Triplication of HSA21-encoded genes modulates Alzheimer's Disease-related phenotypes in vivo

Abstract People with Down syndrome (DS), the genetic condition caused by Trisomy 21 (T21), exhibit early appearance of Alzheimer’s disease (AD), likely due to the triplication of the Amyloid Precursor Protein (APP) gene. However, the impact of many chromosome 21 (HSA21) genes on AD phenotypes in the context of DS remains unknown. To test this, we conducted a detailed phenotypic characterization of how AD-related neuropathology is modulated by an extra copy of genes orthologous to HSA21 by creating a novel DS-AD mouse strain, by crossing Dp16 with 5xFAD mice (models for DS and AD, respectively), generating: WT, Dp16, 5xFAD, and 5xFAD-Dp16 mice. Here, we performed a battery of behavioral assessments longitudinally and paired these analyses with endpoint transcriptional profiling and high-content imaging. We identified that DS-AD mice exacerbate cognitive deficits and show increased neuronal cell loss in multiple brain regions compared to DS and AD mice. Although, DS-AD mice do not present altered amyloid-β (Aβ) pathology compared to AD mice at 9-months of age, an increased number of activated microglia associated to Aβ plaques are present with a distinct transcriptional signature indicative of disease associated and interferon-activated microglia cells in these animals. These results indicate that DS contributes to the neuroinflammation network of AD, causing changes in cellular states consistent with alterations in memory and cognitive decline. However, deeper characterization is needed to understand the mechanisms by which T21 contributes to AD-pathogenesis to determine potential therapeutic intervention to significantly improve neurological health in people with DS. Supported by grants from NIH (R01AI145988 and R01AI150305). Supported by grants from NIH (R01AI145988 and R01AI150305)