Generation of a set of isogenic, gene-edited iPSC lines homozygous for all main APOE variants and an APOE knock-out line
Open accessAbstract
Alzheimer's disease (AD) is the most frequent neurodegenerative disease amongst the elderly. The SNPs rs429358 and rs7412 in the APOE gene are the most common risk factor for sporadic AD, and there are three different alleles commonly referred to as APOE-ε2, APOE-ε3 and APOE-ε4. Induced pluripotent stem cells (iPSCs) hold great promise to model AD as such cells can be differentiated in vitro to the required cell type. Here we report the use of CRISPR/Cas9 technology employed on iPSCs from a healthy individual with an APOE-ε3/ε4 genotype to obtain isogenic APOE-ε2/ε2, APOE-ε3/ε3, APOE-ε4/ε4 lines as well as an APOE-knock-out line.
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Isogenic APOE iPSCs obtained from EBiSC show mono-allelic expression of APOE, or APOE deletion.
“Isogenic APOE iPSCs were obtained from the European Bank for Induced Pluripotent Stem Cells (EBiSC), and show mono-allelic expression of APOE, or APOE deletion (Schmid et al., 2019, 2020).”
From APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes (2022) · cites this paper as Schmid et al., 2019
The Resource table identifies the isogenic APOE iPSC lines as EBiSC resources, and Resource details describes homozygous APOE-ε2/ε2, ε3/ε3 and ε4/ε4 lines plus an APOE knock-out line. The characterization passage confirms the knock-out lacks ApoE protein. None of these passages establishes mono-allelic APOE expression; a homozygous genotype does not by itself demonstrate expression from only one allele. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe iPSC lines used harbor a single APOE2, APOE3, or APOE4 allele generated using CRISPR, or an APOE-KO generated by an insertion-deletion mutation in exon 2.
“iPSC lines were purchased from EBiSC (BIONi010-C-2, -C-3, C-4, and -C-6), harboring a single APOE2, APOE3, or APOE4 allele generated using CRISPR, or an APOE-KO generated by an insertion-deletion mutation in exon 2 (Schmid et al., 2019, 2020).”
From APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes (2022) · cites this paper as Schmid et al., 2019
The Resource table identifies the four EBiSC lines, and Resource details reports CRISPR-generated APOE-ε2/ε2, ε3/ε3 and ε4/ε4 lines plus an APOE knockout with a frameshift in exon 2. The variant lines are homozygous, not single-copy APOE allele lines. The paper describes deleting part of exon 2 but does not specify an insertion-deletion mutation. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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Cites
APOE2 enhances neuroprotection against Alzheimer’s disease through multiple molecular mechanisms
Conejero-Goldberg, C., Gomar, J. J., Bobes-Bascaran, T., Hyde, T. M., Kleinman, J. E., Herman, M. M., Chen, S., Davies, P., & Goldberg, T. E. (2014) · Molecular Psychiatry · doi:10.1038/mp.2013.194 · Cited by 199 · see citing works
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ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756 · see citing works
de Leeuw, S. M., Kirschner, A. W. T., Lindner, K., Rust, R., Budny, V., Wolski, W. E., Gavin, A.-C., Nitsch, R. M., & Tackenberg, C. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.11.007 · Cited by 105 · see citing works
APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons
Budny, V., Knöpfli, Y., Meier, D., Zürcher, K., Bodenmann, C., Peter, S. L., Müller, T., Tardy, M., Cortijo, C., & Tackenberg, C. (2024) · Cells · doi:10.3390/cells13141207 · Cited by 15 · see citing works
APOE genotype-dependent differences in human astrocytic energy metabolism
Budny, V., Bodenmann, C., Zürcher, K. J., Krüger, M., de Leeuw, S. M., Weber, R. Z., Rust, R., Ravotto, L., Ruminot, I., Barros, L. F., et al. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1603657 · Cited by 6 · see citing works
- Authors
- Schmid, B., Prehn, K. R., Nimsanor, N., Garcia, B. I. A., Poulsen, U., Jørring, I., Rasmussen, M. A., Clausen, C., Mau-Holzmann, U. A., Ramakrishna, S., Muddashetty, R., Steeg, R., Bruce, K., Mackintosh, P., Ebneth, A., Holst, B., & Cabrera-Socorro, A.
- Affiliations
- Bioneer (Denmark) (DK)
- Mahidol University (TH)
- University of Tübingen (DE)
- University of Trans-Disciplinary Health Sciences and Technology (IN)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Janssen (Belgium) (BE)
- Corresponding author
- Schmid, Benjamin
- ORCID
- Venue
- Stem Cell Research
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 34
- Pages
- 101349
- ISSN
- 1873-5061 (ISSN-L)
- OpenAlex
- W2908300127
- Cited by
- 40
- References
- 1
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 8 · 2023: 4 · 2022: 4 · 2021: 10 · 2020: 5 · 2019: 1
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Update notices
- erratum (2020-10-01)
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Research (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Danish Agency for Science, Technology and Innovation (6114-00003B-768138)
- European Union's Seventh Framework programme FP7 under REA (PIAPP-GA-2012-324451)
- BrainStem – Stem cell Centre of Excellence in Neurology (4108-00008B)
- Innovative Medicines Initiative (115582)
- European Union's Seventh Framework Programme (FP7/2007-2013)
- EFPIA
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- Alzheimer's disease, apolipoprotein E, induced pluripotent stem cells, CRISPR/Cas9 genome editing, isogenic cell lines, APOE ε4, APOE ε2, APOE ε3, apolipoprotein E deficiency, rs429358, rs7412, disease modeling
- MeSH terms
- Gene Editing, Adolescent, Apolipoproteins E, Cell Line, Homozygote, Humans, Male, Mutation, Cell Culture Techniques, Gene Knockout Techniques, Induced Pluripotent Stem Cells
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