Evidence of Molecular Interactions of A?1-42 with N-Terminal Truncated Beta Amyloids by NMR

A? peptides, the main protein components of Alzheimer's disease (AD) plaques, derive from a proteolytic cleavage of the amyloid precursor protein. Due to heterogeneous cleavage sites, a series of A? peptides, including the major and widely studied species A?1-40 (A?40) and A?1-42 (A?42), are produced. In addition to the C-terminal heterogeneity of A? peptides, significant amounts of N-terminal truncated (A?3-42) and pyroglutamate-modified amyloid-? peptides (A?pE3-42) have been identified in AD affected brains and shown to be more cytotoxic than unmodified A? peptides. Little is known about the properties of their mixtures with A?42. Nuclear Magnetic Resonance spectroscopy is here employed to investigate the interaction of N-truncated peptides with A?42 at different molar ratios. We highlight the critical concentration of N-truncated forms influencing the aggregation kinetics of A?42. We provide evidence, at residue level, that the C-terminal region of A?42 is the locus of transient specific interactions with highly aggregation prone N-truncated alloforms.