Hyper‐sensitive interferon response in a mouse model of Alzheimer’s disease‐Down syndrome

Abstract

AbstractBackgroundDown syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and leads to an elevated risk of early‐onset Alzheimer’s disease. People with DS have a perturbed immune system including an over‐activated interferon response, which is likely due to four genes encoding interferon receptors being located on Hsa21 (1). How this affects inflammation in the brain is not well understood. In this study, we investigate if an extra copy of these genes is sufficient to elevate the interferon response in the brain of mouse models of DS, using in vivo and ex vivo approaches.MethodsThe Dp1Tyb (MGI:5703798) mouse has three‐copies of ∼148 Hsa21 orthologous genes, while the Dp2Tyb (MGI:5703800) mouse has a sub‐region of ∼32 of those Hsa21 orthologous genes in three‐copies, including the four interferon receptor genes. Organotypic brain slice cultures (OBSCs) were prepared from P7‐P9 pups and treated with interferon‐β (24 hours). Slices were collected for western blotting, qPCR, or immunohistochemistry, and media for CXCL10 ELISA.Dp2Tyb mice were crossed with AppNL‐G‐F (MGI:5637817) mice to generate four genotypes, to determine if the amyloid‐β interferon response is elevated by the additional copy of the Dp2Tyb region. Mice were tested in the light‐dark box and marble burying test to assay the effect on anxiety. Amyloid accumulation and interferon response in the brain will be determined by immunofluorescence, MSD amyloid‐β assay and qPCR.ResultsBoth Dp1Tyb and Dp2Tyb OBSCs had a hypersensitive response to interferon‐β treatment, with higher expression of interferon‐stimulated genes in lysed slices and higher levels of CXCL10 protein secreted into the media.ConclusionBoth DS preclinical models displayed a hypersensitive interferon response, indicating that interferon hypersensitivity may occur in the brain of individuals with DS and is likely due to having three‐copies of the interferon receptor genes encoded on Hsa21. Amyloid pathology has been shown to induce an interferon response (2,3). How interferon hypersensitivity in individuals with Down syndrome affects the neuroinflammatory response to amyloid pathology is unknown. To investigate this, we have crossed the Dp2Tyb model with the AppNL‐G‐F mouse model of amyloid pathology.