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

Mol Neurodegener. 2020 Nov 10;15(1):67. doi: 10.1186/s13024-020-00412-5.


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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism*
  • Animals
  • Brain / metabolism*
  • Disease Models, Animal
  • Gene Regulatory Networks / genetics
  • Mice
  • Microglia / metabolism*
  • Transcriptome / physiology*