Innate immune memory mediates increased susceptibility to Alzheimer's disease-like pathology in sepsis surviving mice

Sepsis survivors show long-term impairments, including alterations in memory and executive function. Evidence suggests that systemic inflammation contributes to the progression of Alzheimeis disease (AD), but the mechanisms involved in this process are still unclear. Boosted (trained) and diminished (tolerant) innate immune memory has been described in peripheral immune cells after sepsis. However, the occurrence of long-term innate immune memory in the post-septic brain is fully unexplored. Here, we demonstrate that sepsis causes long-lasting trained innate immune memory in the mouse brain, leading to an increased susceptibility to A beta oligomers (A beta O), central neurotoxins found in AD. Hippocampal micmglia from sepsis-surviving mice shift to an amoeboid/phagocytic morphological profile when exposed to low amounts of A beta O, and this event was accompanied by the upregulation of several pro-inflammatory proteins (IL-1 beta, IL-6, INF-gamma and P2X7 receptor) in the mouse hippocampus, suggesting that a trained innate immune memory occurs in the brain after sepsis. Brain exposure to low amounts of A beta O increased microglial phagocytic ability against hippocampal synapses. Pharmacological blockage of brain phagocytic cells or microglial depletion, using minocycline and colony stimulating factor 1 receptor inhibitor (PLX3397), respectively, prevents cognitive dysfunction induced by A beta O in sepsis-surviving mice. Altogether, our findings suggest that sepsis induces a long-lasting trained innate immune memory in the mouse brain, leading to an increased susceptibility to A beta O-induced neurotoxicity and cognitive impairment.

Automated summary

Sepsis survivors exhibit long-lasting trained innate immune memory in the mouse brain, increasing susceptibility to Aβ oligomers. Changes in hippocampal microglial morphology and pro-inflammatory protein levels suggest the presence of trained innate immune memory in the brain post-sepsis. Pharmacological interventions targeting brain phagocytic cells or microglial depletion prevent cognitive dysfunction induced by Aβ oligomers in sepsis-surviving mice.