Innate Immune Tolerance Regulates Microglia Response to Aβ Oligomers

Microglia are the main innate immune cells residing in the brain parenchyma. Their activation and resulting neuroinflammation have emerged as major pathogenic mechanisms in neurodegenerative disorders, particularly in Alzheimer's disease (AD). The accumulation of amyloid-β oligomers (AβOs) and microglia activation play crucial roles in the pathogenesis of AD. In a second vein, the development of innate immune memory in response to different stimuli is a vital mechanism that enables microglia to adjust their response to subsequent inflammatory challenges. While there is increasing evidence that repeated bouts of peripheral inflammation lead to training or tolerance in microglia, the impact of tolerance on the inflammatory response induced by AβOs remains to be determined. In this study, we investigated whether lipopolysaccharide (LPS)-induced tolerance affects microglial responses to AβOs. For that, organotypic hippocampal cultures were repeatedly challenged with LPS before being exposed to AβOs. We measured cytokine levels and evaluated changes in microglial activation and morphology following exposure of cultures to AβOs. A significant decrease in cytokine production was observed when hippocampal slice cultures were repeatedly challenged with LPS. Interestingly, microglial activation and the resulting inflammatory response induced by AβOs were prevented when these cultures had been previously challenged with LPS. Moreover, the changes in microglial morphology and cytokine production resulting from repeated LPS stimulation were associated with reduced activation of nuclear factor kappa B (NF-κB). These results indicate that preconditioning microglia with LPS induces a physiological immune tolerance response rather than pathological inflammation, which may have implications for developing therapeutic strategies for AD aimed at modulating innate immune memory.