Targeted Replacement of the Mouse Apolipoprotein E Gene with the Common Human APOE3 Allele Enhances Diet-induced Hypercholesterolemia and Atherosclerosis

Sullivan, Patrick M.; Mezdour, Hafid; Aratani, Yasuaki; Knouff, Chris; Najib, Jamila; Reddick, Robert L.; Quarfordt, Steven H.; Maeda, Nobuyo

doi:10.1074/jbc.272.29.17972

Cited by 576Cholesterol and Lipid MetabolismLipoproteins and Cardiovascular HealthLipid metabolism and disorders

Targeted Replacement of the Mouse Apolipoprotein E Gene with the Common Human APOE3 Allele Enhances Diet-induced Hypercholesterolemia and Atherosclerosis

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Sullivan, Patrick M., Mezdour, Hafid, Aratani, Yasuaki, Knouff, Chris, Najib, Jamila, Reddick, Robert L., Quarfordt, Steven H., Maeda, Nobuyo·1997·Journal of Biological Chemistry

DOI 10.1074/jbc.272.29.17972

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Abstract

Apolipoprotein (apo) E, a constituent of several lipoproteins, is a ligand for the low density lipoprotein receptor, and this interaction is important for maintaining cholesterol and triglyceride homeostasis. We have used a gene replacement strategy to generate mice that express the human apoE3 isoform in place of the mouse protein. The levels of apoE mRNA in various tissues are virtually the same in the human apoE3 homozygous (3/3) mice and their littermates having the wild type mouse allele (+/+). Total cholesterol and triglyceride levels in fasted plasma from the 3/3 mice were not different from those in the +/+ mice, when maintained on a normal (low fat) chow diet. We found, however, notable differences in the distribution of plasma lipoproteins and apolipoprotein E between the two groups: beta-migrating lipoproteins and plasma apoB100 levels are decreased in the 3/3 mice, and the apoE distribution is shifted from high density lipoproteins to larger lipoprotein particles. In addition, the fractional catabolic rate of exogenously administered remnant particles without apoE was 6-fold slower in the 3/3 mice compared with the +/+ mice. When the 3/3 and +/+ animals were fed a high fat/high cholesterol diet, the 3/3 animals responded with a dramatic increase (5-fold) in total cholesterol compared with the +/+ mice (1.5-fold), and after 12 weeks on this same diet the 3/3 animals developed significantly (at least 13-fold) larger atherosclerotic plaques in the aortic sinus area t…

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APOE3/3 and APOE4/4 knock-in mice have the endogenous murine Apoe gene replaced with the human APOE3 or APOE4 gene.
“To determine the gene dosage effect of human APOE3 and APOE4 on amyloid deposition, we used knock-in mouse models in which the endogenous murine Apoe gene is replaced with the APOE3 or APOE4 gene.”
From Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis (2011) · cites this paper as Sullivan et al., 1997
APOE ε2-TR or APOE ε4-TR mice retain regulatory sequences of the mouse Apoe gene and the noncoding murine exon 1 surrounding the inserted human exons, and express human apoE protein at physiological levels.
“APOE ε2-TR or APOE ε4-TR mice retain regulatory sequences of the mouse Apoe gene and the noncoding murine exon 1 surrounding the inserted human exons 2′, 3′, and 4′ [17,18] and therefore, they express the human apoE protein at physiological levels.”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [18]
APOE targeted replacement mice express human APOE in place of their mouse Apoe gene and do not develop overt AD pathology.
“APOE targeted replacement mice, which express human APOE in place of their mouse Apoe gene and which do not develop overt AD pathology28,29”
From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [29]
APOE TR mice were previously generated by removing and replacing the endogenous mouse Apoe gene with the human APOE gene.
“These APOE TR mice were previously generated by removing and replacing the endogenous mouse Apoe gene with the human APOE gene 51,52 .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [51]

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The Role of APOE4 in Disrupting the Homeostatic Functions of Astrocytes and Microglia in Aging and Alzheimer’s Disease
Fernandez, C. G., Hamby, M. E., McReynolds, M. L., & Ray, W. J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00014 · Cited by 277 · see citing works
HumanAPOEIsoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice
Bales, K. R., Liu, F., Wu, S., Lin, S., Koger, D., DeLong, C., Hansen, J. C., Sullivan, P. M., & Paul, S. M. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.0887-09.2009 · Cited by 274 · see citing works
Self-citation
The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice
Joyce, C. W., Amar, M. J., Lambert, G. C., Vaisman, B. L., Paigen, B. J., Najib-Fruchart, J., Hoyt, R. F., Neufeld, E. D., Remaley, A. T., Fredrickson, D. S., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.012587699 · Cited by 269 · see citing works
APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease
Youmans, K. L., Tai, L. M., Nwabuisi-Heath, E., Jungbauer, L., Kanekiyo, T., Gan, M., Kim, J., Eimer, W. A., Estus, S., Rebeck, G. W., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.407957 · Cited by 259 · see citing works
“For example, crossing apoE-targeted replacement mice (apoE-TR) (9) with PDAPP mice (10) delays plaque deposition from 10 to 18 months, although once detected, plaque levels are greater with APOE4 than APOE3 (3).”
BackgroundMethod
Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2.
Sullivan, P. M., Mezdour, H., Quarfordt, S. H., & Maeda, N. (1998) · Journal of Clinical Investigation · doi:10.1172/jci2673 · Cited by 254 · see citing works
Self-citation
Chaperoning of Glucocorticoid Receptors
Pratt, W. B., Morishima, Y., Murphy, M. N., & Harrell, M. (2005) · Springer eBooks · doi:10.1007/3-540-29717-0_5 · Cited by 247 · see citing works
ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion in transgenic mice
Vaisman, B. L., Lambert, G. C., Amar, M. J., Joyce, C. W., Ito, T., Shamburek, R. D., Cain, W. J., Fruchart‐Najib, J., Neufeld, E. D., Remaley, A. T., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci12517 · Cited by 240 · see citing works
Alzheimer’s Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways
Zhao, N., Ren, Y., Yamazaki, Y., Qiao, W., Li, F., Felton, L. M., Mahmoudiandehkordi, S., Kueider-Paisley, A., Sonoustoun, B., Arnold, M., et al. (2020) · Neuron · doi:10.1016/j.neuron.2020.02.034 · Cited by 225 · see citing works
APOE genotype alters glial activation and loss of synaptic markers in mice
Zhu, Y., Nwabuisi‐Heath, E., Dumanis, S. B., Tai, L. M., Yu, C., Rebeck, G. W., & Ladu, M. J. (2012) · Glia · doi:10.1002/glia.22289 · Cited by 224 · see citing works
Cholesteryl Ester Transfer Protein Corrects Dysfunctional High Density Lipoproteins and Reduces Aortic Atherosclerosis in Lecithin Cholesterol Acyltransferase Transgenic Mice
Föger, B., Chase, M. B., Amar, M. J., Vaisman, B. L., Shamburek, R. D., Paigen, B. J., Fruchart‐Najib, J., Paiz, J. A., Koch, C. A., Hoyt, R. F., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.52.36912 · Cited by 224 · see citing works
ApoE4 Decreases Spine Density and Dendritic Complexity in Cortical NeuronsIn Vivo
Dumanis, S. B., Tesoriero, J. A., Babus, L. W., Nguyen, M. T., Trotter, J. H., Ladu, M. J., Weeber, E. J., Turner, R. S., Xu, B., Rebeck, G. W., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.4026-09.2009 · Cited by 220 · see citing works
Mouse Models of Atherosclerosis
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Glial fibrillary acidic protein-apolipoprotein E (apoE) transgenic mice: astrocyte-specific expression and differing biological effects of astrocyte-secreted apoE3 and apoE4 lipoproteins.
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 Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins
Huynh, T.-P. V., Davis, A. A., Ulrich, J. D., & Holtzman, D. M. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r075481 · Cited by 210 · see citing works
Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis
Huynh, T.-P. V., Liao, F., Francis, C. M., Robinson, G. O., Serrano, J. R., Jiang, H., Roh, J., Finn, M. B., Sullivan, P. M., Esparza, T. J., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.11.014 · Cited by 209 · see citing works
Self-citation
Gene delivery of human apolipoprotein E alters brain Aβ burden in a mouse model of Alzheimer's disease
Dodart, J.-C., Marr, R. A., Koistinaho, M., Gregersen, B. M., Malkani, S., Verma, I. M., & Paul, S. M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409072102 · Cited by 207 · see citing works
APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge
Lee, S., Devanney, N. A., Golden, L. R., Smith, C. T., Schwartz, J. L., Walsh, A. E., Clarke, H. A., Goulding, D. S., Allenger, E. J., Morillo-Segovia, G., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112196 · Cited by 203 · see citing works
APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints
Yin, Z., Rosenzweig, N., Kleemann, K. L., Zhang, X., Brandão, W., Margeta, M. A., Schroeder, C., Sivanathan, K. N., Silveira, S., Gauthier, C., et al. (2023) · Nature Immunology · doi:10.1038/s41590-023-01627-6 · Cited by 202 · see citing works
Structure, function, and mechanism of the Hsp90 molecular chaperone
Pearl, L. H., & Prodromou, C. (2001) · Advances in protein chemistry · doi:10.1016/s0065-3233(01)59005-1 · Cited by 199 · see citing works
Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis
Kim, J., Jiang, H., Park, S., Eltorai, A. E. M., Stewart, F. R., Yoon, H., Basak, J. M., Finn, M. B., & Holtzman, D. M. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.3773-11.2011 · Cited by 199 · see citing works
“Breeding pairs were gifts from Dr. Patrick Sullivan, Duke University, Durham, NC (Sullivan et al., 1997).”
Method
Electromagnetic Controlled Cortical Impact Device for Precise, Graded Experimental Traumatic Brain Injury
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
Introduction of human apolipoprotein E4 “domain interaction” into mouse apolipoprotein E
Raffaı̈, R. L., Dong, L., Farese, R. V., & Weisgraber, K. H. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.201279298 · Cited by 192 · see citing works
Multifaceted roles of APOE in Alzheimer disease
Jackson, R. J., Hyman, B. T., & Serrano-Pozo, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00988-2 · Cited by 193 · see citing works
Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition
Rodriguez, G. A., Tai, L. M., LaDu, M. J., & Rebeck, G. W. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-111 · Cited by 193 · see citing works
Cholesterol and breast cancer pathophysiology
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Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration
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Self-citation
APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β
Montagne, A., Nikolakopoulou, A. M., Huuskonen, M. T., Sagare, A. P., Lawson, E. J., Lazic, D., Rege, S. V., Grond, A., Zuniga, E., Barnes, S. R., et al. (2021) · Nature Aging · doi:10.1038/s43587-021-00073-z · Cited by 188 · see citing works
Alzheimer's Disease Genetic Risk Factor APOE-ε4 Also Affects Normal Brain Function
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On phagocytes and macular degeneration
Guillonneau, X., Eandi, C. M., Paques, M., Sahel, J.-A., Sapieha, P., & Sennlaub, F. (2017) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2017.06.002 · Cited by 185 · see citing works
Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology
Nuriel, T., Angulo, S. L., Khan, U., Ashok, A., Chen, Q., Figueroa, H. Y., Emrani, S., Liu, L., Herman, M., Barrett, G., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01444-0 · Cited by 181 · see citing works
Purification and characterization of astrocyte-secreted apolipoprotein E and J-containing lipoproteins from wild-type and human apoE transgenic mice
DeMattos, R. B., Brendza, R. P., Heuser, J. E., Kierson, M., Cirrito, J. R., Fryer, J., Sullivan, P. M., Fagan, A. M., Han, X., & Holtzman, D. M. (2001) · Neurochemistry International · doi:10.1016/s0197-0186(01)00049-3 · Cited by 180 · see citing works
Self-citation
Disruption of Arterial Perivascular Drainage of Amyloid-β from the Brains of Mice Expressing the Human APOE ε4 Allele
Hawkes, C. A., Sullivan, P. M., Hands, S. L., Weller, R. O., Nicoll, J. A. R., & Carare, R. O. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041636 · Cited by 177 · see citing works
Self-citation
APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function
Xiong, M., Jiang, H., Serrano, J. R., Gonzales, E. R., Wang, C., Gratuze, M., Hoyle, R., Bien-Ly, N., Silverman, A. P., Sullivan, P. M., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abd7522 · Cited by 179 · see citing works
Self-citation
Apoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function
Koizumi, K., Hattori, Y., Ahn, S. J., Buendia, I., Ciacciarelli, A., Uekawa, K., Wang, G., Hiller, A., Zhao, L., Voss, H. U., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06301-2 · Cited by 179 · see citing works
Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation
Liao, F., Li, A., Xiong, M., Bien-Ly, N., Jiang, H., Zhang, Y., Finn, M. B., Hoyle, R., Keyser, J., Lefton, K. B., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci96429 · Cited by 178 · see citing works
Self-citation
Genetic Modifiers of Atherosclerosis in Mice
Knowles, J. W., & Maeda, N. (2000) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.20.11.2336 · Cited by 171 · see citing works
Self-citation
Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease
Williams, T., Borchelt, D., & Chakrabarty, P. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-0358-9 · Cited by 166 · see citing works
<scp>APOE</scp>‐modulated Aβ‐induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective
Tai, L. M., Ghura, S., Koster, K. P., Liakaite, V., Maienschein‐Cline, M., Kanabar, P., Collins, N., Ben‐Aissa, M., Lei, A. Z., Bahroos, N., et al. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13072 · Cited by 165 · see citing works
ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes
Rawat, V., Wang, S., Sima, J., Bar, R., Liraz, O., Gundimeda, U., Parekh, T., Chan, J., Johansson, J. O., Tang, C., et al. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.1400-19.2019 · Cited by 165 · 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
Retinal ultrastructure of murine models of dry age-related macular degeneration (AMD)
Ramkumar, H. L., Zhang, J., & Chan, C.-C. (2010) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2010.02.002 · Cited by 163 · see citing works
Understanding hyperlipidemia and atherosclerosis: lessons from genetically modified apoe and ldlr mice
Wouters, K., Shiri-Sverdlov, R., van Gorp, P. J., van Bilsen, M., & Hofker, M. H. (2005) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2005.085 · Cited by 163 · see citing works
Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Aβ metabolism in apoE4-targeted replacement mice
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
Human Apolipoprotein E ε4 Expression Impairs Cerebral Vascularization and Blood—Brain Barrier Function in Mice
Alata, W., Ye, Y., St‐Amour, I., Vandal, M., & Calon, F. (2014) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.172 · Cited by 160 · see citing works
The role of APOE on lipid homeostasis and inflammation in normal brains
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Behavioral phenotyping of GFAP-ApoE3 and -ApoE4 transgenic mice: ApoE4 mice show profound working memory impairments in the absence of Alzheimer’s-like neuropathology.
Hartman, 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
APOE in the normal brain
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Human apoE targeted replacement mouse lines: h-apoE4 and h-apoE3 mice differ on spatial memory performance and avoidance behavior.
Grootendorst, J., Bour, A., Vogel, E., Kelche, C., Sullivan, P. M., Dodart, J.-C., Bales, K., & Mathis, C. (2005) · Behavioural Brain Research · doi:10.1016/j.bbr.2004.09.019 · Cited by 148 · see citing works
Self-citation
ole of apoE/Aβ Interactions in the Pathogenesis of Alzheimer's Disease and Cerebral Amyloid Angiopathy
Holtzman, D. M. (2001) · Journal of Molecular Neuroscience · doi:10.1385/jmn:17:2:147 · Cited by 143 · see citing works
Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks.
Bour, A., Grootendorst, J., Vogel, E., Kelche, C., Dodart, J.-C., Bales, K., Moreau, P.-H., Sullivan, P. M., & Mathis, C. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.05.008 · Cited by 141 · see citing works
Self-citation
The endosomal-lysosomal pathway is dysregulated by APOE4 expression in vivo
Nuriel, T., Peng, K. Y., Ashok, A., Dillman, A. A., Figueroa, H. Y., Apuzzo, J., Ambat, J., Levy, E., Cookson, M. R., Mathews, P. M., et al. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00702 · Cited by 140 · see citing works
Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model
Huynh, T.-P. V., Wang, C., Tran, A. C., Tabor, G. T., Mahan, T. E., Francis, C. M., Finn, M. B., Spellman, R., Manis, M., Tanzi, R. E., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0337-1 · Cited by 139 · see citing works
Effect of Apolipoprotein E on the Cerebral Load of Latent Herpes Simplex Virus Type 1 DNA
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The Low Density Lipoprotein Receptor Regulates the Level of CentralNervous System Human and Murine Apolipoprotein E but Does Not Modify AmyloidPlaque Pathology in PDAPPMice
Fryer, J. D., DeMattos, R. B., McCormick, L. M., O'Dell, M. A., Spinner, M. L., Bales, K. R., Paul, S. M., Sullivan, P. M., Parsadanian, M., Bu, G., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m502143200 · Cited by 139 · see citing works
Self-citation
Abca1 Deficiency Affects Alzheimer's Disease-Like Phenotype in Human ApoE4 But Not in ApoE3-Targeted Replacement Mice
Fitz, N. F., Cronican, A. A., Saleem, M., Fauq, A. H., Chapman, R., Lefterov, I. M., & Koldamova, R. P. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1937-12.2012 · Cited by 138 · see citing works
Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology.
Wang, C., Wilson, W. A., Moore, S. D., Mace, B. E., Maeda, N., Schmechel, D. E., & Sullivan, P. M. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.10.013 · Cited by 138 · see citing works
Self-citation
In Vivo Effects of ApoE and Clusterin on Amyloid-β Metabolism and Neuropathology
Holtzman, D. M. (2004) · Journal of Molecular Neuroscience · doi:10.1385/jmn:23:3:247 · Cited by 138 · see citing works
Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-β
Morikawa, M., Fryer, J. D., Sullivan, P. M., Christopher, E., Schindler, S. E., Demattos, R. B., Odell, M., Fagan, A. M., Lashuel, H. A., Walz, T., et al. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.11.005 · Cited by 136 · see citing works
Self-citation
Young APOE4 targeted replacement mice exhibit poor spatial learning and memory, with reduced dendritic spine density in the medial entorhinal cortexPreprint
Rodriguez, G. A., Burns, M. P., Weeber, E. J., & Rebeck, G. W. (2013) · Learning & Memory · doi:10.1101/lm.030031.112 · Cited by 134 · see citing works
Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene
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Apolipoprotein E modulates Alzheimer’s Aβ(1–42)-induced oxidative damage to synaptosomes in an allele-specific manner
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Self-citation
Apolipoprotein E Participates in the Regulation of Very Low Density Lipoprotein-Triglyceride Secretion by the Liver
Mensenkamp, A. R., Jong, M. C., van Goor, H., van Luyn, M. J. A., Bloks, V. W., Havinga, R., Voshol, P. J., Hofker, M. H., van Dijk, K. W., Havekes, L. M., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.50.35711 · Cited by 134 · see citing works
Analysis of Glomerulosclerosis and Atherosclerosis in Lecithin Cholesterol Acyltransferase-deficient Mice
Lambert, G. C., Sakai, N., Vaisman, B. L., Neufeld, E. B., Marteyn, B., Chan, C., Paigen, B. J., Lupia, E., Thomas, A., Striker, L. J., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008466200 · Cited by 131 · see citing works
Mouse models of angiogenesis, arterial stenosis, atherosclerosis and hemostasis
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Structural and functional coupling of Hsp90‐ and Sgt1‐centred multi‐protein complexes
Zhang, M., Botër, M., Li, K., Kadota, Y., Panaretou, B., Prodromou, C., Shirasu, K., & Pearl, L. H. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.190 · Cited by 125 · see citing works
ApoE isoform affects LTP in human targeted replacement mice
Trommer, B. L., Shah, C., Yun, S. H., Gamkrelidze, G., Pasternak, E. S., Ye, G. L., Sotak, M., Sullivan, P. M., Pasternak, J. F., & LaDu, M. J. (2004) · NeuroReport · doi:10.1097/00001756-200412030-00020 · Cited by 124 · see citing works
Self-citation
25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner
Wong, M. Y., Lewis, M., Doherty, J. J., Shi, Y., Cashikar, A. G., Amelianchik, A., Tymchuk, S., Sullivan, P. M., Qian, M., Covey, D. F., et al. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01869-3 · Cited by 121 · see citing works
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ApoE4 induces Aβ42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice
Liraz, O., Boehm-Cagan, A., & Michaelson, D. M. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-16 · Cited by 118 · see citing works
p23, a simple protein with complex activities
Felts, S. J., & Toft, D. O. (2003) · Cell Stress and Chaperones · doi:10.1379/1466-1268(2003)008 · Cited by 116 · see citing works
ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies
Boehm-Cagan, A., Bar, R., Liraz, O., Bielicki, J. K., Johansson, J. O., & Michaelson, D. M. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-160467 · Cited by 116 · see citing works
Genetic Restoration of Plasma ApoE Improves Cognition and Partially Restores Synaptic Defects in ApoE-Deficient Mice
Lane-Donovan, C., Wong, W. M., Durakoglugil, M. S., Wasser, C. R., Jiang, S., Xian, X., & Herz, J. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.1054-16.2016 · Cited by 115 · see citing works
HDL from an Alzheimer's disease perspective
Button, E. B., Robert, J., Caffrey, T. M., Fan, J., Zhao, W., & Wellington, C. L. (2019) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000604 · Cited by 114 · see citing works
Humanising the mouse genome piece by piece
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Reduced levels of human apoE4 protein in an animal model of cognitive impairment
Sullivan, P. M., Han, B., Liu, F., Mace, B. E., Ervin, J. F., Wu, S., Koger, D., Paul, S., & Bales, K. R. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.05.011 · Cited by 113 · see citing works
Self-citation
Neurotoxicity from innate immune response is greatest with targeted replacement of ε4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK
Maezawa, I., Nivison, M. P., Montine, K. S., Maeda, N., & Montine, T. J. (2006) · The FASEB Journal · doi:10.1096/fj.05-5423fje · Cited by 113 · see citing works
Self-citation
Reduction in DHA transport to the brain of mice expressing human APOE 4 compared to APOE 2
Vandal, M., Alata, W., Tremblay, C., Rioux‐Perreault, C., Salem, N., Calon, F., & Plourde, M. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12640 · Cited by 109 · see citing works
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Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2.
Sullivan, P. M., Mezdour, H., Quarfordt, S. H., & Maeda, N. (1998) · Journal of Clinical Investigation · doi:10.1172/jci2673 · Cited by 254 · see citing works
Self-citation
Diet-induced hypercholesterolemia and atherosclerosis in heterozygous apolipoprotein E-deficient mice
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Treatment of severe hypercholesterolemia in apolipoprotein E-deficient mice by intramuscular injection of plasmid DNA
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Authors: Sullivan, P. M., Mezdour, H., Aratani, Y., Knouff, C., Najib, J., Reddick, R. L., Quarfordt, S. H., & Maeda, N.
Affiliations: University of North Carolina at Chapel Hill (US)
Duke Medical Center (US)
Corresponding author: Maeda, Nobuyo
ORCID: Sullivan, Patrick M.
Aratani, Yasuaki
Maeda, Nobuyo
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1997-07
Volume: 272
Issue: 29
Pages: 17972-17980
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.272.29.17972
OpenAlex: W2011885704
Cited by: 575
References: 48
Citations by year: 2026: 17 · 2025: 26 · 2024: 25 · 2023: 39 · 2022: 28 · 2021: 32 · 2020: 31 · 2019: 21 · 2018: 12 · 2017: 20 · 2016: 27 · 2015: 22 · 2014: 29 · 2013: 21 · 2012: 29
FWCI: 15.71
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 8499 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
UNC Libraries
Funders: National Heart, Lung, and Blood Institute (HL 42630)
Topics: Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords: apolipoprotein E, APOE3, gene replacement, transgenic mice, hypercholesterolemia, atherosclerosis, serum lipoproteins, apolipoprotein B-100, high-fat diet, LDL receptor, cholesterol homeostasis, aortic plaque
MeSH terms: Alleles, Animals, Apolipoproteins E, Arteriosclerosis, Cholesterol, Diet, Atherogenic, Female, Homozygote, Humans, Hypercholesterolemia, Cholesterol, HDL, Male, Mice, Transgenic, Stem Cells, Triglycerides, Restriction Mapping, Mice, Apolipoprotein E3

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Targeted Replacement of the Mouse Apolipoprotein E Gene with the Common Human APOE3 Allele Enhances Diet-induced Hypercholesterolemia and Atherosclerosis

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