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

Overview

Authors: Na Wang1,2, Gefei Yu3, Zhen Wang4, Alla Alnobani1, Suren Jeevaratnam1, Xue Zhang4, Meghan McReynolds4, Yuzhou Chang2, Fangfang Qi2, William Tauer2, Cassandra Rosenberg1, Melissa Wren1, Tadafumi C. Ikezu1, Yuka A. Martens1, Minghui Wang3, Bin Zhang3, Gregory W. Carter5, Michael Sasner5, David M. Holtzman6, Junmin Peng4, Long-Jun Wu2,7, Takahisa Kanekiyo1, Chia-Chen Liu1, Guojun Bu1,8
  1. Department of Neuroscience, Mayo Clinic,Jacksonville, FL USA
  2. Department of Neurology, Mayo Clinic,Rochester, MN USA
  3. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai,New York, NY USA
  4. Departments of Structural Biology and Developmental Neurobiology, St. Jude Children’s Research Hospital,Memphis, TN USA
  5. The Jackson Laboratory,Bar Harbor, ME USA
  6. Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine,St. Louis, MO USA
  7. Center for Neuroimmunology and Glial Biology, Institute of Molecular Medicine, University of Texas Health Science Center,Houston, TX USA
  8. Division of Life Science and State Key Laboratory of Nervous System Disorders, The Hong Kong University of Science and Technology,Clear Water Bay, Hong Kong, China
Institutions: Mayo Clinic (United States); Icahn School of Medicine at Mount Sinai (United States); St. Jude Children's Research Hospital (United States); Jackson Laboratory (United States); Washington University in St. Louis (United States); The University of Texas Health Science Center at Houston (United States); Hong Kong University of Science and Technology (Hong Kong SAR China)
Journal: Molecular neurodegeneration, volume 21, issue 1, article 26
Dates: received 25 November 2025; accepted 16 March 2026; published online 24 March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s13024-026-00940-6 · PMID 41877131 · PMCID PMC13185305 · OpenAlex W7140179012
Open access: gold, a free copy (OpenAlex)
Status: code on request (how the code is found and verified)
Categories: genetics / omics (modality), human (organism), mouse (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions, Spectral & time-frequency
Keywords: APOE, Mouse model, Alzheimer’s disease, Lipids, Transcriptomics, Proteomics, Mass spectrometry
MeSH: Alzheimer Disease*, Apolipoproteins E*, Brain*, Animals, Disease Models, Animal, Female, Genotype, Humans, Lipids, Male, Mice, Mice, Transgenic, Transcriptome (* major topic)
Topic: Alzheimer's disease research and treatments (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex
Funding: NIH/NIA (U54AG054345, 1RF1AG055104, U19AG069701)
Citations: cited by 2 papers (Europe PMC); 68 references in the paper

Abstract

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.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13024-026-00940-6.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

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Data

Datasets cited

Data availability

Bulk RNA-seq data have been deposited at Synapse database with accession number syn69774864 (https://doi.org/10.7303/syn69774864) and are available as of the date of publication. Visualization of brain gene expression of this work are available in the “EPAAD” website ([Gene Expresssion Database | EPAAD.org] (https://www.epaad.org/gene-expresssion-database)) as of the date of publication. Further data and code supporting the findings of this study are available from the corresponding authors on request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 24 authors, 7 keywords, 13 MeSH terms, 1 funder, 68 references.

Cite

This paper

Wang, N., Yu, G., Wang, Z., Alnobani, A., Jeevaratnam, S., Zhang, X., McReynolds, M., Chang, Y., Qi, F., Tauer, W., Rosenberg, C., Wren, M., Ikezu, T. C., Martens, Y. A., Wang, M., Zhang, B., Carter, G. W., Sasner, M., Holtzman, D. M., . . . Bu, G. (2026). Molecular characterization of humanized APOE mouse models reveals source and genotype dependent differences. Molecular neurodegeneration, 21(1), 26. https://doi.org/10.1186/s13024-026-00940-6

BibTeX

@article{wang2026molecular,
author = {Wang, Na and Yu, Gefei and Wang, Zhen and Alnobani, Alla and Jeevaratnam, Suren and Zhang, Xue and McReynolds, Meghan and Chang, Yuzhou and Qi, Fangfang and Tauer, William and Rosenberg, Cassandra and Wren, Melissa and Ikezu, Tadafumi C. and Martens, Yuka A. and Wang, Minghui and Zhang, Bin and Carter, Gregory W. and Sasner, Michael and Holtzman, David M. and Peng, Junmin and Wu, Long-Jun and Kanekiyo, Takahisa and Liu, Chia-Chen and Bu, Guojun},
title = {{Molecular characterization of humanized APOE mouse models reveals source and genotype dependent differences}},
journal = {Molecular neurodegeneration},
year = {2026},
month = mar,
volume = {21},
number = {1},
pages = {26},
publisher = {BMC},
issn = {1750-1326},
doi = {10.1186/s13024-026-00940-6},
url = {https://doi.org/10.1186/s13024-026-00940-6},
pmid = {41877131},
pmcid = {PMC13185305}
}

RIS

TY - JOUR
AU - Wang, Na
AU - Yu, Gefei
AU - Wang, Zhen
AU - Alnobani, Alla
AU - Jeevaratnam, Suren
AU - Zhang, Xue
AU - McReynolds, Meghan
AU - Chang, Yuzhou
AU - Qi, Fangfang
AU - Tauer, William
AU - Rosenberg, Cassandra
AU - Wren, Melissa
AU - Ikezu, Tadafumi C.
AU - Martens, Yuka A.
AU - Wang, Minghui
AU - Zhang, Bin
AU - Carter, Gregory W.
AU - Sasner, Michael
AU - Holtzman, David M.
AU - Peng, Junmin
AU - Wu, Long-Jun
AU - Kanekiyo, Takahisa
AU - Liu, Chia-Chen
AU - Bu, Guojun
TI - Molecular characterization of humanized APOE mouse models reveals source and genotype dependent differences
T2 - Molecular neurodegeneration
J2 - Mol Neurodegener
PY - 2026
DA - 2026/03/24
VL - 21
IS - 1
SP - 26
SN - 1750-1326
PB - BMC
DO - 10.1186/s13024-026-00940-6
UR - https://doi.org/10.1186/s13024-026-00940-6
LA - en
ER -

CSL-JSON

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