Evidence of Molecular Interactions of Aß1-42 with N-Terminal Truncated Beta Amyloids by NMR.

Aß 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 Aß peptides, including the major and widely studied species Aß1-40 (Aß40) and Aß1-42 (Aß42), are produced. In addition to the C-terminal heterogeneity of Aß peptides, significant amounts of N-terminal truncated (Aß3-42) and pyroglutamate-modified amyloid-ß peptides (AßpE3-42) have been identified in AD affected brains and shown to be more cytotoxic than unmodified Aß peptides. Little is known about the properties of their mixtures with Aß42. Nuclear Magnetic Resonance spectroscopy is here employed to investigate the interaction of N-truncated peptides with Aß42 at different molar ratios. We highlight the critical concentration of N-truncated forms influencing the aggregation kinetics of Aß42. We provide evidence, at residue level, that the C-terminal region of Aß42 is the locus of transient specific interactions with highly aggregation prone N-truncated alloforms.