SDS-stable complex formation between native apolipoprotein E3 and beta-amyloid peptides

Extracellular senile plaques composed predominantly of fibrillar amyloid-be ta (A beta) are a major neuropathological feature of Alzheimer's disease (A D). Genetic evidence and in vivo studies suggest that apolipoprotein E (apo E) may contribute to amyloid clearance and/or deposition. In vitro studies demonstrate that native apoE2 and E3 form an SDS-stable complex with A beta >(*) over bar * (1-40), while apoE4 forms little such complex. Our current work extends these observations by presenting evidence that apoE3 also bind s to A beta>(*) over bar * (1-42) and with less avidity to modified species of the peptide found in senile plaque cores. These modified peptides inclu de a form that originates at residue 3-Glu as pyroglutamyl and another with isomerization at the 1Asp and 7-Asp positions. In addition, we used bindin g reactions between apoE3 and various A beta fragments, as well as binding reactions with apoE3 and AP(1-40) plus A beta fragments as competitors, to identify the domain(s) of A beta involved in the formation of an SDS-stable complex with apoE3. Residues 13-28 of A beta 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/A beta complex and support t he hypothesis that A beta can be transported in vivo complexed with apoE. T his complex may then be cleared from the interstitial space by apoE recepto rs in the brain or become part of an extracellular amyloid deposit.