Amyloid β-Protein: Monomer Structure and Early Aggregation States of Aβ42 and Its Pro19Alloform

Abstract

The amyloid β-protein (Aβ) is a seminal neuropathic agent in Alzheimer's disease (AD). Recent evidence points to soluble Aβ oligomers as the probable neurotoxic species. Among the naturally occurring Aβ peptides, the 42-residue form Aβ42 is linked particularly strongly with AD, even though it is produced at approximately 10% of the levels of the more abundant 40-residue form Aβ40. Here, we apply mass spectrometry and ion mobility to the study of Aβ42 and its Pro¹⁹ alloform. The Phe¹⁹ → Pro¹⁹ substitution blocks fibril formation by [Pro¹⁹]Aβ42. Evidence indicates that solution-like structures of Aβ monomers are electrosprayed and characterized. Unfiltered solutions of Aβ42 produce only monomers and large oligomers, whereas [Pro¹⁹]Aβ42 solutions produce abundant monomers, dimers, trimers, and tetramers but no large oligomers. When passed through a 10,000 amu filter and immediately sampled, Aβ42 solutions produce monomers, dimers, tetramers, hexamers, and an aggregate of two hexamers that may be the first step in protofibril formation. These results are consistent with recently published photochemical cross-linking data and lend support to recent aggregation mechanisms proposed by Bitan, Teplow, and co-workers [J. Biol. Chem.2003, 278, 34882−34889].