Inflammatory Contributions of Astrocytic RelA in Comorbid VCID/AD

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 VCID and 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 NFêB (RelA) signaling pathway. Targeting canonical NFêB signaling in astrocytes has been demonstrated to spare a variety of disease-related sequelae in animal models of spinal cord injury, ischemia, and multiple sclerosis. Although restricting astrocyte’s utilization of RelA in the previously mentioned models has shown tissue sparing and functional recovery, 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. 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.