Vascular mechanisms of sepsis-induced cognitive dysfunction

Sepsis, the injurious systemic response to infection, is a major cause of death in both industrialized and developing societies. With advances in supportive care, sepsis mortality has improved, leading to increased recognition of the chronic consequences of this critical illness. Nearly 50% of sepsis survivors experience long- term cognitive impairment, akin to accelerated dementia. Despite the substantial societal burden of septic cognitive impairment, no effective therapies are known to prevent or treat this condition. A multidisciplinary collaboration between the laboratories of Drs. Eric Schmidt (an expert in sepsis and vascular glycobiology) and Paco Herson (an expert in brain injury) recently identified a novel mechanism underlying the development of septic cognitive impairment. As detailed in manuscripts published in 2019 in the Journal of Clinical Investigation and the Proceedings of the National Academy of Sciences, we observed that heparan sulfate (HS) fragments, shed into the circulation during septic degradation of the endothelial glycocalyx, specifically penetrate into only one tissue: the hippocampus, a compartment of the brain responsible for spatial memory formation. Hippocampal-penetrating HS fragments sequester a key growth factor necessary for learning, leading to persistent cognitive impairment in both septic animals and humans. The striking hippocampal specificity of HS extravasation during sepsis prompted our laboratory to pursue additional preliminary experiments using a murine lipopolysaccharide (LPS) model of sepsis. LPS-induced hippocampal blood-brain barrier (BBB) hyperpermeability was specific to HS, as similarly-sized dextrans were unable to penetrate the hippocampus. Heparin affinity chromatography and proteomic analyses identified that LPS selectively induces several HS-binding proteins within the hippocampus, including an endothelial protein previously implicated in paracellular BBB permeability (Prion related protein, Prp). This selective induction of hippocampal HS-binding proteins mirrors the hippocampal specificity of HS extravasation during sepsis. Based upon these preliminary data, we hypothesize that sepsis induces expression of HS-binding proteins (such as Prp) released into the blood stream. These proteins facilitate the selective transport of circulating HS into the hippocampus, leading to cognitive impairment in sepsis survivors. Pursuit of this hypothesis will require mechanistic interrogation of sepsis-induced HS-binding proteins as putative mediators of HS uptake by the hippocampal BBB. To achieve this goal requires a multi-disciplinary team to use cutting-edge molecular tools to assess HS transport in animal models and clinical studies to correlate to the human patient population. We will specifically identify 1) the mechanism of HS accumulation into the hippocampus, 2) the role of circulating prion-related protein in neurocognitive dysfunction following experimental sepsis and 3) correlate circulating HS and Prp with cognitive outcome in human sepsis patients