Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model
Individuals with Down syndrome (DS), caused by trisomy of chromosome 21 (chr21, T21), are strongly predisposed to Alzheimer's disease (AD), due to triplication of the <i>APP</i> gene, with ∼100% penetrance of AD brain pathology by age 40 and variable onset of dementia thereafter. It remains unclear what role other triplicated genes play in the pathophysiology of DS-associated AD (DS-AD). Using mouse models of DS-AD, we demonstrate that triplication of other chr21 genes has paradoxical effects on learning and memory in DS-AD mice, exacerbating some phenotypes and attenuating others. Spatial transcriptomic analysis revealed genome-wide alterations typified by upregulation of interferon (IFN) signatures and elevated levels of disease-associated microglia with concomitant decreases in neurons in DS-AD animals. Finally, systemic treatment with a JAK inhibitor improved cognition and rescued gene expression changes in DS-AD animals, indicating that IFN may be a driver of pathophysiology in DS-AD that could be amenable to therapeutic intervention.
Authors
- Paula Araya (ORCID: https://orcid.org/0000-0002-0340-5359)
- Michael P. Ludwig (ORCID: https://orcid.org/0009-0002-5961-1490)
- Matthew D. Galbraith (ORCID: https://orcid.org/0000-0003-0485-3927)
- Kelly D. Sullivan
- Julie A. Siegenthaler
- Brian F. Niemeyer (ORCID: https://orcid.org/0000-0002-2020-2238)
- Lauren N. Dunn (ORCID: https://orcid.org/0000-0001-5520-1561)
- Kyndal A. Schade
- Caitlin C. Winkler (ORCID: https://orcid.org/0000-0002-5947-5989)
- Joaquı́n M. Espinosa (ORCID: https://orcid.org/0000-0001-9048-1941)
- Katherine A. Waugh (ORCID: https://orcid.org/0000-0002-5288-4990)
- Hannah R. Lyford (ORCID: https://orcid.org/0000-0002-5165-9927)
- Eleanor Britton
- Nicolas Busquet
- Connie Brindley
- Chrisstopher Brown
Institutions
- University of Colorado Anschutz Medical Campus (US)
Publication Details
- Journal
- iScience
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1016/j.isci.2025.113130
- Primary Topic
- Down syndrome and intellectual disability research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Boettcher Foundation
- Global Down Syndrome Foundation
- Anna and John J. Sie Foundation
- National Institutes of Health
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- University of Colorado School of Medicine, Anschutz Medical Campus
- Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Anschutz Medical Campus