SDS-stable complex formation between native apolipoprotein E3 and beta-amyloid peptides.
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.
Munson
G W
GW
Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA.
Roher
A E
AE
Kuo
Y M
YM
Gilligan
S M
SM
Reardon
C A
CA
Getz
G S
GS
LaDu
M J
MJ
D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D046911:Macromolecular Substances; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D012967:Sodium Dodecyl Sulfate
D016229:Amyloid beta-Peptides; D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D046911:Macromolecular Substances; D010446:Peptide Fragments; C084358:amyloid beta-protein (1-28); C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C092395:amyloid beta-protein (12-28); D012967:Sodium Dodecyl Sulfate