Inflammatory contributions of astrocytic RelA in comorbid VCID/AD

项目概要/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。睡眠障碍/昼夜节律紊乱是 痴呆症患者的一个关键临床问题。40%至70%的老年人患有睡眠障碍， 这些疾病在阿尔茨海默病和阿尔茨海默病患者中特别普遍 相关痴呆（AD/ADRD），如VCID。这项为期一年的行政补助的目的是 促进摩根蒂和邓肯实验室之间的新的合作研究，以更好地了解双 慢性睡眠障碍/昼夜节律紊乱与VCID发病机制之间的方向关系 星形胶质细胞的炎症机制。该提案将审查两个重点明确的目标， 是我们正在进行的项目在母基金RF 1 NS 118558的扩展： 1.确定慢性睡眠片段化在多大程度上驱动星形胶质细胞特异性炎症反应。 VCID背景下的异质性，以及是否去除星形胶质细胞RelA破坏这些转录 和形态表型。 2.确定慢性睡眠碎片化改变认知功能的程度，以及是否 去除星形胶质细胞-RelA破坏了这些表型。

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. Sleep disturbances/circadian disruption is a key clinical issue in dementia patients. Between 40 and 70% of older adults suffer from sleep disturbances or disorders, which are especially prevalent among patients with Alzheimer's Disease and Alzheimer’s Disease Related Dementias (AD/ADRD), such as VCID. The purpose of this one-year administrative supplement is to facilitate new collaborative research between the Morganti and Duncan labs to better understand the bi- directional relationship between chronic sleep disturbances/circadian disruption and VCID pathogenesis in the context of inflammatory mechanisms of astrocytes. This proposal will examine 2 focused specific aims, which are extensions of our ongoing projects in the parent grant RF1NS118558: 1. Determine the extent to which chronic sleep fragmentation drives astrocyte-specific inflammatory heterogeneity in the context of VCID, and whether removal astrocytic-RelA disrupts these transcriptional and morphological phenotypes. 2. Determine the extent to which chronic sleep fragmentation alters cognitive function, and whether removal astrocytic-RelA disrupts these phenotypes.