Enhancement of Brain Dysfunction in Sepsis Survivors by Alzheimer’s Disease Neuropathology

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PROJECT SUMMARY/ABSTRACT Sepsis survivors carry over a 3-fold risk of new chronic brain dysfunction, including long-term cognitive and mood disorders, but risk factors for brain dysfunction in sepsis survivors remain poorly understood. Amyloid beta (Aβ) pathology is present in 20-50% of cognitively normal individuals over age 60 and is thus a common risk factor even in sepsis survivors without a preexisting Alzheimer’s disease diagnosis. Alzheimer’s disease in humans and Aβ pathology in mice increase brain levels of complement receptors which are critical to innate immunity. The complement system is strongly activated in bacterial sepsis. We therefore hypothesize that sepsis driven complement ligands in the presence of Aβ induced potentiation of complement receptors enhance microglial activation and synapse loss, increasing vulnerability to new brain dysfunction. We will examine the role of complement-driven injury and early Aβ deposition in enhanced brain dysfunction using a murine model of amyloidosis (5xFAD mice) which have survived sepsis. Specifically, we will: Aim 1: Determine if sepsis and presymptomatic Aβ deposition enhance complement-mediated neuroinflammation and synapse loss in 5xFAD sepsis survivor mice. We hypothesize that chronic Aβ induction of complement receptor C3aR combined with sepsis induced C3 expression results in microglial activation, increased synaptic phagocytosis, and reduced synaptic transmission. Aim 2: Determine if sepsis and presymptomatic Aβ deposition enhance complement-mediated behavioral impairment in 5xFAD sepsis survivor mice. We hypothesize that deficits in spatial memory, context discrimination, and motivation underly impairments in high level tasks and will determine the dependence of these deficits on C3 signaling through C3a receptor inhibition or inducible C3 deletion. Aim 3: Determine if synaptic phagocytosis in 5xFAD sepsis survivor mice is dependent on C3 driven microglial activation. While others have proposed that microglial senescence contributes to neurodegeneration, we hypothesize that microglial activation drives Aβ enhanced synapse loss in sepsis. Using a novel microfluidic cell culture platform, we will determine if C3a signaling in the setting of Alzheimer’s disease neuropathology is required for enhanced microglial cytokine secretion and synaptosome phagocytosis. Understanding mechanisms of brain injury in sepsis survivors with Aβ neuropathology will provide an important basis for personalized strategies in future trials of brain injury prevention directed at complement activation.