# Innate Immune Tolerance Regulates Microglia Response to Aβ Oligomers

## TL;DR

The study shows that preconditioning microglia with LPS reduces their inflammatory response to amyloid-beta oligomers, suggesting a potential new approach for Alzheimer's disease treatment.

## Contribution

The study demonstrates that LPS-induced immune tolerance in microglia reduces their inflammatory response to Aβ oligomers, a novel insight into AD pathogenesis.

## Key findings

- Preconditioning with LPS significantly decreased cytokine production in hippocampal slice cultures.
- LPS preconditioning prevented microglial activation and inflammatory response induced by Aβ oligomers.
- Reduced NF-κB activation was associated with changes in microglial morphology and cytokine production.

## Abstract

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.

Microglia are the primary innate immune cells residing in the brain parenchyma, and their activation in Alzheimer's disease (AD) results in increased neuroinflammation. The development of innate immune memory in response to various stimuli is a crucial mechanism that allows microglia to tailor their responses to future inflammatory challenges. Our study shows that preconditioning microglia with lipopolysaccharide (LPS) triggers a physiological immune tolerance response rather than causing pathological inflammation, thereby reducing the increased cytokine production caused by amyloid‐β oligomers (AβOs). This finding may have important implications for developing therapeutic strategies for AD that focus on modulating innate immune memory.