Gas Phase Studies of the Amyloid-β Peptide

Abstract

The amyloid-β (Aβ) peptide is an amphiphilic peptide that exhibits self-aggregating properties forming the amyloid fibrils that can be found in the brains of Alzheimer patients. Today it is believed that that it is the soluble Aβ oligomers rather than the mature fibrils that are the main neurotoxic species. These small peptide-assembles are known to associate with membranes and form pores that can transport Ca2+ into the cell, which in part could be responsible for their neurotoxic properties. However, most biophysical methods that have been developed to study Aβ target either the monomer or the mature fibrils, and not the low abundance and polydisperse oligomers.We have developed a soft ionization mass spectrometry (MS) method that retains and detects these non-covalent oligomer interactions in the gas phase. And since MS is a non-averaging technique the aggregation kinetics for different oligomeric species, as well as reduced and oxidized peptides, could be followed simultaneously. The high-resolution MS was also coupled to an ion mobility spectrometer that separates ions of the same m/z according to collisional cross section, yielding information about peptide conformations in the gas phase. Additionally, peptide interactions with other molecules, such as membrane mimicking detergents can be monitored. Large complexes between Aβ(1-40) and detergent micelles was shown to survive in the MS and could be identified. Detergent head group charges seem to be essential for peptide-micelle interactions, both in the gas phase and in solution, as no structure induction is observed upon addition of non-ionic detergent. The developed methodology is promising for future detection of pore-forming oligomers in micelles, and probably also in other more sophisticated membrane models.