Inflammatory contributions of astrocytic RelA in comorbid VCID/AD

项目总结/摘要 在人类和动物模型中的多条证据表明，通过神经细胞介导的神经炎症， 反应性神经胶质增生，起着关键作用，与血管贡献的开始和进展， 认知障碍和痴呆（VCID）和阿尔茨海默病（AD），可能表明收敛 病理生理机制特别是，这些神经炎性标志中的几个在共病患者中， VCID/AD动物模型与反应性星形胶质细胞的功能障碍反应有关。在 对于健康的大脑，众所周知星形胶质细胞在维持各种稳态中起关键作用。 机制等然而，作为对损伤或疾病的反应，星形胶质细胞能够快速反应， 广义的描述称为星形胶质细胞增生症，具有各种神经炎性模式，最近 有证据表明可能会导致神经元的功能失调反应。当代的工作表明， 星形胶质细胞的这些营养不良性神经炎性反应的关键组成部分是它们利用典型的 NFkB（RelA）信号通路。然而，关于RelA在星形胶质细胞中的作用知之甚少， 暴露于VCID/AD中的共病退行性环境，代表该领域的关键知识差距。 我们对这一提议的总体假设是，星形胶质细胞RelA代表了一个会聚的 在共病VCID/AD环境中驱动功能障碍后遗症的炎症机制。这项建议 将研究三个具体目标，以确定星形胶质细胞如何利用RelA塑造内在和非内在的 细胞对共病VCID/AD退行性环境的自主性功能障碍反应： 1.确定星形胶质细胞-RelA在小胶质细胞增殖炎症表型中的能力， 共病VCID/AD中的星形胶质细胞。 2.确定星形胶质细胞RelA在VCID/AD共病患者脑血管功能障碍中的作用。 3.确定VCID/AD中的突触和认知功能障碍是否与星形胶质细胞中的RelA表达有关。

PROJECT SUMMARY/ABSTRACT Multiple lines of evidence in both humans and animal models suggest that neuroinflammation, mediated via reactive gliosis, plays a critical role associated with the initiation and progression of vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD), potentially suggesting convergent pathophysiological mechanisms. In particular, several of these neuroinflammatory hallmarks in comorbid VCID/AD animal models have been linked with the dysfunctional responses of reactive astrocytes. In the healthy brain, it is well known that astrocytes play a critical role in maintaining a variety of homeostatic mechanisms. However, as a response to injury or disease, astrocytes are able to rapidly respond, in a generalized description referred as astrogliosis, with a variety of neuroinflammatory modalities, which recent evidence suggests may cause dysfunctional responses of neurons. Contemporary work has demonstrated a critical component to these dystrophic neuroinflammatory response of astrocytes is their utilization of canonical NFkB (RelA) signaling pathway. However, relatively little is known regarding the role of RelA in astrocytes exposed to the co-morbid degenerative milieu in VCID/AD, representing a critical knowledge gap for the field. Our overarching hypothesis for this proposal is that astrocytic RelA represents a convergent inflammatory mechanism driving dysfunctional sequelae in the comorbid VCID/AD milieu. This proposal will examine three specific aims to determine how RelA utilization by astrocytes shapes both intrinsic and non- cell autonomous dysfunctional responses to the comorbid VCID/AD degenerative environment: 1. Determine the capacity of astrocytic-RelA in propagating inflammatory phenotypes of microglia and astrocytes in comorbid VCID/AD. 2. Determine the role of astrocytic-RelA in driving cerebrovascular dysfunction in comorbid VCID/AD. 3. Determine if synaptic and cognitive dysfunction in VCID/AD is linked with RelA expression in astrocytes.