Assessing neuroinflammation and inflammasome activity in mouse models of Down syndrome

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is a leading genetic cause of Alzheimer's disease. Neuroinflammation is altered in the post-mortem brain of people with DS, with altered microglial morphology and upregulated proinflammatory cytokines, including IL-1β. IL-1β is produced by inflammasome activity activating caspase-1 which cleaves and releases active IL-1β. We hypothesize that IL-1β levels are raised in the DS brain via upregulation of inflammasome activity, which persists when people with DS develop AD.Levels of 10 cytokines IL-1β, TNFα, IFNγ, IL-6, IL-2, IL-4, IL-5, IL-10, IL-12p70 and KC/GRO were measured (MSD) in the 3-month hippocampus of a panel of segmental duplication models of DS, Dp1Tyb, Dp2Tyb, Dp3Tyb, Dp9Tyb and Dp17Yey. These models have a duplication on one chromosome of a number of orthologues for Hsa21 genes.Raised IL-1β abundance was identified in the hippocampus of the Dp1Tyb mouse, which has an additional copy of 148 mouse orthologues for Hsa21 genes. No difference in IL-1β or any other cytokines measured were identified in the Dp3Tyb (39 genes duplicated), Dp9Tyb models (76 genes duplicated), Dp2Tyb (33 genes duplicated) or Dp17Yey (19 genes duplicated).Raised IL-1β in the Dp1Tyb brain is a multigenic phenotype, caused by having 3 copies of more than one gene/region of Hsa21. Next, we will prepare organotypic hippocampal slice cultures from the Dp1Tyb model and stimulate these with LPS, nigericin and amyloid-β to understand how having three copies of Hsa21 orthologues modulates the neuroinflammatory and inflammasome response.