Genomics

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


ABSTRACT: Background: 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 three mouse models based on LOAD genetics, carrying APOE4 and TREM2*R47H alleles and the 5xFAD mouse, a widely used amyloid pathology model, demonstrated overlaps with distinct human AD modules that, in turn, are functionally enriched in key disease-associated pathways. Comprehensive comparison with full transcriptome data from same-sample RNA-Seq shows 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 Overall design: In this study, a cohort of 155 mice from four four different strains carrying Alzheimer associated genetic risk variants was used to to correlate key human disease processes and pathways with mRNA from mouse brains. Three novel mouse models, harboring two LOAD risk alleles, were used to translate co-expression profiles between human and mouse brain transcriptome data using our novel Mouse AD panel. Transcriptome analysis was performed for the APOE4 KI mouse, carrying a humanized version of the strongest LOAD associated risk allele (APOE-ε4) and the Trem2*R47H mouse, which harbors a rare deleterious variant in TREM2. The rare TREM2 R47H missense variant (rs75932628) has been previously associated with LOAD in multiple independent studies. In addition, we added the 5xFAD model, a commonly used mouse model carrying transgenes with a total of five AD-linked familial mutations in APP and PSEN1 to our analysis in order to compare our novel LOAD models to a model that resembles the early onset form of the disease with a high amyloid burden.Mouse transcriptome data for half brains was analyzed at different ages (2-14 months) to estimate the overlap with human post-mortem co-expression modules during aging.

INSTRUMENT(S): NanoString nCounter® Mouse AD panel

ORGANISM(S): Mus musculus  

SUBMITTER: Christoph Preuss  

PROVIDER: GSE141509 | GEO | 2020-02-03

REPOSITORIES: GEO

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