Structural Investigation of Amyloid Oligomers via IM-MS and Infrared-Spectroscopy

A hallmark of the Alzheimer´s disease (AD) is the spontaneous transition of Abeta peptides from soluble, unstructured monomers into insoluble amyloid fibrils. Recent evidences increasingly suggest that not the mature fibrils but rather polydisperse Abeta 42 oligomers represent the toxic species. H/D exchange experiments, which rely on the solvent accessibility, have shown that especially the central hydrophobic core as well as the C terminus are highly involved in the aggregation cascade. Furthermore, the Abeta 42 peptide, which just differs in two additional C terminal amino acids, is more cytotoxic than the Abeta 40. A fundamental understanding of all involved structures is crucial for the development of effective drugs. Traditional condensed phase methods, however, only provide averaged information of the assembly. On the other hand, gas phase techniques are able to isolate and characterize one species in the presence of many others without affecting their underlying equilibrium. Especially, ion mobility mass spectrometry (IM MS) is routinely applied for the structural characterization of amyloid oligomers. It provides information on the ion´s shape and size and it can further serve as a filter for a subsequent analysis by orthogonal methods such as infrared (IR) spectroscopy. IR spectroscopy depends on intramolecular vibrations and is therefore highly sensitive towards the secondary structure, adopted by proteins and peptides. The combination of IM MS and IR spectroscopy therefore allows to obtain tertiary/quaternary as well as secondary structure information of individual oligomers. In this thesis, fragments derived from the central hydrophobic core and the C terminus of the Abeta peptide as well as the full length Abeta 40 and Abeta 42 peptides were investigated. The data show that the last alanine residue (Ala 42) play the most important role for the aggregation into β sheet rich aggregates. Both full length Abeta monomers and the Abeta 40 dimer adopt turn like conformations in the gas phase and therefore the characteristic transition into highly structured aggregates occurs through higher oligomers