The α-helical to β-strand transition in the amino-terminal fragment of the amyloid β-peptide modulates amyloid formation

Abstract

Amyloid-β peptide (Aβ) consists of a hydrophobic C-terminal domain (residues 29-42) that adopts β-strand conformation and an N-terminal domain (amino acids 10-24) whose sequence permits the existence of a dynamic equilibrium between an α-helix and a β-strand. In this paper we analyzed the effect of the alternate N-terminal conformations on amyloid fibril formation through the study of the analogous Aβ peptides containing single amino acidic substitutions. The single mutation of valine 18 to alanine induces a significant increment of the α-helical content of Aβ, determined by Fourier transform infrared spectroscopy and circular dichroism and dramatically diminishes fibrillogenesis, measured by turbidity, thioflavine T binding, Congo red staining, and electron microscopic examination. In hereditary Dutch cerebral hemorrhage with amyloidosis (a variant of Alzheimer's disease), the substitution of glutamine for glutamic acid at position 22 decreased the propensity of the Aβ N-terminal domain to adopt an α-helical structure, with a concomitant increase in amyloid formation. We propose that Aβ exists in an equilibrium between two species: one 'able' and another 'unable' to form amyloid, depending on the secondary structure adopted by the N-terminal domain. Thus, manipulation of the Aβ secondary structure with therapeutical compounds that promote the α-helical conformation may provides a tool to control the amyloid deposition observed in Alzheimer's disease patients.