THE ALPHA-HELICAL TO BETA-STRAND TRANSITION IN THE AMINO-TERMINAL FRAGMENT OF THE AMYLOID BETA-PEPTIDE MODULATES AMYLOID FORMATION

Amyloid-beta peptide (A beta) consists of a hydrophobic C-terminal dom ain (residues 29-42) that adopts beta-strand coniformation and an N-te rminal domain (amino acids 10-24) whose sequence permits the existence of a dynamic equilibrium between an alpha-helix and a beta-strand, In this paper we analyzed the effect of the alternate N-terminal conform ations on amyloid fibril formation through the study of the analogous A beta peptides containing single amino acidic substitutions, The sing le mutation of valine 18 to alanine induces a significant increment of the alpha-helical content of A beta, determined by Fourier transform infrared spectroscopy and circular dichroism and dramatically diminish es fibrillogenesis, measured by turbidity, thioflavine T binding, Cong o red staining, and electron microscopic examination, In hereditary Du tch cerebral hemorrhage with amyloidosis (a variant of Alzheimer's dis ease), the substitution of glutamine for glutamic acid at position 22 decreased the propensity of the A beta N-terminal domain to adopt an a lpha-helical structure, with a concomitant increase in amyloid formati on, We propose that A beta exists in an equilibrium between two specie s: one ''able'' and another ''unable'' to form amyloid, depending on t he secondary structure adopted by the N-terminal domain, Thus, manipul ation of the A beta secondary structure with therapeutical compounds t hat promote the alpha-helical conformation may provides a tool to cont rol the amyloid deposition observed in Alzheimer's disease patients.