炎症表型的转化，以及3.)这个 星形胶质细胞在突触回路脆弱性和记忆受损中的作用，这是相关的关键标志 使用TBI/ADRD。累积起来，这些研究将有助于阐明细胞和分子底物。 通过它，老化的大脑对脑外伤的反应促进了进行性神经退行性后遗症，从而可以 最终导致AD/ADRD。我们突出的发现将最终决定Rela在多大程度上是一个关键 这些AD相关后遗症中的介体，有可能阐明其新的治疗靶点 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.