A significant proportion of the elderly population is affected by progressive neurodegenerative diseases, characterized by the accumulation of insoluble fibrils and plaques in the brain. The formation and accumulation of fibrillar plaques and aggregates of β-amyloid peptide (Aβ) and α-synuclein (Syn) in the brain have been recognized as characteristics of Alzheimer’s disease (AD) and Parkinson’s disease (PD).(1-3) Aβ is a polypeptide containing 39-43 amino acid residues derived from proteolytic cleavage of the transmembrane Aβ precursor protein (APP). Recently the formation of Aβ-oligomers has become of particular interest, since oligomers have been suggested to be key neurotoxic species for progressive neurodegeneration(2,4,5); however, molecular details of the pathophysiological degradation of APP and of Aβ-aggregation pathways are hitherto unclear.(6) Despite the lack of molecular mechanism(s), studies towards the development of immunotherapeutic approaches for AD(7) have shown initial success in the production of therapeutic antibodies that disaggregate Aβ-fibrils and improve the memory impairment in transgenic AD mice. (8-11) The identification of the epitopes recognized by both Aβ-plaque-specific and aggregation-preventing antibodies, and the discovery of their Aβ-oligomer specificity are presently causing enhanced interest in the elucidation of Aβ-oligomeric structures.(12-16)

Ion mobility mass spectrometry (IMS-MS) has received increasing attention as a tool for the characterization of molecular assemblies according to their conformation and/or topography.(17-20) The IMS-MS instrument employed in this study consists of two parts: (i) an ion mobility drift cell where ions are separated within an electric field according to their collisional cross section, and (ii) a quadrupole time-of-flight mass spectrometer (SYNAPT-QTOF-MS).(21) Thus the IMS-MS implements a new mode of separation that provides the differentiation of conformational states of polypeptides. In conjunction with spectroscopic, proteomic, and electron paramagnetic resonance (EPR) studies of spin-labeled Aβ-peptides in our laboratory aimed at the structural identification of Aβ-aggregates,(22-26) IMS-MS was applied in this study of Aβ-oligomer preparations of Aβ(1-40) in vitro. First applications revealed molecular details of Aβ-oligomerization such as the identification of oxidative structure modifications.