Early amyloid pathology in mice synergistically worsens post-sepsis behavioral impairment and microglial synaptic phagocytosis.

Sepsis survivors often experience long-term cognitive and mental health impairment. We lack a clear understanding of the biological mechanisms driving impairment after sepsis and the factors that make a brain vulnerable to dysfunction after sepsis. We hypothesize that amyloid pathology, which is neuroinflammatory and accumulates with age even in cognitively normal people, is a latent risk factor for post-sepsis decline driven in part by neuroinflammation and microglial dysfunction. We induced sepsis via polymicrobial abdominal infection (cecal ligation and puncture; CLP) in young adult 5xFAD mice to model early amyloid pathology. 5xFAD CLP mice demonstrated generalized conditioned fear response and impaired cognition in the puzzle box task. Brain transcriptomics revealed persistent upregulation of neuroinflammatory pathways after resolution of the infection, with a distinct increase in 5xFAD CLP survivor mice. Complement gene expression and C3aR protein were heightened in 5xFAD mice, while C3 increased after infection. Microglial synaptic phagocytosis, a potential mechanism driving brain dysfunction after sepsis, was increased in 5xFAD CLP survivor mice 3 weeks after infection. While there was a small C3aRhigh microglial population in 5xFAD brains, the change in synaptic phagocytosis occurred in microglia with basal levels of C3aR expression. Overall, our findings suggest that early amyloid pathology synergistically heightens the behavioral change, neuroinflammation, and microglial synaptic phagocytosis caused by sepsis.