Amyloid-β Oligomers: Now for the Structure in the Membrane

Abstract

Small oligomers of Amyloid-β (Aβ), rather than the mature fibrils, are suspected to initiate Alzheimer's disease (AD). The structures of these oligomers in the solution, and in the membrane phase, are expected to provide significant cues for addressing their toxicity. However, it is difficult to determine the structure of these peptides as they are transient, and only exist at low μM concentrations. We recently combined rapid fluorescence techniques with slower two-dimensional solid state NMR to obtain useful atomic-level information on their structure in the solution phase1,2. However, though membrane interaction is a necessary step for this extra-cellular peptide to be toxic3, their structure in the membrane phase remains elusive. We have developed a modified Surface Enhanced Raman Spectroscopy method which is able to probe the structure of membrane proteins at individual residue levels. Using this technique, we determine the region-wise structure of the membrane-active oligomers, and compare these with those determined by solid state NMR spectroscopy. We show that there are critical differences in the structure of the oligomers and the fibrils, even though they share the same gross molecular architecture. These differences may be the key to understanding.References1)Sarkar et al., Structure of Transient Amyloid-β Oligomers from Less-Toxic Fibrils in reggions Known to harbour Familial Alzhimer's Mutations, Angew Chem. Int. Ed. Engl. 2014, http://dx.doi.org/10.1002/anie.2012)Nag et al., A folding transition underlies the emergence of membrane affinity in amyloid-beta. Phys. Chem. Chem. Phys. 2013, 15, 19129-19133.3)Sarkar et al., Thermodynamically Stable Amyloid-β monomers have much lower membrane affinity than the small oligomers, Frontiers in Physiology, 2013, 4, 1-11