Reduced levels of human apoE4 protein in an animal model of cognitive impairment
Abstract
The APOE4 allele is the most common genetic determinant for Alzheimer's disease (AD) in the developed world. APOE genotype specific differences in brain apolipoprotein E protein levels have been observed in numerous studies since the discovery of APOE4's link to AD. Since the human apoE4 targeted replacement mice display characteristics of cognitive impairment we sought to determine if reduced levels of apoE might provide one explanation for this impairment. We developed a novel mass spectrometry method to measure apoE protein levels in plasma. Additionally, we developed an ELISA that replicates the mass spectrometry data and enables the rapid quantitation of apoE in plasma, brain and cerebrospinal fluid. We detected a significant decrease in plasma, brain and cerebrospinal fluid apoE levels in the apoE4 mice compared to apoE2 and E3 mice. We also measured a small (∼19%) decrease in brain apoE levels from aged, non-demented APOE4 carriers. Our findings suggest that a fraction of APOE4-linked AD may be due to insufficient levels of functional apoE required to maintain neuronal health.
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The advantage of using N2a cells was that the transfected cells expressed comparable human ApoE, which enabled comparisons of the three ApoE isoforms in parallel and precluded compounding complexity resulting from differences in ApoE expression levels as reported in hApoE-TR mice.
“The advantage of using N2a cells was that the transfected cells expressed comparable human ApoE, which enabled the comparisons of the three ApoE isoforms in parallel and precluded compounding complexity resulting from the differences in ApoE expression levels as reported in the hApoE-TR mice (Riddell et al., 2008;Sullivan et al., 2011).”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Sullivan et al., 2011
Cites
Apolipoprotein E polymorphism and atherosclerosis.
Davignon, J., Gregg, R. E., & Sing, C. F. (1988) · Arteriosclerosis: An Official Journal of the American Heart Association, Inc. · doi:10.1161/01.atv.8.1.1 · Cited by 1,981 · see citing works
Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition
Bales, K. R., Verina, T., Dodel, R. C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnstone, E. M., Little, S. P., Cummins, D. J., et al. (1997) · Nature Genetics · doi:10.1038/ng1197-263 · Cited by 830 · 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-citationSynaptic and neuritic alterations during the progression of Alzheimer's disease
Masliah, E., Mallory, M., Hansen, L., Richard, D., Alford, M., & Terry, R. (1994) · Neuroscience Letters · doi:10.1016/0304-3940(94)90121-x · Cited by 370 · see citing works
Abnormal in vivo metabolism of apolipoprotein E4 in humans.
Gregg, R. E., Zech, L. A., Schaefer, E. J., Stark, D., Wilson, D., & Brewer, H. B. (1986) · Journal of Clinical Investigation · doi:10.1172/jci112645 · Cited by 345 · see citing works
Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels
Riddell, D. R., Zhou, H., Atchison, K., Warwick, H. K., Atkinson, P. J., Jefferson, J., Xu, L., Aschmies, S., Kirksey, Y., Hu, Y., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1972-08.2008 · Cited by 342 · see citing works
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-citationHirsch-Reinshagen, V., Maia, L. F., Burgess, B. L., Blain, J.-F., Naus, K. E., McIsaac, S. A., Parkinson, P. F., Chan, J. Y., Tansley, G. H., Hayden, M. R., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508781200 · Cited by 233 · see citing works
Apolipoprotein E4 Forms a Molten Globule
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
ApoE isoform-specific effects on LTP: blockade by oligomeric amyloid-β1–42
Trommer, B. L., Shah, C., Yun, S. H., Gamkrelidze, G., Pasternak, E. S., Blaine Stine, W., Manelli, A., Sullivan, P., Pasternak, J. F., & LaDu, M. J. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.08.011 · Cited by 82 · see citing works
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Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459 · see citing works
The Amyloid-β Pathway in Alzheimer’s Disease
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01249-0 · Cited by 1,952 · see citing works
Apolipoprotein E controls cerebrovascular integrity via cyclophilin A
Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., Holtzman, D. M., Betsholtz, C., Armulik, A., Sallstrom, J., et al. (2012) · Nature · doi:10.1038/nature11087 · Cited by 1,293 · see citing works
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
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
“Total apoE4 levels are lower compared with apoE2 and apoE3 in human plasma and cerebrospinal fluid for both AD patients (26–31) and age-matched controls (32), brain homogenates from AD patients (3, 33), brain homogenates from apoE-TR mice (3, 28, 34), and brain homogenates from apoETR/PDAPP-Tgmice (3).”
BackgroundApoE4 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
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
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
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
Wu, L., Zhang, X., & Zhao, L. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.2262-17.2018 · Cited by 185 · see citing works
Bien-Ly, N., Gillespie, A. K., Walker, D., Yoon, S. Y., & Huang, Y. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.0033-12.2012 · Cited by 170 · see citing works
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
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
APOE ε2 is associated with increased tau pathology in primary tauopathy
Zhao, N., Liu, C.-C., Van Ingelgom, A. J., Linares, C., Kurti, A., Knight, J. A., Heckman, M. G., Diehl, N. N., Shinohara, M., Martens, Y. A., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06783-0 · Cited by 139 · see citing works
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
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
Liraz, O., Boehm-Cagan, A., & Michaelson, D. M. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-16 · Cited by 118 · see citing works
Zhao, L., Gottesdiener, A. J., Parmar, M., Li, M., Kaminsky, S. M., Chiuchiolo, M. J., Sondhi, D., Sullivan, P. M., Holtzman, D. M., Crystal, R. G., et al. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.04.020 · Cited by 107 · see citing works
Self-citationThe Oxygen Paradox, the French Paradox, and age-related diseases
Davies, J. M. S., Cillard, J., Friguet, B., Cadenas, E., Cadet, J., Cayce, R., Fishmann, A., Liao, D., Bulteau, A.-L., Derbré, F., et al. (2017) · GeroScience · doi:10.1007/s11357-017-0002-y · Cited by 82 · see citing works
Introducing Human <i>APOE</i> into A<i>β</i> Transgenic Mouse Models
Tai, L. M., Youmans, K. L., Jungbauer, L., Yu, C., & LaDu, M. J. (2011) · International Journal of Alzheimer’s Disease · doi:10.4061/2011/810981 · Cited by 52 · see citing works
Chan, E. S., Shetty, M. S., Sajikumar, S., Chen, C., Soong, T. W., & Wong, B.-S. (2016) · Scientific Reports · doi:10.1038/srep26119 · Cited by 39 · see citing works
Extracellular Proteolysis of Apolipoprotein E (apoE) by Secreted Serine Neuronal Protease
Tamboli, I. Y., Heo, D., & Rebeck, G. W. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093120 · Cited by 35 · see citing works
ApoE expression across the CNS: Who, What, Where, When, and How (much)?
Nolt, G. L., Lucido, C. C., Smith, L. M., & Johnson, L. A. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00028-x · Cited by 2 · see citing works
- Authors
- Sullivan, P. M., Han, B., Liu, F., Mace, B. E., Ervin, J. F., Wu, S., Koger, D., Paul, S., & Bales, K. R.
- Affiliations
- Duke Medical Center (US)
- Eli Lilly (United States) (US)
- Corresponding author
- Sullivan, P.M.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 32
- Issue
- 5
- Pages
- 791-801
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2095013452
- Cited by
- 113
- References
- 10
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 7 · 2022: 7 · 2021: 4 · 2020: 7 · 2019: 8 · 2018: 6 · 2017: 6 · 2016: 13 · 2015: 8 · 2014: 12 · 2013: 8 · 2012: 8
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P50AG005128)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E, APOE ε4, Alzheimer's disease, cognitive impairment, APOE2, APOE3, neuronal health
- MeSH terms
- Aged, Alzheimer Disease, Amino Acid Sequence, Animals, Brain, Brain Chemistry, Cognition Disorders, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Mice, Transgenic, Molecular Sequence Data, Mass Spectrometry, Mice, Apolipoprotein E4
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