BINDING OF HUMAN APOLIPOPROTEIN-E TO SYNTHETIC AMYLOID-BETA PEPTIDE -ISOFORM-SPECIFIC EFFECTS AND IMPLICATIONS FOR LATE-ONSET ALZHEIMER-DISEASE

Apolipoprotein E (apoE), a plasma apolipoprotein that plays a central role in lipoprotein metabolism, is localized in the senile plaques, co ngophilic 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, epsilon4, suggesting apoE4 is associated with increased susceptibility to disea se. To follow up on this suggestion, we compared the binding of synthe tic amyloid beta (beta/A4) peptide to purified apoE4 and apoE3, the mo st common isoform. Both isoforms bound synthetic beta/A4 peptide, the primary constituent of the plaque and angiopathy, forming a complex th at resisted dissociation by boiling in SDS. Oxygen-mediated complex fo rmation was implicated because binding was increased in oxygenated buf fer, reduced in nitrogen-purged buffer, and prevented by reduction wit h 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 com plex formation. Both oxidized apoE4 and apoE3 bound beta/A4 peptide; h owever, binding to apoE4 was observed in minutes, whereas binding to a poE3 required hours. In addition, apoE4 did not bind beta/A4 peptide a t pH < 6.6, whereas apoE3 bound beta/A4 peptide from pH 7.6 to 4.6. To gether these results indicate differences in the two isoforms in compl exing with the beta/A4 peptide. Binding of beta/A4 peptide by oxidized apoE may determine the sequestration or targeting of either apoE or b eta/A4 peptide, and isoform-specific differences in apoE binding or ox idation may be involved in the pathogenesis of the intra- and extracel lular lesions of Alzheimer disease.