Isoform-specific binding of apolipoprotein E to beta-amyloid.

LaDu, M.J.; Falduto, M.T.; Manelli, A.M.; Reardon, C.A.; Getz, G.S.; Frail, D.E.

doi:10.1016/s0021-9258(17)31529-6

Cited by 540Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Isoform-specific binding of apolipoprotein E to beta-amyloid.

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LaDu, M.J., Falduto, M.T., Manelli, A.M., Reardon, C.A., Getz, G.S., Frail, D.E.·1994·Journal of Biological Chemistry

DOI 10.1016/s0021-9258(17)31529-6

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Abstract

Apolipoprotein E (apoE), particularly the e4 allele, is genetically linked to the incidence of Alzheimer's disease. ApoE is present in the extracellular senile plaques and intracellular neurofibrillary tangles associated with Alzheimer's disease. In vitro, apoE has been shown to bind beta-amyloid (A beta), an amyloidogenic proteolytic product of amyloid precursor protein. To analyze the interaction of A beta and apoE, we used Western immunoblotting of human A beta-(1-40)-peptide incubated with conditioned medium from HEK-293 cells transfected with either human apoE3 or apoE4 (products of the e3 and e4 alleles, respectively) cDNA. Nonreducing SDS-polyacrylamide gel electrophoresis revealed the presence of an approximately 45-kDa complex with both A beta and apoE immunoreactivity. The level of the apoE3.A beta complex was approximately 20-fold greater than that of the apoE4.A beta complex. This apoE isoform-specific binding pattern was maintained from pH 5.0 to 9.0, from 2 min to 24 h of peptide incubation, and at concentrations of apoE from 5 to 100 micrograms/ml and of A beta from 10 microM to 1 mM. The higher level of apoE3 binding to A beta is in contrast to previously published data using purified apoE (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). Factors responsible for the isoform-specific interactions between apoE and A beta will require further study before the apparent discrepancy between these data can be reconciled.

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APOE facilitates Aβ clearance and inhibits its aggregation through the formation of APOE-Aβ complexes, with APOE3-Aβ complexes being approximately 20 times more prevalent than APOE4-Aβ complexes.
“Moreover, APOE facilitates Aβ clearance and inhibits its aggregation through the formation of APOE-Aβ complexes, with APOE3-Aβ complexes being approximately 20 times more prevalent than APOE4-Aβ complexes [11, 12].”
From Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE (2024) · cites this paper as [11]
APOE modulates APP metabolism in an isoform-dependent manner through distinct mechanisms, including influencing APP processing via effects on lipid metabolism and modulating Aβ clearance and aggregation via the formation of APOE-Aβ complexes.
“APOE modulates APP metabolism in an isoform-dependent manner through distinct mechanisms: 1) influencing APP processing via effects on lipid metabolism [8–10], and 2) modulating Aβ clearance and aggregation via the formation of APOE-Aβ complexes [11, 12].”
From Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE (2024) · cites this paper as [11]
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 [54]
Several in vitro studies have demonstrated that lipidated apoE2 and apoE3 bind Aβ with greater affinity compared to apoE4.
“Several in vitro studies have demonstrated that lipidated apoE2 and apoE3 bind Aβ with greater affinity compared to apoE4 (39, 51-54).”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [51]
ApoE ɛ2 and ɛ3 bind to Aβ; this binding is lost in the apoE ɛ4 variant.
“ApoE ɛ2 and ɛ3 bind to Aβ; however, this is lost in the apoE ɛ4 variant [11, 12].”
From Discovery of a Missense Mutation (Q222K) of the APOE Gene from the Australian Imaging, Biomarker and Lifestyle Study (2023) · cites this paper as [11]

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Authors: LaDu, M. J., Falduto, M. T., Manelli, A. M., Reardon, C. A., Getz, G. S., & Frail, D. E.
Affiliations: University of Chicago (US)
ORCID: LaDu, M.J.
Getz, G.S.
Frail, D.E.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1994-09
Volume: 269
Issue: 38
Pages: 23403-23406
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1016/s0021-9258(17)31529-6
OpenAlex: W2128565374
Cited by: 540
References: 25
Citations by year: 2026: 9 · 2025: 6 · 2024: 7 · 2023: 11 · 2022: 11 · 2021: 6 · 2020: 20 · 2019: 8 · 2018: 10 · 2017: 12 · 2016: 15 · 2015: 16 · 2014: 18 · 2013: 18 · 2012: 14
FWCI: 13.63
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 9550 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Institutes of Health (7p01ag010481-05, 1f32hl008833-01, 5p50hl015062-25)
National Institute on Aging (AG10481)
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, protein-protein binding, Alzheimer's disease, amyloid precursor protein, amyloid plaques, neurofibrillary tangles
MeSH terms: Apolipoproteins E, Humans, Hydrogen-Ion Concentration, Protein Binding, Recombinant Proteins, Time Factors, Amyloid beta-Peptides, In Vitro Techniques

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Isoform-specific binding of apolipoprotein E to beta-amyloid.

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