Purification of Apolipoprotein E Attenuates Isoform-specific Binding to β-Amyloid
Open accessAbstract
Apolipoprotein E (apoE), particularly the e4 allele, is genetically linked to the incidence of Alzheimer's disease. In vitro, apoE has been shown to bind beta-amyloid (A beta), an amyloidogenic peptide that aggregates to form the primary component of senile plaques. In previous work, we demonstrated that apoE3 from tissue culture medium binds to A beta with greater avidity than apoE4 (LaDu, M. J., Falduto, M. T., Manelli, A. M., Reardon, C. A., Getz, G. S., and Frail, D. E. (1994) J. Biol. Chem. 269, 23403-23406). This is in contrast to data using purified apoE isoforms as substrate for A beta (Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L.-M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., and Roses, A. D. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 8098-8102). Here we resolve this apparent discrepancy by demonstrating that the preferential binding of A beta to apoE3 is attenuated and even abolished with purification, a process that includes delipidation and denaturation. We compared the A beta binding capacity of unpurified apoE isoforms from both tissue culture medium and intact human very low density lipoproteins with that of apoE purified from these two sources. The interaction of human A beta-(1-40)-peptide and apoE was analyzed by nonreducing SDS-polyacrylamide gel electrophoresis followed by Western immunoblotting for either A beta or apoE immunoreactivity. While the level of the apoE3.A beta complex was approximately 20-fold greater compared with the apoE4.A beta complex in unpurified conditioned medium, apoE3 and apoE4 purified from this medium bound to A beta with comparable avidity. Moreover, using endogenous apoE on very low density lipoproteins from plasma of apoE3/3 and apoE4/4 homozygotes, apoE3 was again a better substrate for A beta than apoE4. However, apoE purified from these plasma lipoproteins exhibited little isoform specificity in binding to A beta. These results suggest that native preparations of apoE may be a more physiologically relevant substrate for A beta binding than purified apoE and further underscore the importance of subtle differences in apoE conformation to its biological activity.
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The literature suggests that there are isoform-dependent differences in ApoE-plaque associations but that several factors, such as ApoE lipidation state, compartment or cell type of origin, and Aβ conformational state, also have important roles in ApoE-Aβ interactions.
“The literature suggests that there are isoform-dependent differences in ApoE–plaque associations but that several factors, such as ApoE lipidation state, compartment or cell type of origin, and Aβ conformational state, also have important roles in ApoE–Aβ interactions52–56.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [53]
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- Authors
- LaDu, M. J., Pederson, T. M., Frail, D. E., Reardon, C. A., Getz, G. S., & Falduto, M. T.
- Affiliations
- University of Chicago (US)
- Abbott (United States) (US)
- Corresponding author
- LaDu, Mary Jo
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1995-04
- Volume
- 270
- Issue
- 16
- Pages
- 9039-9042
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2031715075
- Cited by
- 189
- References
- 1
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 8 · 2019: 3 · 2018: 1 · 2017: 2 · 2016: 4 · 2015: 3 · 2014: 4 · 2013: 1 · 2012: 2
- FWCI
- 8.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1f32hl008833-01, 5p50hl015062-25)
- National Heart, Lung, and Blood Institute (HL-15062, 1F32 HL08833-01)
- 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, amyloid-beta, APOE isoforms, APOE3, APOE ε4, Alzheimer's disease, protein-protein binding, binding avidity, VLDL, delipidation, denaturation, conditioned medium, amyloid plaques
- MeSH terms
- Alzheimer Disease, Apolipoproteins E, Culture Media, Humans, Lipoproteins, VLDL, Protein Denaturation, Amyloid beta-Peptides
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