Extracellular
senile plaques composed predominantly of fibrillar
amyloid-beta (Abeta) are a major neuropathological feature of
Alzheimer's disease (AD). Genetic evidence and in vivo studies suggest that
apolipoprotein E (
apoE) may contribute to
amyloid clearance and/or deposition. In vitro studies demonstrate that native
apoE2 and E3 form an SDS-stable complex with Abeta(1-40), while
apoE4 forms little such complex. Our current work extends these observations by presenting evidence that
apoE3 also binds to
Abeta(1-42) and with less avidity to modified species of the
peptide found in
senile plaque cores. These modified
peptides include a form that originates at residue 3-Glu as pyroglutamyl and another with isomerization at the 1-Asp and 7-Asp positions. In addition, we used binding reactions between
apoE3 and various Abeta fragments, as well as binding reactions with
apoE3 and Abeta(1-40) plus Abeta fragments as competitors, to identify the domain(s) of Abeta involved in the formation of an SDS-stable complex with
apoE3. Residues 13-28 of Abeta appear to be necessary, while complex formation is further enhanced by the presence of residues at the C-terminus of the
peptide. These results contribute to our understanding of the biochemical basis for the SDS-stable
apoE3/Abeta complex and support the hypothesis that Abeta can be transported in vivo complexed with
apoE. This complex may then be cleared from the interstitial space by
apoE receptors in the brain or become part of an extracellular
amyloid deposit.