A novel systems biology approach to evaluate mouse models of late-onset Alzheimer’s disease

Preuss, ChristophPandey, RaviPiazza, ErinFine, AlexanderUyar, AsliPerumal, ThanneerGarceau, DylanKotredes, Kevin P.Williams, HarrietMangravite, Lara M.Lamb, Bruce T.Oblak, Adrian L.Howell, Gareth R.Sasner, MichaelLogsdon, Benjamin A.Carter, Gregory W.2021-11-052021-11-052020-11-10Preuss, C., Pandey, R., Piazza, E., Fine, A., Uyar, A., Perumal, T., Garceau, D., Kotredes, K. P., Williams, H., Mangravite, L. M., Lamb, B. T., Oblak, A. L., Howell, G. R., Sasner, M., Logsdon, B. A., & Carter, G. W. (2020). A novel systems biology approach to evaluate mouse models of late-onset Alzheimer’s disease. Molecular Neurodegeneration, 15, 67. https://doi.org/10.1186/s13024-020-00412-51750-1326https://hdl.handle.net/1805/26952Background Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia worldwide. To date, animal models of Alzheimer’s have focused on rare familial mutations, due to a lack of frank neuropathology from models based on common disease genes. Recent multi-cohort studies of postmortem human brain transcriptomes have identified a set of 30 gene co-expression modules associated with LOAD, providing a molecular catalog of relevant endophenotypes. Results This resource enables precise gene-based alignment between new animal models and human molecular signatures of disease. Here, we describe a new resource to efficiently screen mouse models for LOAD relevance. A new NanoString nCounter® Mouse AD panel was designed to correlate key human disease processes and pathways with mRNA from mouse brains. Analysis of the 5xFAD mouse, a widely used amyloid pathology model, and three mouse models based on LOAD genetics carrying APOE4 and TREM2*R47H alleles demonstrated overlaps with distinct human AD modules that, in turn, were functionally enriched in key disease-associated pathways. Comprehensive comparison with full transcriptome data from same-sample RNA-Seq showed strong correlation between gene expression changes independent of experimental platform. Conclusions Taken together, we show that the nCounter Mouse AD panel offers a rapid, cost-effective and highly reproducible approach to assess disease relevance of potential LOAD mouse models. Supplementary information Supplementary information accompanies this paper at 10.1186/s13024-020-00412-5.enAttribution 4.0 United StatesAlzheimer's DiseaseDementiaLate-onset Alzheimer's DiseaseA novel systems biology approach to evaluate mouse models of late-onset Alzheimer’s diseaseArticle