Genetically diverse mouse models of Alzheimer’s Disease reveal an association between amyloid deposition and glycan metabolism in the brain

Abstract Background Varying degrees of cerebral amyloid angiopathy (CAA) co‐occur with parenchymal amyloid deposition in majority of Alzheimer’s Disease (AD) cases. However, common mouse models of familial AD generated on a single inbred strain do not recapitulate the spectrum of parenchymal and vascular amyloid pathogenesis in the brain. To better represent phenotypic diversity in AD, we generated a panel of genetically diverse Collaborative Cross (CC) mouse strains harboring APOE4 allele and amyloidogenic mutations. Method Five CC strains (CC002, CC006, CC013, CC037 and CC041) were selected for maximal genetic and transcriptional variation in AD‐relevant genes. Selected CC strains were crossed to C57BL/6J (B6J) mice homozygous for humanized APOE4 allele and carrying mutant APP and PS1 alleles ( APP swe , PS1 de9 ). Cohorts of male and female B6JCCnF1. APOE4 . APP/PS1 mice and controls were aged to 8 months, and brain hemispheres were processed for RNA‐Seq transcriptomics and neuropathological assessment. Weighted Gene Co‐Expression Networks Analysis (WGCNA) and gene set enrichment analysis were performed to identify gene modules and biological pathways associated with plaque deposition and CAA in CC strains. Result Neuropathological assessment revealed significant strain and sex‐dependent differences in both parenchymal and vascular amyloid pathology. Highest levels of plaque deposition in cortex and hippocampus was observed in female CC002 mice. Female mice had higher plaque load compared to male mice in all strains, whereas CAA score was higher in males and in CC037 strain. CC006 represented lowest levels of plaque deposition and CAA at comparable levels with B6J mice. RNA‐Seq data revealed a common microglia/neuroinflammation related transcriptional response observed in all strains and both sexes. On the other hand, gene expression signatures associated with varying levels of plaque deposition and CAA revealed alterations in metabolic pathways, in particular glucose, lipid and glycan metabolisms. Conclusion Our results suggest that major genetic diversity modulates distinctive parenchymal and vascular amyloid phenotypes, and differentially impacts transcriptomic signatures in the mouse brain. Overall, CC lines mouse models better represent the spectrum of neuropathological and molecular phenotypes associated with AD.