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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Human ApoE targeted-replacement mice express ApoE via the endogenous promoter, so ApoE turnover should reflect natural synthesis and clearance rates.
“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]
Under aging and stress conditions, neurons also produce apoE, albeit at lower levels than astrocytes.
“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]
Aging and/or stress induces neuronal expression of apoE.
“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]
Cited by
Sorted by citations
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · see citing works
“Following these initial studies with apoE knock-out mice, several lines of transgenic mice were generated to study the role of human apoE isoforms in AD pathogenesis (Raber et al., 1998; Sun et al., 1998; Xu et al., 1996).”
Mahley, R. W., Weisgraber, K. H., & Huang, Y. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600549103 · Cited by 912 · see citing works
Pharmacogenetics and the practice of medicine
Roses, A. D. (2000) · Nature · doi:10.1038/35015728 · Cited by 814 · see citing works
Self-citationSullivan, P. M., Mezdour, H., Aratani, Y., Knouff, C., Najib, J., Reddick, R. L., Quarfordt, S. H., & Maeda, N. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.29.17972 · Cited by 575 · see citing works
Self-citationXu, Q., Bernardo, A., Walker, D., Kanegawa, T., Mahley, R. W., & Huang, Y. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.5476-05.2006 · Cited by 524 · see citing works
“…that at least some neurons express apoE (Diedrich et al., 1991; Poirier et al., 1991; Han et al., 1994; Bao et al., 1996; Metzger et al., 1996; Xu et al., 1996, 1999a,b; Dupont-Wallois et al., 1997; Boschert et al., 1999; Ferreira et al., 2000; Dekroon and Armati, 2001; Hartman et al., 2001;…”
BackgroundBrecht, W. J., Harris, F. M., Chang, S., Tesseur, I., Yu, G.-Q., Xu, Q., Dee Fish, J., Wyss-Coray, T., Buttini, M., Mucke, L., et al. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.4315-03.2004 · Cited by 403 · see citing works
“…conditions (Diedrich et al., 1991; Poirier et al., 1991; Han et al., 1994; Bao et al., 1996; Beffert and Poirier, 1996; Metzger et al., 1996; Xu et al., 1996; Dupont-Wallois et al., 1997; Boschert et al., 1999; Xu et al., 1999a,b; Ferreira et al., 2000; Dekroon and Armati, 2001; Hartman et…”
BackgroundRaber, J., Wong, D., Buttini, M., Orth, M., Bellosta, S., Pitas, R. E., Mahley, R. W., & Mucke, L. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.18.10914 · Cited by 364 · see citing works
Buttini, M., Orth, M., Bellosta, S., Akeefe, H., Pitas, R. E., Wyss‐Coray, T., Mucke, L., & Mahley, R. W. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-12-04867.1999 · Cited by 361 · see citing works
“Answers to these questions can only be provided by related models in which different human apoE isoforms are expressed in multiple organs (Xu et al., 1996; Sullivan et al., 1997).”
BackgroundAPOE genotype-specific differences in the innate immune response
Vitek, M. P., Brown, C. M., & Colton, C. A. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.11.014 · Cited by 362 · see citing works
Harris, F. M., Brecht, W. J., Xu, Q., Tesseur, I., Kekonius, L., Wyss-Coray, T., Fish, J. D., Masliah, E., Hopkins, P. C., Scearce-Levie, K., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1434398100 · Cited by 342 · see citing works
Chang, S., Ma, T. R., Miranda, R. D., Balestra, M. E., Mahley, R. W., & Huang, Y. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508254102 · Cited by 319 · see citing works
Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives
Béard, E., Lengacher, S., Dias, S., Magistretti, P. J., & Finsterwald, C. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2021.825816 · Cited by 309 · see citing works
Modulation of Secreted β-Amyloid Precursor Protein and Amyloid β-Peptide in Brain by Cholesterol
Howland, D., Trusko, S. P., Savage, M. J., Reaume, A. G., Lang, D. M., Hirsch, J. D., Maeda, N., Siman, R., Greenberg, B., Scott, R. W., et al. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.26.16576 · Cited by 254 · see citing works
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 · see citing works
“, 1999a) and transgenic mice expressing human apoE under the control of the human apoE promoter (Xu et al., 1996).”
Tesseur, I. C., Dorpe, J. V., Spittaels, K., den Haute, C. V., Moechars, D., & LEUVEN, F. V. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64963-2 · Cited by 241 · see citing works
Laws, S. M., Hone, E., Gandy, S., & Martins, R. N. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01615.x · Cited by 223 · see citing works
“Finally, apoE4 transgenic mice have been illustrated to be more susceptible to focal ischaemia than apoE3 mice (Xu et al. 1996).”
BackgroundExercise improves cognition and hippocampal plasticity in <i>APOE</i> ɛ4 mice
Nichol, K., Deeny, S. P., Seif, J., Camaclang, K., & Cotman, C. W. (2009) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2009.02.006 · Cited by 213 · see citing works
“Embryonic stem cells containing the recombination were then introduced into C57Bl/6J embryos and chimeric offspring bred again to C57Bl/6J, and then interbred to generate homozygotes [22] (see also www.”
Sun, Y., Wu, S., Bu, G., Onifade, M. K., Patel, S. N., LaDu, M. J., Fagan, A. M., & Holtzman, D. M. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-09-03261.1998 · Cited by 213 · see citing works
Apolipoprotein E and the CNS Response to Injury
Laskowitz, D. T., Horsburgh, K., & Roses, A. D. (1998) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-199805000-00001 · Cited by 201 · see citing works
Self-citationApolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease
Najm, R., Jones, E. A., & Huang, Y. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0324-6 · Cited by 183 · see citing works
Brody, D. L., Donald, C. M., Kessens, C. C., Yuede, C. M., Parsadanian, M., Spinner, M., Kim, E., Schwetye, K. E., Holtzman, D. M., & Bayly, P. V. (2007) · Journal of Neurotrauma · doi:10.1089/neu.2006.0011 · Cited by 198 · see citing works
The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease
Beffert, U. (1998) · Brain Research Reviews · doi:10.1016/s0165-0173(98)00008-3 · Cited by 188 · see citing works
Specific Regional Transcription of Apolipoprotein E in Human Brain Neurons
Xu, P., Gilbert, J. R., Qiu, H.-L., Ervin, J. F., Rothrock‐Christian, T., Hulette, C., & Schmechel, D. E. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65305-9 · Cited by 177 · see citing works
“The pattern of intense apoE immunoreactivity of Bergmann glial cells and their long radial processes and the lack of neuronal apoE immunoreactivity seen in human cerebellar cortex is similar to the pattern observed in normal rat and mouse.(6,51,52) The presence of apoEimmunoreactive neurons in human frontal cortex and…”
BackgroundMethodResultInfluentialSelf-citationAβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease
Huang, Y. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.04.004 · Cited by 170 · see citing works
Horsburgh, K. J., McCarron, M. O., White, F., & Nicoll, J. A. R. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00097-x · Cited by 169 · see citing works
Neuroplasticity in Alzheimer's disease
Teter, B., & Ashford, J. W. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10441 · Cited by 170 · see citing works
“This is also an advantage of the human apoE transgenic mice (see Section 3.6); transgenic line also expresses apoE in vivo with cellular specificity like that seen in humans (Xu et al., 1996, 1998, 1999) (see Section 4.1).”
BackgroundInfluentialApolipoprotein E-deficient mice have increased susceptibility to focal cerebral ischemia
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 · see citing works
Self-citationApolipoprotein E4 enhances brain inflammation by modulation of the NF-κB signaling cascade
Ophir, G., Amariglio, N., Jacob‐Hirsch, J., Elkon, R., Rechavi, G., & Michaelson, D. M. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.05.002 · Cited by 166 · see citing works
Apolipoprotein E and cholesterol in aging and disease in the brain
de Chaves, E. P., Narayanaswami, V., Christoffersen, C., & Nielsen, L. B. (2008) · Future Lipidology · doi:10.2217/17460875.3.5.505 · Cited by 164 · see citing works
Expression and secretion of <scp>apoE</scp> isoforms in astrocytes and microglia during inflammation
Lanfranco, M. F., Sepulveda, J., Kopetsky, G., & Rebeck, G. W. (2021) · Glia · doi:10.1002/glia.23974 · Cited by 164 · see citing works
ApoE4 upregulates the activity of mitochondria‐associated ER membranes
Tambini, M. D., Pera, M., Kanter, E., Yang, H., Guardia‐Laguarta, C., Holtzman, D., Sulzer, D., Area‐Gomez, E., & Schon, E. A. (2016) · The EMBO Reports · doi:10.15252/embr.201540614 · Cited by 166 · see citing works
Hu, J., Liu, C.-C., Chen, X.-F., Zhang, Y.-W., Xu, H., & Bu, G. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0001-3 · Cited by 161 · see citing works
“Thus, apoE-TR mice express human apoE isoforms at the physiological levels and respond to regulatory pathways in a physiological setting [22-25], providing an excellent in vivo system to explore the normal function of each APOE allele and apoEassociated diseases.”
BackgroundHartman, R. E., Wozniak, D. F., Nardi, A., Olney, J. W., Sartorius, L., & Holtzman, D. M. (2001) · Experimental Neurology · doi:10.1006/exnr.2001.7715 · Cited by 157 · see citing works
Direct Transcriptional Effects of Apolipoprotein E
Theendakara, V., Peters-Libeu, C. A., Spilman, P., Poksay, K. S., Bredesen, D. E., & Rao, R. V. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.3562-15.2016 · Cited by 152 · see citing works
“Human ApoE3 and ApoE4 transgenic mice (driven by the human APOE promoter) were made in the ApoE-ko background (Xu et al., 1996; Sullivan et al., 1997; Holtzman et al., 1999; Teter et al., 2002; Arold et al., 2012).”
BackgroundLevi, O., Jongen‐Rêlo, A. L., Feldon, J., Roses, A. D., & Michaelson, D. M. (2003) · Neurobiology of Disease · doi:10.1016/s0969-9961(03)00045-7 · Cited by 145 · see citing works
Self-citationApolipoprotein E Isoform-Specific Differences in Outcome from Focal Ischemia in Transgenic Mice
Sheng, H., Laskowitz, D. T., Bennett, E. R., Schmechel, D. E., Bart, R. D., Saunders, A. M., Pearlstein, R. D., Roses, A. D., & Warner, D. S. (1998) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-199804000-00003 · Cited by 143 · see citing works
Self-citationTesseur, I. C., Dorpe, J. V., Bruynseels, K., Bronfman, F. C., Sciot, R., Lommel, A. V., & LEUVEN, F. V. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64788-8 · Cited by 141 · see citing works
“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.”
BackgroundColton, C. A., Brown, C. M., COOK, D., Needham, L. K., XU, Q., Czapiga, M., SAUNDERS, A., Schmechel, D. E., Rasheed, K., & Vitek, M. P. (2002) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00016-7 · Cited by 140 · see citing works
Self-citationPalmitoylation in Alzheimers disease and other neurodegenerative diseases
Cho, E., & Park, M. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.06.008 · Cited by 142 · see citing works
Astroglial Regulation of Apolipoprotein E Expression in Neuronal Cells
Harris, F. M., Tesseur, I., Brecht, W. J., Xu, Q., Mullendorff, K., Chang, S., Wyss-Coray, T., Mahley, R. W., & Huang, Y. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m309475200 · Cited by 135 · see citing works
White, F., Nicoll, J. A. R., Roses, A. D., & Horsburgh, K. (2001) · Neurobiology of Disease · doi:10.1006/nbdi.2001.0401 · Cited by 128 · see citing works
Self-citationBrain Metabolic Alterations in Alzheimer’s Disease
Ardanaz, C. G., Ramírez, M. J., & Solas, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073785 · Cited by 130 · see citing works
Behavioural, physiological and morphological analysis of a line of apolipoprotein E knockout mouse
Anderson, R., Barnes, J. C., Bliss, T. V. P., Cain, D. P., Cambon, K., Davies, H. A., Errington, M. L., Fellows, L. A., Gray, R. A., Hoh, T., et al. (1998) · Neuroscience · doi:10.1016/s0306-4522(97)00598-8 · Cited by 119 · see citing works
Behavioural analysis and susceptibility to CNS injury of four inbred strains of mice
Royle, S., Collins, F. C., Rupniak, H. T., Barnes, J. C., & Anderson, R. (1999) · Brain Research · doi:10.1016/s0006-8993(98)01122-6 · Cited by 119 · see citing works
Apolipoprotein E Deficiency Worsens Outcome From Global Cerebral Ischemia in the Mouse
Sheng, H., Laskowitz, D. T., Mackensen, G. B., Kudo, M., Pearlstein, R. D., & Warner, D. S. (1999) · Stroke · doi:10.1161/01.str.30.5.1118 · Cited by 118 · see citing works
Marked regional differences of brain human apolipoprotein e expression in targeted replacement mice
Sullivan, P. M., Mace, B. E., Maeda, N., & Schmechel, D. E. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2003.10.011 · Cited by 113 · see citing works
Self-citationApolipoprotein E Expression by Neurons Surviving Excitotoxic Stress
Boschert, U., Merlo‐Pich, E., Higgins, G. A., Roses, A. D., & Catsicas, S. (1999) · Neurobiology of Disease · doi:10.1006/nbdi.1999.0251 · Cited by 110 · see citing works
Self-citationApolipoprotein E and Alzheimer disease
Huang, Y. (2006) · Neurology · doi:10.1212/01.wnl.0000192102.41141.9e · Cited by 106 · see citing works
Sabo, T., Lomnitski, L., Nyska, A., Beni, S., Maronpot, R. R., Shohami, E., Roses, A. D., & Michaelson, D. M. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00438-3 · Cited by 104 · see citing works
Self-citationKeene, C. D., Cudaback, E., Li, X., Montine, K. S., & Montine, T. J. (2011) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2011.08.002 · Cited by 103 · see citing works
Dolev, I., & Michaelson, D. M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404458101 · Cited by 102 · see citing works
Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice
Hamanaka, H. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.3.353 · Cited by 96 · see citing works
“(44) introduced large segments of human”
Levi, O., & Michaelson, D. M. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04189.x · Cited by 94 · see citing works
Teter, B., Xu, P. ‐., Gilbert, J. R., Roses, A. D., Galasko, D., & Cole, G. M. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0732613.x · Cited by 88 · see citing works
“Human ApoE3 and ApoE4 (driven by the human ApoE promoter) transgenic mice were made in the ApoE-ko background (Xu et al., 1996).”
Self-citationApolipoprotein E, a Gene with Complex Biological Interactions in the Aging Brain
Roses, A. D. (1997) · Neurobiology of Disease · doi:10.1006/nbdi.1997.0161 · Cited by 87 · see citing works
Self-citationMahley, R. W., & Huang, Y. (2006) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.2006.00679.x · Cited by 82 · see citing works
Mechanisms linking apolipoprotein E isoforms with cardiovascular and neurological diseases.
Huang, Y. (2010) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e32833af368 · Cited by 82 · see citing works
Xu, Q., Brecht, W. J., Weisgraber, K. H., Mahley, R. W., & Huang, Y. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311256200 · Cited by 80 · see citing works
Apolipoprotein E and ALzheimer's Disease: The Tip of the Susceptibility Iceberg
Roses, A. D. (1998) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1998.tb10653.x · Cited by 78 · see citing works
Self-citationStranahan, A. M., Martin, B., & Maudsley, S. R. (2012) · Current Alzheimer Research · doi:10.2174/156720512799015019 · Cited by 78 · see citing works
APOE and Alzheimer’s Disease: Neuroimaging of Metabolic and Cerebrovascular Dysfunction
Brandon, J. A., Farmer, B. C., Williams, H. C., & Johnson, L. A. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00180 · Cited by 75 · see citing works
Defective neuronal sprouting by human apolipoprotein E4 is a gain-of-negative function.
Teter, B., Xu, P., Gilbert, J. R., Roses, A. D., Galasko, D., & Cole, G. M. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10221 · Cited by 74 · see citing works
“Results presented here use human APOE- 3 and APOE- 4 transgenics that express apoE in vivo with cellular specificity like that seen in humans (Xu et al., 1996, 1998, 1999) and, therefore, in a physiologically relevant lipidation state.”
Self-citationApoE, Alzheimer's Disease, and Recovery from Brain Stressa
Roses, A. D., & Saunders, A. M. (1997) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1997.tb48471.x · Cited by 72 · see citing works
Self-citationAβ42 neurotoxicity in primary co-cultures: effect of apoE isoform and Aβ conformation
Manelli, A. M., Bulfinch, L. C., Sullivan, P. M., & LaDu, M. J. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.05.024 · Cited by 72 · see citing works
Self-citationEpigenetic signature and enhancer activity of the human APOE gene
Yu, C., Cudaback, E., Foraker, J. E., Thomson, Z., Leong, L., Lutz, F., Gill, J. A., Saxton, A. D., Kraemer, B. C., Navas, P. A., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt354 · Cited by 70 · see citing works
Sex steroids, APOE genotype and the innate immune system
Colton, C. A., Brown, C. M., & Vitek, M. P. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.08.001 · Cited by 71 · see citing works
4‐Hydroxynonenal Immunoreactivity is Increased in Human Hippocampus After Global Ischemia
McCracken, E., Graham, D. I., Nilsen, M., Stewart, J., Nicoll, J. A. R., & Horsburgh, K. J. (2001) · Brain Pathology · doi:10.1111/j.1750-3639.2001.tb00409.x · Cited by 68 · see citing works
Apolipoprotein E and the Response of the Brain to Injury
Graham, D. I., Horsburgh, K. J., Nicoll, J. A. R., & Teasdale, G. M. (1999) · Acta neurochirurgica. Supplementum · doi:10.1007/978-3-7091-6391-7_15 · Cited by 66 · see citing works
Uncovering Disease Mechanisms in a Novel Mouse Model Expressing Humanized APOEε4 and Trem2*R47H
Kotredes, K. P., Oblak, A., Pandey, R. S., Lin, P. B.-C., Garceau, D., Williams, H., Uyar, A., O’Rourke, R., O’Rourke, S., Ingraham, C., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.735524 · Cited by 66 · see citing works
Horsburgh, K. J., McCulloch, J., Nilsen, M., Roses, A. D., & Nicoll, J. A. R. (2000) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2000.01339.x · Cited by 70 · see citing works
“APOE transgenic mice have been produced in which the endogenous mouse APOE gene has been deleted and replaced with human APOE alleles permitting human apoE isoform-speci®c differences to be elucidated (Xu et al., 1996).”
BackgroundMethodInfluentialSelf-citationCambon, K., Davies, H. A., & Stewart, M. G. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00065-8 · Cited by 63 · see citing works
Apolipoprotein E and Alzheimer's Disease: A Review of Recent Studies
Higgins, G. A., Large, C. H., Rupniak, H. T., & Barnes, J. C. (1997) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(96)00420-0 · Cited by 60 · see citing works
Apolipoprotein E-genotype dependent hippocampal and cortical responses to traumatic brain injury
Crawford, F., Wood, M., Ferguson, S., Mathura, V. S., Gupta, P., Humphrey, J., Mouzon, B., Laporte, V., Margenthaler, E., O'Steen, B. E., et al. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.01.033 · Cited by 58 · see citing works
Self-citationApolipoprotein E isoform‐dependent microglia migration
Cudaback, E., Li, X., Montine, K. S., Montine, T. J., & Keene, C. D. (2011) · The FASEB Journal · doi:10.1096/fj.10-176891 · Cited by 58 · see citing works
“Homozygous APOE ε2, APOE ε3, and APOE ε4 targeted replacement mice “humanized” at apoE were developed by Maeda and colleagues (54, 55).”
BackgroundRohn, T. T. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140714908 · Cited by 56 · see citing works
“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
Yin, J., Nielsen, M., Carcione, T., Li, S., & Shi, J. (2019) · Aging · doi:10.18632/aging.102516 · Cited by 53 · see citing works
Absence of central cholinergic deficits in ApoE knockout mice
Anderson, R., & Higgins, G. A. (1997) · Psychopharmacology · doi:10.1007/s002130050329 · Cited by 55 · see citing works
In Vivo Human Apolipoprotein E Isoform Fractional Turnover Rates in the CNS
Wildsmith, K. R., Basak, J. M., Patterson, B. W., Pyatkivskyy, Y., Kim, J., Yarasheski, K. E., Wang, J. X., Mawuenyega, K. G., Jiang, H., Parsadanian, M., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038013 · Cited by 54 · see citing works
“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].”
BackgroundApolipoprotein C-I is an APOE genotype-dependent suppressor of glial activation
Cudaback, E., Li, X., Yang, Y., Yoo, T. B., Montine, K. S., Craft, S., Montine, T. J., & Keene, C. D. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-192 · Cited by 53 · see citing works
“Maeda [31,32].”
In Vivo Chimeric Alzheimer’s Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons
Najm, R., Zalocusky, K. A., Zilberter, M., Yoon, S. Y., Hao, Y., Koutsodendris, N., Nelson, M., Rao, A., Taubes, A., Jones, E. A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107962 · Cited by 52 · see citing works
Neuronal nicotinic acetylcholine receptor expression by O2A/oligodendrocyte progenitor cells
Rogers, S. W., Gregori, N. Z., Carlson, N. G., Gahring, L. C., & Noble, M. (2001) · Glia · doi:10.1002/1098-1136(20010315)33:4 · Cited by 94 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
Self-citationEngstrom, A. K., Snyder, J. M., Maeda, N., & Xia, Z. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0155-2 · Cited by 50 · see citing works
“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 48 · see citing works
Huang, Y. (2011) · Biochemical Society Transactions · doi:10.1042/bst0390924 · Cited by 48 · see citing works
Zhang, L., Wang, H., Abel, G. M., Storm, D. R., & Xia, Z. (2019) · Toxicological Sciences · doi:10.1093/toxsci/kfz218 · Cited by 48 · see citing works
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 48 · see citing works
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 46 · see citing works
“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 · see citing works
“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 46 · see citing works
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 · see citing works
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 46 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 37 · see citing works
“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 · see citing works
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 46 · see citing works
- 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
- Health Sciences › Medicine › Physiology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
