Proteomic, metabolomic, and transcriptomic examination of APOE transgenic mice

Abstract Background ADAPTED (Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development) is an Innovative Medicines Initiative (IMI) project that focuses on apolipoprotein E (APOE) as it relates to Alzheimer’s disease. As part of this effort, the utility of APOE transgenic mice as a model of human apoE function was investigated. Specifically, proteomic, metabolomic, and transcriptomic analyses were conducted in aged APOE transgenic mice: ε2/2, ε3/3, ε4/4, knock‐out (KO). Methods Two studies were conducted. An initial proteomic and metabolomic study was conducted in brain tissue from male and female 22‐month old APOE ε3/3 and ε4/4 mice. A second proteomic, metabolomic, and transcriptomic study was conducted in brain tissue from 16‐month old APOE ε2/2, ε3/3, ε4/4, or KO mice receiving a low‐fat/low‐sucrose or high‐fat/high‐sucrose diet. Results Protein changes (upregulated and downregulated) in 22‐month old APOE ε4 males and females relative to age/sex matched ε3 mice were related to apoE function (LDL), immune function (IgGs) and cellular structure/function. Metabolomic differences in APOE ε4 female and/or male mice relative to ε3 mice were observed for lysophospholipid metabolites, sphinganine; and cholic acid. Enrichment analysis of top genes from the different comparisons involving the ε4 allele (ε 4vs ε3, ε4vs ε2 and ε4 vs KO) showed effects in mitochondrial/respiratory chain and immune‐related pathways. Conclusion Proteomic, metabolomic, and transcriptomic examination in APOE ε4 transgenic mice indicate genotype differences consistent with previously described effects of apoE on immune function and lipid signaling. Additional work in ADAPTED will characterize proteomic and metabolomic phenotypes in human‐derived inducible pluripotent stem cells and human patient samples. Comparison of the results across human cells, human samples, and the present findings will demonstrate the potential utility (or lack thereof) for APOE animal models. Disclosure: This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115975. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This study was sponsored by AbbVie, Inc. AbbVie contributed to the study design, research, and interpretation of data, writing, reviewing, and approving the abstract. Some authors are currently employed by AbbVie and may own AbbVie stock.