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

• Published in: Alzheimer's & dementia Vol. 17; no. S2; pp. e058441 - n/a
• Main Authors: Mumford, Paige, Noy, Suzanna, Tybulewicz, Victor L, Fisher, Elizabeth, Hong, Soyon, Wiseman, Frances K
• Format: Journal Article
• Language: English
• Published: United States 01.12.2021
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.058441

Background 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). People with DS have a perturbed immune system, with elevated pro‐inflammatory cytokines and an over‐activated interferon response (2,3). Several genes on Hsa21 have been implicated in inflammation differences in DS but how these genes modify neuroinflammation, an important aspect of AD, 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. Method Mouse models used had three copies of Hsa21 orthologous genes in the mouse, including our five candidate genes; the Dp2Tyb strain (three copies of ∼33 genes) and Dp1Tyb strain (three copies of ∼148 genes). Techniques used were qPCR, immunohistochemistry, and MSD immunoassay. Result The Dp1Tyb and Dp2Tyb brain has increased expression of Hsa21 candidate genes. The Dp1Tyb model has increased microglia number in the hippocampus, elevated levels of IL‐1β, and elevated Oas2, C3, and C1qa expression (n=11 wild‐type, n=10 Dp1Tyb). The Dp2Tyb model has elevated levels of interferon‐γ in the cortex but few changes to interferon‐stimulated genes (n=12 wild‐type, n=12 Dp2Tyb). Conclusion The Dp1Tyb and Dp2Tyb models have neuroinflammatory changes that reflect those seen in people with DS, though the phenotypes of the Dp1Tyb are more pronounced. The increased microglial number, IL‐1β levels, and neuroinflammatory genes found in the Dp1Tyb were not seen in the Dp2Tyb, suggesting these changes are due to gene(s) which are in three‐copies in the Dp1Tyb but not the Dp2Tyb. One such candidate gene is USP25, which was recently found to exacerbate neuroinflammation in a mouse model of amyloid pathology (4). References: 1. Wiseman FK et al. Nat Rev Neurosci. 2015;16(9):564‐574. doi:10.1038/nrn3983 2. Sullivan KD et al. Elife. 2016;5:e16220. doi:10.7554/eLife.16220 3. Sullivan KD et al. Sci Rep. 2017;7(1):14818. doi:10.1038/s41598‐017‐13858‐3 4. Zheng Q et al. Sci Adv. 2021;7(1):eabe1340. doi:10.1126/sciadv.abe1340