Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth
Open accessAbstract
Previously, we demonstrated in cultured dorsal root ganglion neurons that, in the presence of beta-migrating very low density lipoproteins (beta-VLDL), apolipoprotein (apo) E4, but not apoE3, suppresses neurite outgrowth. In the current studies, murine neuroblastoma cells (Neuro-2a) were stably transfected with human apoE3 or apoE4 cDNA, and the effect on neurite outgrowth was examined. The stably transfected cells secreted nanogram quantities of apoE (44-89 ng/mg of cell protein in 48 h). In the absence of lipoproteins, neurite outgrowth was similar in the apoE3- and apoE4-secreting cells. The apoE4-secreting cells, when incubated with beta-VLDL, VLDL, cerebrospinal fluid lipoproteins (d < 1.21 g/ml), or with triglyceride/phospholipid (2.7:1 (w/w)) emulsions, showed a reduction in the number of neurites/cell, a decrease in neurite branching, and an inhibition of neurite extension, whereas in the apoE3-secreting cells in the presence of a lipid source, neurite extension was increased. Uptake of beta-VLDL occurred to a similar extent in both the apoE3- and apoE4-secreting cells. With low density lipoproteins or with dimyristoylphosphatidylcholine emulsions, either alone or complexed with cholesterol, no differential effect on neurite outgrowth was observed. A slight differential effect was observed with apoE-containing high density lipoproteins. The differential effect of apoE3 and apoE4 in the presence of beta-VLDL was blocked by incubation of the cells with heparinase and chlorate, with lactoferrin, or with receptor-associated protein, all of which prevent the uptake of lipoproteins by the low density lipoprotein receptor-related protein (LRP). The data suggest that the secreted and/or cell surface-bound apoE interact with the lipoproteins and facilitate their internalization via the heparan sulfate proteoglycan-LRP pathway. The mechanism by which apoE3 and apoE4 exert differential effects on neurite outgrowth remains speculative. However, the data suggest that apoE4, which has been shown to be associated with late onset familial and sporadic Alzheimer's disease, may inhibit neuronal remodeling and contribute to the progression of the disease.
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Most studies have shown that apoE3 augments neurite outgrowth to a greater extent than apoE4.
“Most studies have shown that apoE3 augments neurite outgrowth to a greater extent than apoE4 (Bellosta et al., 1995; Nathan et al., 1994; Nathan et al., 2002; Sun et al., 1998; Teter et al., 1999).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Bellosta et al., 1995
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Cites
Apolipoprotein E: Structure-Function Relationships
Weisgraber, K. H. (1994) · Advances in Protein Chemistry · doi:10.1016/s0065-3233(08)60642-7 · Cited by 830 · see citing works
Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins
Pitas, R. E., Boyles, J. K., Lee, S. H., Foss, D., & Mahley, R. W. (1987) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(87)90295-5 · Cited by 693 · see citing works
Self-citationPhenotypes of apolipoprotein B and apolipoprotein E after liver transplantation.
Linton, M. F., Gish, R., Hubl, S. T., Bütler, E., Esquivel, C., Bry, W. I., Boyles, J. K., Wardell, M. R., & Young, S. G. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115288 · Cited by 367 · see citing works
The receptor-binding domain of human apolipoprotein E. Binding of apolipoprotein E fragments.
Innerarity, T. L., Friedlander, E. J., Rall, S. C., Weisgraber, K. H., & Mahley, R. W. (1983) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)44180-9 · Cited by 276 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 10
- Elshourbagy, N. A., Liao, W. S., Mahley, R. W., and Taylor, J. M. (1985) Proc. Natl. Acad. Sci. U. S. A. 82, 203-207
- Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., and Roses, A. D. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 1977-1981
- Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., and Pericak-Vance, M. A. (1993) Science 261, 921-923
- Saunders, A. M., Strittmatter, W. J., Schmechel, D., St. George-Hyslop, P. H., Pericak-Vance, M. A., Joo, S. H., Rosi, B. L., Gusella, J. F., Crapper- MacLachlan, D. R., Alberts, M. J., Hulette, C., Crain, B., Goldgaber, D., and Roses, A. D. (1993) Neurology 43, 1467-1472
- Kowal, R. C., Herz, J., Goldstein, J. L., Esser, V., and Brown, M. S. (1989) Proc. Natl. Acad. Sci. U. S. A. 86, 5810 -5814
- Roheim, P. S., Carey, M., Forte, T., and Vega, G. L. (1979) Proc. Natl. Acad. Sci. U. S. A. 76, 4646 -4649
- Holtzman, D. M., Pitas, R. E., Kilbridge, J., Nathan, B., Mahley, R. W., Bu, G., and Schwartz, A. L. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 9480 -9484
- Huang, D. Y., Goedert, M., Jakes, R., Weisgraber, K. H., Garner, C. C., Saunders, A. M., Pericak-Vance, M. A., Schmechel, D. E., Roses, A. D., and Strittmatter, W. J. (1994) Neurosci. Lett. 182, 55-58
- Strittmatter, W. J., Weisgraber, K. H., Goedert, M., Saunders, A. M., Huang, D., Corder, E. H., Dong, L.-M., Jakes, R., Alberts, M. J., Gilbert, J. R., Han, S.-H., Hulette, C., Einstein, G., Schmechel, D. E., Pericak-Vance, M. A., and Roses, A. D. (1994) Exp. Neurol. 125, 163-171
- Han, S.-H., Einstein, G., Weisgraber, K. H., Strittmatter, W. J., Saunders, A. M., Pericak-Vance, M., Roses, A. D., and Schmechel, D. E. (1994) J. Neu- ropathol. Exp. Neurol. 53, 535-544
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Apolipoprotein E: Far More Than a Lipid Transport Protein
Mahley, R. W., & Rall, S. C. (2000) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.1.1.507 · Cited by 1,836 · see citing works
Self-citationMasters, C. L., Bateman, R., Blennow, K., Rowe, C. C., Sperling, R. A., & Cummings, J. L. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.56 · Cited by 1,853 · see citing works
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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
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
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Huang, Y., & Mahley, R. W. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.025 · Cited by 829 · see citing works
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Mahley, R. W., & Huang, Y. (2012) · Neuron · doi:10.1016/j.neuron.2012.11.020 · Cited by 412 · see citing works
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Self-citationRaber, 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
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Graham, D. I., McIntosh, T. K., Maxwell, W. L., & Nicoll, J. A. R. (2000) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/59.8.641 · Cited by 328 · see citing works
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Koffie, R. M., Hashimoto, T., Tai, H.-C., Kay, K. R., Serrano-Pozo, A., Joyner, D., Hou, S., Kopeikina, K. J., Frosch, M. P., Lee, V. M., et al. (2012) · Brain · doi:10.1093/brain/aws127 · Cited by 327 · see citing works
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Dong, L.-M., & Weisgraber, K. H. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.32.19053 · Cited by 318 · see citing works
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Huang, 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
Self-citationApoE4 Decreases Spine Density and Dendritic Complexity in Cortical Neurons<i>In Vivo</i>
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
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
Downregulation of microglial activation by apolipoprotein E and apoE-mimetic peptides
Laskowitz, D. T., Thekdi, A. D., Thekdi, S. D., Han, S. K. D., Myers, J. K., Pizzo, S. V., & Bennett, E. R. (2001) · Experimental Neurology · doi:10.1006/exnr.2001.7541 · Cited by 206 · see citing works
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Morrow, J. A., Hatters, D. M., Lu, B., Höchtl, P., Oberg, K. A., Rupp, B., & Weisgraber, K. H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204898200 · Cited by 204 · 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
Ji, Y., Gong, Y., Gan, W., Beach, T., Holtzman, D. M., & Wisniewski, T. (2003) · Neuroscience · doi:10.1016/j.neuroscience.2003.08.007 · Cited by 189 · see citing works
Ji, Z.-S., Miranda, R. D., Newhouse, Y. M., Weisgraber, K. H., Huang, Y., & Mahley, R. W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112109200 · Cited by 177 · see citing works
Self-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
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
Harris, F. M., Brecht, W. J., Xu, Q., Mahley, R. W., & Huang, Y. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408127200 · Cited by 151 · see citing works
Self-citationJi, Z.-S., Pitas, R. E., & Mahley, R. W. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.22.13452 · Cited by 134 · see citing works
Self-citationWhite, 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
DeMattos, R. B., Curtiss, L. K., & Williams, D. L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.7.4206 · Cited by 123 · see citing works
Fagan, A. M., Murphy, B. A., Patel, S. N., Kilbridge, J. F., Mobley, W. C., Bu, G., & Holtzman, D. M. (1998) · Experimental Neurology · doi:10.1006/exnr.1998.6818 · Cited by 116 · see citing works
New Insights into the Heparan Sulfate Proteoglycan-binding Activity of Apolipoprotein E
Libeu, C. P., Lund-Katz, S., Phillips, M. C., Wehrli, S., Hernáiz, M. J., Capila, I., Linhardt, R. J., Raffaı̈, R. L., Newhouse, Y. M., Zhou, F., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104746200 · Cited by 113 · see citing works
Inhibition of the canonical Wnt signaling pathway by apolipoprotein E4 in PC12 cells
Caruso, A., Motolese, M., Iacovelli, L., Caraci, F., Copani, A., Nicoletti, F., Terstappen, G. C., Gaviraghi, G., & Caricasole, A. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03867.x · Cited by 101 · see citing works
Apolipoprotein E and Alzheimer's disease: the protective effects of ApoE2 and E3
Rebeck, G. W., Kindy, M., & LaDu, M. J. (2002) · Journal of Alzheimer's Disease · doi:10.3233/jad-2002-4304 · Cited by 89 · 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
Apolipoprotein E as a β-amyloid-independent factor in Alzheimer’s disease
Wolf, A. B., Valla, J., Bu, G., Kim, J., LaDu, M., Reiman, E. M., & Caselli, R. J. (2013) · Alzheimer's Research & Therapy · doi:10.1186/alzrt204 · Cited by 55 · see citing works
Apolipoprotein E decreases tau kinases and phospho-tau levels in primary neurons.
Hoe, H.-S., Freeman, J., & Rebeck, G. W. (2006) · Molecular Neurodegeneration · doi:10.1186/1750-1326-1-18 · Cited by 45 · see citing works
The presence of apoE4, not the absence of apoE3, contributes to AD pathology
Teter, B., Raber, J., Nathan, B., & Crutcher, K. A. (2002) · Journal of Alzheimer's Disease · doi:10.3233/jad-2002-4305 · Cited by 37 · see citing works
Self-citationMarques, M. A., Owens, P. A., & Crutcher, K. A. (2004) · Journal of Molecular Neuroscience · doi:10.1385/jmn:24:1:073 · Cited by 29 · see citing works
- Authors
- Bellosta, S., Nathan, B. P., Orth, M., Dong, L.-M., Mahley, R. W., & Pitas, R. E.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Pitas, Robert E.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1995-11
- Volume
- 270
- Issue
- 45
- Pages
- 27063-27071
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2060352042
- Cited by
- 313
- References
- 4
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 3 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 7 · 2017: 5 · 2016: 6 · 2015: 7 · 2014: 4 · 2013: 8 · 2012: 10
- FWCI
- 11.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- The Keep (Eastern Illinois University) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG013619, AG13619)
- National Heart, Lung, and Blood Institute (HL-41633, P01HL041633)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E3, APOE ε4, neurite outgrowth, neuroblastoma cells, beta-VLDL, lipoprotein uptake, low density lipoprotein receptor-related protein, heparan sulfate proteoglycans, receptor-associated protein, high-density lipoprotein, lipoprotein internalization
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Humans, Lipoproteins, VLDL, Liposomes, Neuroblastoma, Rabbits, Transfection, Tumor Cells, Cultured, Gene Expression, Neurites, DNA, Complementary, Mice, Apolipoprotein E3, Apolipoprotein E4
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