Interferon hypersensitivity in the brain of a Down syndrome preclinical model

Abstract

AbstractBackgroundDown syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21). People with DS have altered neuroinflammation, including abnormal microglial morphology and elevated cytokines. The peripheral immune system is also different in DS, including an over‐activated interferon response likely due to four genes encoding interferon receptors being located on Hsa21. How this affects neuroinflammation is unknown. The “ex vivo” model system of organotypic brain slice cultures (OBSCs) derived from mouse brain can be used to model neuroinflammation. We created OBSCs from a DS preclinical mouse model containing three copies of the interferon receptor genes, and treated them with interferon‐β to investigate if this model had a hyper‐sensitive interferon response in the brain.MethodThe Dp(16)2Tyb (Dp(16Mis18a‐Runx1)2TybEmcf, MGI 5703800) mouse strain was used, which has the region Mis18a‐Runx1 on mouse chromosome 16 in three copies, containing ∼33 Hsa21 orthologous genes including the four interferon receptor genes. Cortico‐hippocampal OBSCs were prepared from Dp(16)2Tyb pups at age P8‐P9, grown in culture and treated at DIV14 with interferon‐β for 24‐hours. Slices were used for western blotting or qPCR, and conditioned media used for ELISAs.ResultDp(16)2Tyb OBSCs treated with interferon‐β had a significantly elevated response to treatment compared to treated wild‐type littermates, with higher expression of interferon‐stimulated genes in slice tissue and higher levels of CXCL10 protein secreted into the conditioned media.ConclusionWe found that Dp(16)2Tyb OBSCs displayed a hypersensitive interferon response. The apparent candidate genes for this interferon hypersensitivity are the four interferon receptor genes encoded on Hsa21. How this interferon hypersensitivity effects neuroinflammation in the presence of amyloid pathology is unknown. Next, we will cross the Dp(16)2Tyb with the AppNL‐G‐F mouse model of amyloid pathology to investigate how interferon hypersensitivity alters neuroinflammation in response to amyloid pathology.