Differential Binding of Apolipoprotein E Isoforms to Tau and Other Cytoskeletal Proteins
Open accessAbstract
The apolipoprotein E4 (apoE4) gene dose is a major risk factor for late-onset and sporadic Alzheimer's disease with 50% of homozygous patients developing the disease by age 70. Previous studies have shown localization of apoE to the cytoplasm of certain neurons within the brain. In addition, apoE3, but not apoE4, forms SDS-stable complexes with the microtubule-associated proteins tau and MAP-2. To extend these studies and quantitate the association of apoE with other proteins, the association of apoE3 and apoE4 with several cytoskeletal proteins was examined using both gel shift and overlay assays. In the gel shift assay, apoE3 formed SDS-stable complexes with the longest isoform of human recombinant tau (T4L), the shortest isoform of human recombinant tau (T3), and the 160-kDa neurofilament protein (NFM). ApoE4 did not bind T3, T4L, or NFM in this assay. The association of apoE3 and apoE4 with T4L, actin, or tubulin was further examined in an overlay assay with known amounts of the cytoskeletal proteins slot-blotted onto nitrocellulose and incubated in 0.15 microM (5 microg/ml) apoE3 or apoE4. In this assay, apoE3 and apoE4 bound T4L and tubulin equally well. In contrast, apoE3 bound actin with a significantly greater affinity than did apoE4. These results indicate that apoE isoforms interact with cytoskeletal proteins with at least two different binding affinities. The more avid interaction results in the formation of complexes which are SDS stable and occurs almost exclusively with apoE3, while the other interactions between apoE and cytoskeletal proteins are specific for apoE3.
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ApoE3, but not ApoE4, avidly binds to human tau in vitro.
“Early studies showed that ApoE3, but not ApoE4, avidly binds to human tau in vitro102,103”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [103]
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“Finally, APOE was shown to be important for microtubular stability in the brain due to its interaction with tau and MAP2C (59, 104, 105), the microtubule-associated proteins.”
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MethodInfluentialSelf-citationImpact of APOE genotype on prion-type propagation of tauopathy
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Self-citationHuman apolipoprotein E accelerates microtubule polymerization in vitro
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“A probable mechanism linking ApoE to the pathology of AD has been demonstrated by studies that show that the ApoE protein interacts with both b-amyloid and tau in an isoform-specific manner (Fleming et al. 1996; Strittmatter et al. 2003).”
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“Based on the identification of apoE4 as a genetic risk factor for AD, initial studies focused on disease-specific pathologies, such as isoform-specific effects on Aβ metabolism and deposition [47] and interactions with the microtubule-associated protein tau [48].”
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“Although ApoE and some cytoskeletal proteins, including neurofilaments, potentially interact with each other [ 10 ], this discrepancy suggests that participation of ApoE and its interaction with NF proteins are not prerequisite for the formation of BNs in general.”
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“ApoE3 Repeat domains Lipid carrier [195, 196]”
Kong, F., Wu, T., Dai, J., Cai, J., Zhai, Z., Zhu, Z., Xu, Y., & Sun, T. (2024) · PLoS ONE · doi:10.1371/journal.pone.0295008 · Cited by 8 · see citing works
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“ApoE interaction with cytoskeletal proteins is not limited to tau, but also includes proteins such as microtubule associated protein 2 (MAP2), actin and tubulin [18,25].”
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“ApoE interactions and binding to tau [43], LRP1 [44], ABCA1 [45], and TREM2 [46] have already been demonstrated, but the role of the apoE glycan in these interactions is unknown.”
Apolipoprotein E influences neuronal death and repair
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Additional file 12 of Impact of APOE genotype on prion-type propagation of tauopathy
Williams, T., Ruiz, A. J., Ruiz, A. M., Vo, Q., Tsering, W., Xu, G., McFarland, K., Giasson, B. I., Sullivan, P. M., Borchelt, D. R., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19619142
A critical appraisal of the link between apolipoprotein E and Tau
Das, S., Hyman, B. T., & Serrano‐Pozo, A. (2026) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001459
Isoform-Specific Metabolism of Apolipoprotein E: Implications for Alzheimer ’s Disease
Strittmatter, W. J. (1997) · Birkhäuser Boston eBooks · doi:10.1007/978-1-4612-4116-4_8
Self-citationA unifying hypothesis of alzheimer’s disease: III—Risk factors
Heininger, K. (2000) · Human Psychopharmacology: Clinical and Experimental · doi:10.1002/(sici)1099-1077(200001)15:1
- Authors
- Fleming, L. M., Weisgraber, K. H., Strittmatter, W. J., Troncoso, J. C., & Johnson, G. V. W.
- Affiliations
- University of Alabama (US)
- University of California, San Francisco (US)
- Duke University (US)
- Johns Hopkins University (US)
- University of Alabama at Birmingham (US)
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 1996-04
- Volume
- 138
- Issue
- 2
- Pages
- 252-260
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W2045178237
- Cited by
- 82
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 1 · 2018: 3 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 2 · 2013: 1
- FWCI
- 5.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Experimental Neurology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01ag006569-13)
- National Institute on Aging (AG06569)
- National Heart, Lung, and Blood Institute (HL-41633, P01HL041633)
- National Institute of Neurological Disorders and Stroke (NS-27538)
- 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, APOE3, APOE ε4, tau protein, cytoskeletal proteins, protein-protein binding, neurofilaments, tubulin, actin, MAP2, Alzheimer's disease, gene dosage
- MeSH terms
- Animals, Apolipoproteins E, Cattle, Cytoskeletal Proteins, Electrophoresis, Polyacrylamide Gel, Humans, Isomerism, Immunoblotting, tau Proteins, Neurofilament Proteins
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