Th183 - Systemic Hyperfibrinogenemia and Neutrophilia Link Respiratory Inflammation with Alzheimer’s-associated Neuropathology Relevant to SARS-CoV-2 Post-Sequalae

Abstract Text: Chronic illness from post-acute sequelae SARS-CoV-2 infection (PASC), is a healthcare burden that is ever-evolving, particularly concerning neurological disease (NeuroPASC). Growing evidence links SARS-CoV-2 infection and an increased risk for neurodegenerative disease, especially in at-risk populations. However, to adequately develop therapeutic strategies for this ensuing healthcare burden, insights into key mechanistic regulators of NeuroPASC are needed. Thus, we will present a potential mechanistic map of key regulatory events that link inflammatory activation of the respiratory tract to neuroinflammatory activation via changes in the circulatory profile of inflammatory regulators. Specifically, we will present our working hypothesis of a regulatory interaction between neutrophils and fibrinogen at the blood-brain barrier (BBB) that alters neurovascular health and ultimately dysregulated microglial function, leading to amyloid aggregation relevant to Alzheimer's Disease (AD). We developed this hypothesis from immunohistochemical observations acquired via high-content microscopy of brain tissue from wild-type and AD (5xFAD) genetic mouse lines given a combinatorial treatment of intranasal delivery lipopolysaccharide (LPS) and retro-orbital delivery of quantum dot virus-like nanoparticles for SARS-CoV-2 (COVID-QDs); this combination served to replicate acute lung injury (ALI) and viremia in circulation, respectively, similar to that observed in moderate to severe COVID-19 clinical cases. We complemented these in-vivo observations with transwell co-culture systems that recapitulate the interactions between microglia and the BBB. Altogether, these results implicate systemic neutrophilia and hyperfibrinogenemia that damage the neurovascular unit, leading to neutrophil ingress and perivascular deposition of both fibrinogen and COVID-QDs that alter the homeostasis of microglia health and amyloid processing.