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Background <p>Humanized <i>APOE</i> targeted-replacement (TR) mice are essential tools for studying apoE isoform effects in Alzheimer’s disease (AD) and other apoE-related disorders. Despite their widespread use, existing <i>APOE</i> mouse models, generated with different gene targeting strategies, have not been directly compared in terms of apoE isoform expression, lipid profiles, and transcriptomic signatures. Such differences could impact how we interpret <i>APOE</i> genotype-related outcomes, as well as related underlying molecular mechanisms.</p> Methods <p>We conducted a comprehensive molecular comparison of humanized <i>APOE</i> mouse models from three sources: Taconic Biosciences (TAC), the Cure Alzheimer’s Fund (CAF), and The Jackson Laboratory (JAX). We assessed apoE protein and transcript levels, peripheral plasma lipid composition, and bulk brain transcriptomics. ApoE isoform levels were evaluated by biochemical and proteomic measurements. Peripheral lipids, including low-density lipoprotein (LDL), high-density lipoprotein (HDL), cholesterol, and triglycerides, were also measured. We employed complementary bioinformatics analyses to evaluate brain transcriptomes and identify differentially expressed genes (DEGs) and networks based on source, <i>APOE</i> genotype, and sex.</p> Results <p>We found that apoE isoforms exhibited differential levels among the three sources in the brain, liver, and plasma. Peripheral lipoproteins and lipids, including LDL, HDL, cholesterol, and triglycerides, also showed distinct concentrations in each source and genotype. Importantly, we identified distinct brain transcriptional signatures among these mouse models, which were influenced by source, <i>APOE</i> genotype, and sex. Finally, our analysis revealed specific differentially expressed genes and pathways impacted by source, genotype, and sex.</p> Conclusions <p>Our findings highlight <i>APOE</i> genotype- and source-dependent variations in apoE isoform levels, lipid profiles, and molecular pathways. This study underscores the importance of consistency and caution in choosing and utilizing humanized <i>APOE</i> mouse models, offering molecular insights into key apoE-related outcomes.</p>

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Molecular characterization of humanized APOE mouse models reveals source and genotype dependent differences

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月24日

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  • Na Wang,
  • Gefei Yu,
  • Zhen Wang,
  • Alla Alnobani,
  • Suren Jeevaratnam,
  • Xue Zhang,
  • Meghan McReynolds,
  • Yuzhou Chang,
  • Fangfang Qi,
  • William Tauer,
  • Cassandra Rosenberg,
  • Melissa Wren,
  • Tadafumi C. Ikezu,
  • Yuka A. Martens,
  • Minghui Wang,
  • Bin Zhang,
  • Gregory W. Carter,
  • Michael Sasner,
  • David M. Holtzman,
  • Junmin Peng,
  • Long-Jun Wu,
  • Takahisa Kanekiyo,
  • Chia-Chen Liu,
  • Guojun Bu

摘要

Background

Humanized APOE targeted-replacement (TR) mice are essential tools for studying apoE isoform effects in Alzheimer’s disease (AD) and other apoE-related disorders. Despite their widespread use, existing APOE mouse models, generated with different gene targeting strategies, have not been directly compared in terms of apoE isoform expression, lipid profiles, and transcriptomic signatures. Such differences could impact how we interpret APOE genotype-related outcomes, as well as related underlying molecular mechanisms.

Methods

We conducted a comprehensive molecular comparison of humanized APOE mouse models from three sources: Taconic Biosciences (TAC), the Cure Alzheimer’s Fund (CAF), and The Jackson Laboratory (JAX). We assessed apoE protein and transcript levels, peripheral plasma lipid composition, and bulk brain transcriptomics. ApoE isoform levels were evaluated by biochemical and proteomic measurements. Peripheral lipids, including low-density lipoprotein (LDL), high-density lipoprotein (HDL), cholesterol, and triglycerides, were also measured. We employed complementary bioinformatics analyses to evaluate brain transcriptomes and identify differentially expressed genes (DEGs) and networks based on source, APOE genotype, and sex.

Results

We found that apoE isoforms exhibited differential levels among the three sources in the brain, liver, and plasma. Peripheral lipoproteins and lipids, including LDL, HDL, cholesterol, and triglycerides, also showed distinct concentrations in each source and genotype. Importantly, we identified distinct brain transcriptional signatures among these mouse models, which were influenced by source, APOE genotype, and sex. Finally, our analysis revealed specific differentially expressed genes and pathways impacted by source, genotype, and sex.

Conclusions

Our findings highlight APOE genotype- and source-dependent variations in apoE isoform levels, lipid profiles, and molecular pathways. This study underscores the importance of consistency and caution in choosing and utilizing humanized APOE mouse models, offering molecular insights into key apoE-related outcomes.