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Their activation and resulting neuroinflammation have emerged as major pathogenic mechanisms in neurodegenerative disorders, particularly in Alzheimer's disease (AD). The accumulation of amyloid\u2010\u03b2 oligomers (A\u03b2Os) 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 A\u03b2Os remains to be determined. In this study, we investigated whether lipopolysaccharide (LPS)\u2010induced tolerance affects microglial responses to A\u03b2Os. For that, organotypic hippocampal cultures were repeatedly challenged with LPS before being exposed to A\u03b2Os. We measured cytokine levels and evaluated changes in microglial activation and morphology following exposure of cultures to A\u03b2Os. 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 A\u03b2Os 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\u2010\u03baB). 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.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70341-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  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