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 fus ion of liposomes in vitro. We proposed that these properties could med iate a direct interaction of the amyloid peptide with cell membranes a nd account for part of the cytotoxicity of the amyloid peptide. In vie w of the epidemiologic and biochemical linkages between the pathology of Alzheimer's disease and apolipoprotein E (apoE) polymorphism, we ex amined the potential interaction between the three common apoE isoform s and the C-terminal fragments of the amyloid peptide. We show that, a t low concentration, only apoE2 and apoE3 are potent inhibitors of the amyloid peptide fusogenic and aggregational properties, whereas the a poE4 isoform has no effect. We further show that the protective effect of apoE is mediated by the formation of stable apoE/amyloid peptide c omplexes, as determined by tryptophan emission fluorescence measuremen ts and by gel electrophoresis. The interaction specificity between apo E2 and apoE3 and the amyloid fragments is demonstrated here, since oth er apolipoproteins (e.g. apolipoprotein A-I and A-II), with similar am phipathic structures, do not interact with the amyloid C-terminal frag ments. Finally, we show that, reciprocally, the amyloid peptide can in teract directly with the apoE2 and apoE3 isoforms to decrease or pertu rb their normal association with lipids. These data suggest that the 2 9-40 and 29-42 domains of the amyloid peptide could be critical for th e 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.