Specific modulation of the fusogenic properties of the Alzheimer beta-amyloid peptide by apolipoprotein E isoforms.
C-terminal fragments of the Alzheimer amyloid peptide (amino acids 29-40 and 29-42) have physico-chemical properties related to those of the fusion peptides of viral proteins and they are able to induce the fusion of liposomes in vitro. We proposed that these properties could mediate a direct interaction of the amyloid peptide with cell membranes and account for part of the cytotoxicity of the amyloid peptide. In view of the epidemiologic and biochemical linkages between the pathology of Alzheimer's disease and apolipoprotein E (apoE) polymorphism, we examined the potential interaction between the three common apoE isoforms and the C-terminal fragments of the amyloid peptide. We show that, at low concentration, only apoE2 and apoE3 are potent inhibitors of the amyloid peptide fusogenic and aggregational properties, whereas the apoE4 isoform has no effect. We further show that the protective effect of apoE is mediated by the formation of stable apoE/amyloid peptide complexes, as determined by tryptophan emission fluorescence measurements and by gel electrophoresis. The interaction specificity between apoE2 and apoE3 and the amyloid fragments is demonstrated here, since other apolipoproteins (e.g. apolipoprotein A-I and A-II), with similar amphipathic structures, do not interact with the amyloid C-terminal fragments. Finally, we show that, reciprocally, the amyloid peptide can interact directly with the apoE2 and apoE3 isoforms to decrease or perturb their normal association with lipids. These data suggest that the 29-40 and 29-42 domains of the amyloid peptide could be critical for the amyloid-apoE interaction, and that apoE2 and apoE3 isoforms, but not apoE4, could play a protective role against the formation of amyloid aggregates and/or against their interaction with cellular membranes.
Pillot
T
T
Laboratory for Lipoprotein Chemistry, University Gent, Belgium.
Goethals
M
M
Vanloo
B
B
Lins
L
L
Brasseur
R
R
Vandekerckhove
J
J
Rosseneu
M
M
D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D001057:Apolipoproteins E / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007536:Isomerism; D008081:Liposomes / Q000378:metabolism; D008561:Membrane Fusion / Q000187:drug effects*; D009391:Nephelometry and Turbidimetry; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects; D013053:Spectrophotometry
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D008081:Liposomes; D010446:Peptide Fragments