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Human Apolipoprotein E2, E3, and E4 Isoform-Specific Transgenic Mice: Human-like Pattern of GlialandNeuronal Immunoreactivity in Central Nervous System Not Observed in Wild-Type Mice
Abstract
Apolipoprotein E (apoE) and its three major alleles (APOE2, E3, and E4) have been implicated in Alzheimer's disease and other neurological disorders. Little is known of the role apoE plays in normal brain function and pathology. To create a model to study apoE in brain, we have generated APOE transgenic mice using microinjection of allele-specific human genomic fragments to establish founders which were then bred to APOE knockout mice lacking a functional mouse apoE protein. This allows the study of apoE without interference from the endogenous mouse APOE gene. Results demonstrate that transgenic lines have been established that transcribe and express apoE appropriately in brain, liver, and other tissues. High cholesterol levels found in APOE knockout mice are substantially corrected in the APOE transgenic lines. ApoE immunoreactivity has been detected in glial cells and selected classes of neurons in all three isoform-specific transgenics. This pattern of immunoreactivity is similar to that observed in nonhuman primates and man, and contrasts with the strictly glial staining pattern of normal rodents.
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“These mice express ApoE via the endogenous promoter, and as a result, the turnover of ApoE should reflect the natural synthesis and clearance rates of the protein [22].”
From In Vivo Human Apolipoprotein E Isoform Fractional Turnover Rates in the CNS (2012) · cites this paper as [22]
In the citing paper
“However, under aging and stress conditions, neurons also produce apoE, albeit at lower levels than astrocytes [25, 26].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [26]
In the citing paper
“working model: Aging and/or stress induces neuronal expression of apoE.”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [26]
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Self-citationHuang, Y., Weisgraber, K. H., Mucke, L., & Mahley, R. W. (2004) · Journal of Molecular Neuroscience · doi:10.1385/jmn:23:3:189 · Cited by 242
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Laskowitz, D. T., Sheng, H., Bart, R. D., Joyner, K. A., Roses, A. D., & Warner, D. S. (1997) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-199707000-00005 · Cited by 166
Self-citationApolipoprotein E4 enhances brain inflammation by modulation of the NF-κB signaling cascade
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“30–32,61–63 Effects on learning and exploratory behavior were demonstrated in female NSE-ApoE4 transgenic mice at the age of 6 months, but no axonopathy was reported.”
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Self-citationApolipoprotein E, a Gene with Complex Biological Interactions in the Aging Brain
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Self-citationApolipoprotein E isoform‐dependent microglia migration
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“CNS apoE is synthesized locally in the brain by neurons [44], astrocytes [45], and microglia [46].”
Apolipoprotein E regulates mitochondrial function through the PGC-1α-sirtuin 3 pathway
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Absence of central cholinergic deficits in ApoE knockout mice
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In Vivo Human Apolipoprotein E Isoform Fractional Turnover Rates in the CNS
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“These mice express ApoE via the endogenous promoter, and as a result, the turnover of ApoE should reflect the natural synthesis and clearance rates of the protein [22].”
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Apolipoprotein‐E Allele‐Specific Regulation of Nitric Oxide Production
Colton, C. A., Brown, C. M., Czapiga, M., & Vitek, M. P. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb04070.x · Cited by 52
Proteomic Analysis of Mitochondria in APOE Transgenic Mice and in Response to an Ischemic Challenge
James, R., Searcy, J. L., Bihan, T. L., Martin, S. F., Gliddon, C. M., Povey, J. E., Deighton, R. F., Kerr, L. E., McCulloch, J., & Horsburgh, K. J. (2011) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2011.120 · Cited by 51
“APOE Transgenic Mice APOE-e3 and APOE-e4 transgenic mice were produced as described previously (Xu et al, 1996).”
MethodRegionally specific neuronal expression of human APOE gene in transgenic mice
Xu, P., Gilbert, J. R., Qiu, H.-L., Rothrock‐Christian, T., Settles, D. L., Roses, A. D., & Schmechel, D. E. (1998) · Neuroscience Letters · doi:10.1016/s0304-3940(98)00247-x · Cited by 50
Self-citationEngstrom, A. K., Snyder, J. M., Maeda, N., & Xia, Z. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0155-2 · Cited by 51
“Mice Humanized Apolipoprotein E3 and E4 knock-in (ApoE3KI and ApoE4-KI) mice were generated as previously described [42] and provided by Dr.”
MethodSelf-citationA Multifaceted Role for apoE in the Clearance of Beta-Amyloid across the Blood-Brain Barrier
Bachmeier, C. J., Paris, D., Beaulieu‐Abdelahad, D., Mouzon, B., MULLAN, M. J., & Crawford, F. (2012) · Neurodegenerative Diseases · doi:10.1159/000337231 · Cited by 53
Huang, Y. (2011) · Biochemical Society Transactions · doi:10.1042/bst0390924 · Cited by 53
Zhang, L., Wang, H., Abel, G. M., Storm, D. R., & Xia, Z. (2019) · Toxicological Sciences · doi:10.1093/toxsci/kfz218 · Cited by 48
Human apoE3 but not apoE4 rescues impaired astrocyte activation in apoE null mice
Ophir, G., Meilin, S., Efrati, M., Chapman, J., Karussis, D., Roses, A. D., & Michaelson, D. M. (2003) · Neurobiology of Disease · doi:10.1016/s0969-9961(02)00005-0 · Cited by 49
Self-citationAPOEgenotype-dependent modulation of astrocyte chemokine CCL3 production
Cudaback, E., Yang, Y. J., Montine, T. J., & Keene, C. D. (2014) · Glia · doi:10.1002/glia.22732 · Cited by 47
“Maeda and colleagues (Sullivan et al., 1997; Xu et al., 1996) previously generated transgenic “humanized” mice homozygous for APOE E2, E3, or E4, providing a useful animal model for investigation of APOE influence of inflammatory response.”
BackgroundApoE Synthesis in Human Neuroblastoma Cells
Dupont-Wallois, L., Soulié, C., Sergeant, N., Wrieze, N. W.-D., Chartier‐Harlin, M., Delacourte, A., & Caillet‐Boudin, M. (1997) · Neurobiology of Disease · doi:10.1006/nbdi.1997.0155 · Cited by 45
“In rodent brains, immunocytochemistry for apoE revealed immunoreactivity in several cellular types, in particular in astrocytes, but not in neurons (Schmechel et al., 1996; Xu et al., 1996).”
Horsburgh, K. J., Fitzpatrick, M. O., Nilsen, M., & Nicoll, J. A. R. (1997) · Brain Research · doi:10.1016/s0006-8993(97)00411-3 · Cited by 47
Differential neurotrophic effects of apolipoprotein E in aged transgenic mice.
Veinbergs, I., Mallory, M., Mante, M., Rockenstein, E., Gilbert, J. R., & Masliah, E. (1999) · Neuroscience Letters · doi:10.1016/s0304-3940(99)00243-8 · Cited by 46
Self-citationXu, P., Schmechel, D. E., Qiu, H.-L., Herbstreith, M. H., Rothrock‐Christian, T., Eyster, M. V., Roses, A. D., & Gilbert, J. R. (1999) · Neurobiology of Disease · doi:10.1006/nbdi.1998.0213 · Cited by 49
Self-citationGene-Environment Interaction Research and Transgenic Mouse Models of Alzheimer's Disease (Erratum)
Chouliaras, L., Sierksma, A. S. R., Kenis, G., Prickaerts, J., Lemmens, M. A. M., Brasnjevic, I., van Donkelaar, E. L., Martínez‐Martínez, P., Losen, M. H., Baets, M. H. D., et al. (2010) · International Journal of Alzheimer s Disease · doi:10.4061/2010/356862 · Cited by 44
“Human APOE genomic DNA fragments injected in single cell emryos fertilized by APOE knockout mice APOE knockout and C57BL6 Expression of human APOE in the brain, high cholesterol levels [28]”
MethodYin, J., Turner, G. H., Lin, H.-J., Coons, S. W., & Shi, J. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-110479 · Cited by 41
ApoE genotype-specific inhibition of apoptosis
DeKroon, R. M., Mihovilovic, M., Goodger, Z. V., Robinette, J. B., Sullivan, P. M., Saunders, A. M., & Strittmatter, W. J. (2003) · Journal of Lipid Research · doi:10.1194/jlr.m300097-jlr200 · Cited by 40
Self-citationHaghani, A., Cacciottolo, M., Doty, K. R., D’Agostino, C., Thorwald, M. A., Safi, N., Levine, M. E., Sioutas, C., Town, T., Forman, H. J., et al. (2020) · eLife · doi:10.7554/elife.54822 · Cited by 40
“The C57BL/6J and APOE-TR (Xu et al., 1996) mice were aged 2 months at exposure onset (Cacciottolo et al.”
BackgroundMicroglial function in human APOE3 and APOE4 transgenic mice: altered arginine transport
Czapiga, M., & Colton, C. A. (2003) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(02)00394-6 · Cited by 38
Rao, A. T., Chen, N., Kim, M. J., Blumenfeld, J. R., Yip, O., Liang, Z., Shostak, D. M., Hao, Y., Nelson, M. R., Koutsodendris, N., et al. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.10.005 · Cited by 48
Metadata
- Authors
- Xu, P.-T., Schmechel, D., Rothrock-Christian, T., Burkhart, D. S., Qiu, H.-L., Popko, B., Sullivan, P., Maeda, N., Saunders, A. M., Roses, A. D., & Gilbert, J. R.
- Affiliations
- Duke University (US)
- University of North Carolina at Chapel Hill (US)
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 1996-06
- Volume
- 3
- Issue
- 3
- Pages
- 229-245
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W2081122171
- Cited by
- 178
- References
- 0
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 6 · 2018: 2 · 2017: 5 · 2016: 4 · 2015: 2 · 2014: 2 · 2013: 4 · 2012: 6
- FWCI
- 7.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r35ag007922-07)
- National Institute on Aging (AG05 128, P50AG005128, AG07922)
- National Institute of Environmental Health Sciences (Y01-ES-40290)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- apolipoprotein E, APOE isoforms, APOE2, APOE3, APOE ε4, transgenic mice, ApoE-deficient mice, glial cells, neuronal expression, central nervous system, Alzheimer's disease, cholesterol levels
- MeSH terms
- Alleles, Animals, Apolipoproteins E, Central Nervous System, DNA, Humans, Mice, Transgenic, Neuroglia, Neurons, Reference Values, Transcription, Genetic, Protein Biosynthesis, Gene Library, Genome, Transgenes, Mice, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2
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