Apolipoprotein E associates with beta amyloid peptide of Alzheimer's disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3
Open accessAbstract
Late-onset and sporadic Alzheimer's disease are associated with the apolipoprotein E (apoE) type 4 allele expressing the protein isoform apoE4. Apolipoprotein E binds avidly to beta amyloid (A beta) peptide, a major component of senile plaque of Alzheimer's disease, in an isoform-specific manner. The apoE4 isoform binds to A beta peptide more rapidly than apoE3. We observed that soluble SDS-stable complexes of apoE3 or apoE4, formed by coincubation with A beta peptide, precipitated after several days of incubation at 37 degrees C with apoE4 complexes precipitating more rapidly than apoE3 complexes. A beta(1-28) and A beta(1-40) peptides were incubated in the presence or absence of apoE3, apoE4, or bovine serum albumin for 4 d at 37 degrees C (pH 7.3). Negative stain electron microscopy revealed that the A beta peptide alone self-assembled into twisted ribbons containing two or three strands but occasionally into multistranded sheets. The apoE/A beta coincubates yielded monofibrils 7 nm in diameter. ApoE4/A beta coincubates yielded a denser matrix of monofibrils than apoE3/A beta coincubates. Unlike purely monofibrillar apoE4/A beta coincubates, apoE3/A beta coincubates also contained double- and triple-stranded structures. Both apoE isoforms were shown by immunogold labeling to be uniformly distributed along the A beta peptide monofibrils. Monofibrils appeared earlier in apoE4/A beta than in apoE3/A beta in time-course experiments. Thus apoE3 and apoE4 each interact with beta amyloid peptide to form novel monofibrillar structures, apoE4 more avidly, a finding consistent with the biochemical and genetic association between apoE4 and Alzheimer's disease.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Lipid-free apoE formed SDS-stable complexes with Aβ, and apoE4 bound to Aβ more rapidly than apoE3.
“Initially, it was demonstrated that lipid-free apoE formed SDS-stable complexes with Aβ, and that apoE4 bound to Aβ more rapidly than apoE3 (Sanan et al., 1994; Strittmatter et al., 1993b).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Sanan et al., 1994
The Introduction states that apoE forms complexes with Aβ that resist heating in SDS and that apoE4 binds more rapidly than apoE3; the Results also describe SDS-stable apoE–Aβ complexes. The Methods describe purified apoE incubated with Aβ in buffer, but our copy does not explicitly establish that the apoE was lipid-free. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Assembly and aggregation properties of synthetic Alzheimer's A4/beta amyloid peptide analogs.
Burdick, D., Soreghan, B., Kwon, M., Kosmoski, J., Knauer, M., Henschen, A., Yates, J., Cotman, C., & Glabe, C. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)48529-8 · Cited by 1,014 · 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-citation
Flagged first, then by citations
Research works printed but not linked: 7
- Strittmatter, W. J., A. M. Saunders, D. Schmechel, M. Pericak-Vance, J. Enghild, G. S. Salvesen, and A. D. Roses. 1993. Apolipoprotein E: high avidity binding to ,/-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer's disease. Proc. Nati. Acad. Sci. USA. 90:1977-1981.
- Ignatius, M. J., P. J. Gebicke-Harter, J. H. P. Skene, J. W. Schilling, K. H. Weisgraber, R. W. Mahley, and E. M. Shooter. 1986. Expression of apolipoprotein E during nerve degeneration and regeneration. Proc. Natl. Acad. Sci. USA. 83:1125-1129.
- Snipes, G. J., C. B. McGuire, J. J. Norden, and J. A. Freeman. 1986. Nerve injury stimulates the secretion of apolipoprotein E by nonneuronal cells. Proc. Natl. Acad. Sci. USA. 83:1130-1134.
- Saunders, A. M., W. J. Strittmatter, D. Schmechel, P. H. St. George- Hyslop, M. A. Pericak-Vance, S. H. Joo, B. L. Rosi, J. F. Gusella, D. R. Crapper- MacLachlan, M. J. Alberts, C. Hulette, B. Crain, D. Goldgaber, and A. D. Roses. 1993. Association of apolipoprotein E allele e4 with late-onset familial and spo- radic Alzheimer's disease. Neurology. 43:1467-1472.
- Corder, E. H., A. M. Saunders, W. J. Strittmatter, D. E. Schmechel, P. C. Gaskell, G. W. Small, A. D. Roses, J. L. Haines, and M. A. Pericak-Vance. 1993. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science (Wash. DC). 261:921-923. 868 Sanan et al. 19. Schmechel, D. E., A. M. Saunders, W. J. Strittmatter, B. J. Crain, C. M. Hulette, S. H. Joo, M. A. Pericak-Vance, D. Goldgaber, and A. D. Roses. 1993. Increased amyloid P-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer's disease. Proc. Nadl. Acad. Sci. USA. 90:9649-9653.
- Strittmatter, W. J., K. H. Weisgraber, D. Y. Huang, L.-M. Dong, G. S. Salvesen, M. Pericak-Vance, D. Schmechel, A. M. Saunders, D. Goldgaber, and A. D. Roses. 1993. Binding of human apolipoprotein E to synthetic amyloid /3 peptide: isoform-specific effects and implications for late-onset Alzheimer's dis- ease. Proc. Nadl. Acad. Sci. USA. 90:8098-8102.
- Kirschner, D. A., H. Inouye, L. K. Duffy, A. Sinclair, M. Lind, and D. J. Selkoe. 1987. Synthetic peptide homologous to /3 protein from Alzheimer's dis- ease forms amyloid-like fibrils in vitro. Proc. Nati. Acad Sci. USA. 84:6953- 6957.
Cited by
Sorted by citations
Inflammation and Alzheimer’s disease
Akiyama, H. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00124-x · Cited by 4,514 · see citing works
Blood-Brain Barrier: From Physiology to Disease and Back
Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,294 · see citing works
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-citationThe 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
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
Self-citationMa, J., Yee, A., Brewer, H. B., Das, S., & Potter, H. (1994) · Nature · doi:10.1038/372092a0 · Cited by 871 · see citing works
Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease
Holtzman, D. M., Herz, J., & Bu, G. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006312 · Cited by 782 · see citing works
Verghese, P. B., Castellano, J. M., Garai, K., Wang, Y., Jiang, H., Shah, A., Bu, G., Frieden, C., & Holtzman, D. M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220484110 · Cited by 556 · see citing works
Xu, 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
Self-citationAlzheimer’s Disease Genetics: From the Bench to the Clinic
Karch, C. M., Cruchaga, C., & Goate, A. M. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.041 · Cited by 473 · see citing works
Apolipoprotein e sets the stage: response to injury triggers neuropathology
Mahley, R. W., & Huang, Y. (2012) · Neuron · doi:10.1016/j.neuron.2012.11.020 · Cited by 412 · see citing works
Self-citationHuang, Y., Liu, X. Q., Wyss-Coray, T., Brecht, W. J., Sanan, D. A., & Mahley, R. W. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.151254698 · Cited by 392 · see citing works
Self-citationHoltzman, D. M., Bales, K. R., Wu, S., Bhat, P., Parsadanian, M., Fagan, A. M., Chang, L. K., Sun, Y., & Paul, S. M. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6179 · Cited by 349 · see citing works
Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases
Vance, J. E. (2012) · Disease Models & Mechanisms · doi:10.1242/dmm.010124 · Cited by 342 · see citing works
A4POE*4-associated Alzheimer's disease risk is modified by α1–antichymotrypsin polymorphism
Kamboh, M. I., Sanghera, D. K., Ferrell, R. E., & DeKosky, S. T. (1995) · Nature Genetics · doi:10.1038/ng0895-486 · Cited by 336 · see citing works
Human Apolipoprotein E4 Domain Interaction
Dong, L.-M., & Weisgraber, K. H. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.32.19053 · Cited by 318 · see citing works
Self-citationPIB is a non-specific imaging marker of amyloid-beta (A ) peptide-related cerebral amyloidosis
Lockhart, A., Lamb, J. R., Osredkar, T., Sue, L. I., Joyce, J. N., Ye, L., Libri, V., Leppert, D., & Beach, T. G. (2007) · Brain · doi:10.1093/brain/awm191 · Cited by 302 · see citing works
Rogers, J. T., Leiter, L. M., McPhee, J., Cahill, C. M., Zhan, S.-S., Potter, H., & Nilsson, L. N. G. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.10.6421 · Cited by 290 · see citing works
Ye, S., Huang, Y., Müllendorff, K., Dong, L., Giedt, G., Meng, E. C., Cohen, F. E., Kuntz, I. D., Weisgraber, K. H., & Mahley, R. W. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508693102 · Cited by 275 · see citing works
Self-citationNagy, Z. S., Esiri, M. M., Jobst, K. A., Johnston, C., Litchfield, S., Sim, E., & Smith, A. D. (1995) · Neuroscience · doi:10.1016/0306-4522(95)00331-c · Cited by 250 · see citing works
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-citationLing, Y., Morgan, K., & Kalsheker, N. (2003) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(03)00133-x · Cited by 224 · see citing works
Fagan, A. M., Holtzman, D. M., Munson, G., Mathur, T., Schneider, D., Chang, L. K., Getz, G. S., Reardon, C. A., Lukens, J., Shah, J. A., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.42.30001 · Cited by 222 · see citing works
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
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
Self-citationDodart, 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
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-citationJi, 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
Self-citationDeMattos, 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
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-citationBien-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
Martínez-Morillo, E., Hansson, O., Atagi, Y., Bu, G., Minthon, L., Diamandis, E. P., & Nielsen, H. M. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1266-2 · Cited by 168 · 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
Understanding the association of apolipoprotein E4 with Alzheimer disease: clues from its structure
Zhong, N., & Weisgraber, K. H. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.r800009200 · Cited by 159 · see citing works
Self-citationOverlap between neurodegenerative disorders
Armstrong, R. A., Lantos, P. L., & Cairns, N. J. (2005) · Neuropathology · doi:10.1111/j.1440-1789.2005.00605.x · Cited by 146 · see citing works
Nilsson, L. N. G., Bales, K. R., DiCarlo, G., Gordon, M. N., Morgan, D., Paul, S. M., & Potter, H. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-05-01444.2001 · Cited by 137 · see citing works
APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction
Soto, I., Graham, L. C., Richter, H. J., Simeone, S. N., Radell, J. E., Grabowska, W., Funkhouser, W. K., Howell, M. C., & Howell, G. R. (2015) · PLOS Biology · doi:10.1371/journal.pbio.1002279 · Cited by 140 · see citing works
Amino-terminal domain stability mediates apolipoprotein E aggregation into neurotoxic fibrils
Hatters, D. M., Zhong, N., Rutenber, E., & Weisgraber, K. H. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.06.080 · Cited by 105 · see citing works
Self-citationApolipoprotein 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
The generation and function of soluble apoE receptors in the CNS
Rebeck, G. W., LaDu, M. J., Estus, S., Bu, G., & Weeber, E. J. (2006) · Molecular Neurodegeneration · doi:10.1186/1750-1326-1-15 · Cited by 66 · see citing works
Han, S.-H., Park, J.-C., & Mook-Jung, I. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.12.004 · Cited by 67 · see citing works
A subset of senile dementia with high incidence of the apolipoprotein E ϵ2 allele
Ikeda, K., Akiyama, H., Arai, T., Sahara, N., Mori, H., Usami, M., Sakata, M., Mizutani, T., Wakabayashi, K., & Takahashi, H. (1997) · Annals of Neurology · doi:10.1002/ana.410410522 · Cited by 55 · see citing works
Xu, Z., Shen, X., Pan, W., & Initiative, F. T. A. D. N. (2014) · PLoS ONE · doi:10.1371/journal.pone.0102312 · Cited by 51 · see citing works
Ayton, S., & Bush, A. I. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101212 · Cited by 45 · see citing works
Lannfelt, L., Basun, H., Vigo-Pelfrey, C., Wahlund, L.-O., Winblad, B., Lieberburg, I., & Schenk, D. (1995) · Neuroscience Letters · doi:10.1016/0304-3940(95)12059-d · Cited by 39 · see citing works
ApoE mimetic peptide decreases Aβ production in vitro and in vivo
Minami, S. S., Cordova, A., Cirrito, J. R., Tesoriero, J. A., Babus, L. W., Davis, G. C., Dakshanamurthy, S., Turner, R. S., Pak, D. T., Rebeck, G. W., et al. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-16 · Cited by 34 · see citing works
Use of Genetic Variation as Biomarkers for Alzheimer's Disease
Reitz, C., & Mayeux, R. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.04945.x · Cited by 24 · see citing works
Gal, J., Katsumata, Y., Zhu, H., Srinivasan, S., Chen, J., Johnson, L. A., Wang, W.-X., Golden, L. R., Wilcock, D. M., Jicha, G. A., et al. (2022) · The American Journal of Pathology · doi:10.1016/j.ajpath.2021.11.013 · Cited by 17 · see citing works
KAPLITT, M., GOURAS, G. K., MAKIMURA, H., JOVANOVIC, J., SWEENEY, D., GREENGARD, P., RELKIN, N. R., & GANDY, S. (1996) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1996.tb32597.x · Cited by 12 · see citing works
- Authors
- Sanan, D. A., Weisgraber, K. H., Russell, S. J., Mahley, R. W., Huang, D., Saunders, A., Schmechel, D., Wisniewski, T., Frangione, B., & Roses, A. D.
- Affiliations
- Gladstone Institutes (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1994-08-01
- Volume
- 94
- Issue
- 2
- Pages
- 860-869
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC296168
- OpenAlex
- W2131068139
- Cited by
- 404
- References
- 2
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 17 · 2021: 10 · 2020: 9 · 2019: 5 · 2018: 8 · 2017: 7 · 2016: 10 · 2015: 9 · 2014: 13 · 2013: 8 · 2012: 12
- FWCI
- 19.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (5R15AG07922, P50AG005128, R35AG010953)
- 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, apolipoprotein E3, beta-amyloid peptide, Alzheimer's disease, amyloid fibril formation, protein-peptide complex, amyloid fibril structure, amyloid plaques
- MeSH terms
- Alzheimer Disease, Apolipoproteins E, Humans, Immunohistochemistry, Microscopy, Electron, Amyloid beta-Peptides, Apolipoprotein E3, Apolipoprotein E4
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
