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

Warren J. Strittmatter, Karl H. Weisgraber, David Y. Huang, Li Ming Dong, Guy S. Salvesen, Margaret Pericak-Vance, Donald Schmechel, Ann M. Saunders, Dmitry Goldgaber, Allen D. Roses

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1133 Scopus citations


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, ε4, suggesting apoE4 is associated with increased susceptibility to disease. To follow up on this suggestion, we compared the binding of synthetic amyloid β (β/ A4) peptide to purified apoE4 and apoE3, the most common isoform. Both isoforms bound synthetic β/ 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 β/ 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 β/ A4 peptide; however, binding to apoE4 was observed in minutes, whereas binding to apoE3 required hours. In addition, apoE4 did not bind β/ A4 peptide at pH < 6.6, whereas apoE3 bound β/ A4 peptide from pH 7.6 to 4.6. Together these results indicate differences in the two isoforms in complexing with the β/ A4 peptide. Binding of β/ A4 peptide by oxidized apoE may determine the sequestration or targeting of either apoE or β/ 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.

Original languageEnglish (US)
Pages (from-to)8098-8102
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
StatePublished - Sep 1 1993
Externally publishedYes

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