USING GENETICALLY DIVERSE COLLABORATIVE CROSS MOUSE STRAINS TO MODEL ALZHEIMER’S DISEASE
- Asli Uyar, United States of America
Abstract
Aims
Mouse models of Alzheimer’s disease (AD), carrying rare variants in genes such as APP and PS1 (APP/PS1), have usually been created on the C57BL/6J (B6J) genetic background. While these strains often exhibit amyloid accumulation and neuroinflammation, many additional molecular alterations present in human AD are absent. To broaden the phenotypes of mouse models, we introduced genetic diversity by incorporating Collaborative Cross (CC) lines, a recombinant inbred mouse panel created from eight highly diverse founder strains.
Methods
Five CC strains were selected for maximal genetic and gene expression variation at twelve late-onset GWAS loci, including TREM2, BIN1, and CLU. Transgenic APPand PS1alleles with a humanized APOE4 allele on a B6J background were crossed with each CC line. Brain hemisphere transcriptomes and neuropathology were assessed at 8-months. Neuropathology focused on amyloid deposition, glial cell activation and neuronal health.
Results
The effect of humanized APOE4 demonstrated differences across CC lines and in the presence of mutant APP and PS1 transgenes. RNA-Seq data revealed allele-specific gene expression profiles associated with neuropathological differences. We mapped strain specific transcriptional signatures to Late-Onset AD subtypes identified in the study cohorts from AMP-AD consortium and observed correlations with subtypes specific to APP/PS1 and APOE4 alleles.
Conclusions
The findings provide new insights into the role of APOE4 in amyloid pathogenesis. Diverse genetic backgrounds of CC lines exhibit a unique resource to assess genome-wide allele-specific gene expression connecting AD risk variants to molecular and neuropathological profiles.This study suggests use of CC lines mouse models to better represent the genetic variation in AD.