Amyloid-?-neuropeptide interactions assessed by ion mobility-mass spectrometry.

ABSTRACT: Recently, small peptides have been shown to modulate aggregation and toxicity of the amyloid-? protein (A?). As such, these new scaffolds may help discover a new class of biotherapeutics useful in the treatment of Alzheimer's disease. Many of these inhibitory peptide sequences have been derived from natural sources or from A? itself (e.g., C-terminal A? fragments). In addition, much earlier work indicates that tachykinins, a broad class of neuropeptides, display neurotrophic properties, presumably through direct interactions with either A? or its receptors. Based on this work, we undertook a limited screen of neuropeptides using ion mobility-mass spectrometry to search for similar such peptides with direct A? binding properties. Our results reveal that the neuropeptides leucine enkephalin (LE) and galanin interact with both the monomeric and small oligomeric forms of A?(1-40) to create a range of complexes having diverse stoichiometries, while some tachyknins (i.e., substance P) do not. LE interacts with A? more strongly than galanin, and we utilized ion mobility-mass spectrometry, molecular dynamics simulations, gel electrophoresis/Western blot, and transmission electron microscopy to study the influence of this peptide on the structure of A? monomer, small A? oligomers, as well as the eventual formation of A? fibrils. We find that LE binds selectively within a region of A? between its N-terminal tail and hydrophobic core. Furthermore, our data indicate that LE modulates fibril generation, producing shorter fibrillar aggregates when added in stoichiometric excess relative to A?.

SUBMITTER: Soper MT 

PROVIDER: S-EPMC3664942 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature