Interactions of amyloid-β peptides on lipid bilayer studied by single molecule imaging and tracking

The amyloid-beta peptides (A beta 40 and A beta 42) feature prominently in the synaptic dysfunction and neuronal loss associated with Alzheimer's disease (AD). This has been proposed to be due either to interactions between A beta and cell surface receptors affecting cell signaling, or to the formation of calcium-permeable channels in the membrane that disrupt calcium homeostasis. In both mechanisms the cell membrane is the primary cellular structure with which A beta interacts. A beta concentrations in human bodily fluids are very low (pM-nM) rendering studies of the size, composition, cellular binding sites and mechanism of action of the oligomers formed in vivo very challenging. Most studies, therefore, have utilized A beta oligomers prepared at micromolar peptide concentrations, where A beta forms oligomeric species which possess easily observable cell toxicity. Such toxicity has not been observed when nM concentrations of peptide are used in the experiment highlighting the importance of employing physiologically relevant peptide concentrations for the results to be of biological significance. In this paper singlemolecule microscopy was used to monitor A beta oligomer formation and diffusion on a supported lipid bilayer at nanomolar peptide concentrations. A beta monomers, the dominant species in solution, tightly associate with the membrane and are highly mobile whereas trimers and higherorder oligomers are largely immobile. AO dimers exist in a mixture of mobile and immobile states. Oligomer growth on the membrane is more rapid for A beta 40 than for the more amyloidogenic A beta 42 but is largely inhibited for a 1:1 A beta 40:A beta 42 mixture. The mechanism underlying these A beta 40-A beta 42 interactions may feature in Alzheimer's pathology.