Preclinical modelling in the mouse of altered neuroinflammation in Alzheimer’s disease – Down syndrome

Abstract

People with Down syndrome (DS) develop Alzheimer's disease (AD) pathology, amyloid plaques and neurofibrillary tangles, by age 40 and the majority will develop dementia, due to having three copies of the chromosome 21 (Hsa21) gene APP leading to raised Aβ. How trisomy of the other Hsa21 protein-encoding genes affects AD is unclear (1). Neuroinflammation, an important aspect of AD, is changed in people with DS, and people with DS have general perturbations to their immune system, including elevated pro-inflammatory cytokine levels and an over-activated interferon response (2,3). Several genes on Hsa21 have been implicated in inflammation differences in DS, but how these genes when in three copies modify neuroinflammation in AD-DS is unknown. We are investigating how an extra copy of five Hsa21 candidate genes (RUNX1, IFNAR1, IFNAR2, IFNGR2, and IL10RB) modify neuroinflammation in response to Aβ. Mouse models used had three copies of Hsa21 orthologous genes in the mouse, including our five candidate genes; the Dp2Tyb strain (three copies of ∼36 genes) and Dp1Tyb strain (three copies of ∼148 genes). Techniques used were real-time PCR, immunohistochemistry, and MSD immunoassay. The Dp1Tyb and Dp2Tyb brain has increased expression of Hsa21 candidate genes. The Dp1Tyb model has increased microglia number in the dentate gyrus of the hippocampus and elevated levels of IL-1β (n=11 wild-type, n=10 Dp1Tyb). The Dp2Tyb model has reduced microglia number in the CA3 of the hippocampus and elevated levels of interferon-γ in the cortex (n=12 wild-type, n=12 Dp2Tyb). Interferon-γ is an activator of microglia (4), and people with DS have hyper-sensitivity to interferons due to three copies of my Hsa21 candidate genes IFNAR1, IFNAR2, IFNGR2, and IL10RB (2,3). Thus, the Dp2Tyb strain has elevated interferon-γ and raised interferon receptor levels that may modify the microglial response to Aβ. Next, to test this we will cross the Dp2Tyb strain with the NL-G-F model of amyloid pathology.