Cited by 1,363Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease.

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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, Roses, A D·1993·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.90.17.8098PMC PMC47295

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Abstract

Apolipoprotein E (apoE), a plasma apolipoprotein that plays a central role in lipoprotein metabolism, is localized in the senile plaques, congophilic angiopathy, and neurofibrillary tangles of Alzheimer disease. Late-onset familial and sporadic Alzheimer disease patients have an increased frequency of one of the three common apoE alleles, epsilon 4, suggesting apoE4 is associated with increased susceptibility to disease. To follow up on this suggestion, we compared the binding of synthetic amyloid beta (beta/A4) peptide to purified apoE4 and apoE3, the most common isoform. Both isoforms bound synthetic beta/A4 peptide, the primary constituent of the plaque and angiopathy, forming a complex that resisted dissociation by boiling in SDS. Oxygen-mediated complex formation was implicated because binding was increased in oxygenated buffer, reduced in nitrogen-purged buffer, and prevented by reduction with dithiothreitol or 2-mercaptoethanol. Binding of beta/A4 peptide was saturable at 10(-4) M peptide and required residues 12-28. Examination of apoE fragments revealed that residues 244-272 are critical for complex formation. Both oxidized apoE4 and apoE3 bound beta/A4 peptide; however, binding to apoE4 was observed in minutes, whereas binding to apoE3 required hours. In addition, apoE4 did not bind beta/A4 peptide at pH < 6.6, whereas apoE3 bound beta/A4 peptide from pH 7.6 to 4.6. Together these results indicate differences in the two isoforms in complexing with the beta/A4 peptide. Binding of beta/A4 peptide by oxidized apoE may determine the sequestration or targeting of either apoE or beta/A4 peptide, and isoform-specific differences in apoE binding or oxidation may be involved in the pathogenesis of the intra- and extracellular lesions of Alzheimer disease.

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“The 4 allele of apolipoprotein E (apoE) has been established as the strongest genetic risk factor for late-onset AD (Corder et al., 1993; Strittmatter et al., 1993a; Strittmatter et al., 1993b; Corder et al., 1994; Belinson and Michaelson, 2009).”
Background
The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease
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Authors: 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., & Roses, A. D.
Affiliations: Department of Medicine (Neurology), Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Durham, NC.
University of California, San Francisco (US)
Duke University (US)
Stony Brook University (US)
ORCID: Huang, D Y
Dong, L M
Salvesen, G S
Saunders, A M
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1993-09
Volume: 90
Issue: 17
Pages: 8098-8102
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.90.17.8098
PMC: PMC47295
OpenAlex: W2006409771
Cited by: 1,363
References: 9
Citations by year: 2026: 13 · 2025: 20 · 2024: 14 · 2023: 21 · 2022: 38 · 2021: 29 · 2020: 44 · 2019: 32 · 2018: 30 · 2017: 33 · 2016: 34 · 2015: 20 · 2014: 41 · 2013: 31 · 2012: 50
FWCI: 53.78
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: L. K. Whittier Foundation
National Institutes of Health (5r35ag007922-07)
National Institute on Aging (5 R35-AG-07922, P50AG005128, 5P50AG05128)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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 ε4, APOE3, late-onset Alzheimer's disease, protein-protein complex formation, protein oxidation, binding site residues, pH-dependent binding, amyloid plaques
MeSH terms: Aged, Alzheimer Disease, Apolipoproteins E, Electrophoresis, Polyacrylamide Gel, Humans, Peptide Fragments, Protein Binding, Recombinant Proteins, Amyloid beta-Peptides, Apolipoprotein E3, Apolipoprotein E4

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Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease.

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