Inflammatory contributions of astrocytic RelA in comorbid VCID/AD

点击翻译按钮获取中文摘要

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.