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. 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.