Is amyloid deposition in Alzheimer's disease preceded by an environment-induced double conformational transition?

Fragments of amyloid polypeptide (A4 or beta-protein) were synthesized on solid phase. Circular dichroism (CD) measurements showed that the N-terminal 1-12 fragment assumes an unordered conformation in water, but probably adopts a type I(III) beta-turn in trifluoroethanol (TFE). The central 11-25 fragment has a beta-sheet conformation in aqueous solution, while the full-length N-terminal 1-28 peptide shows helical features in TFE as well as in TFE-water mixtures. Based on secondary structural predictions, molecular mechanical calculations, and the differing and size-dependent conformational propensities of the smaller fragments in aqueous solution, the amyloid peptide is likely to undergo a double conformational transition that is characterized by a pleating process of its central segment. This conformational transition may start spontaneously above a critical peptide concentration, or it may be triggered by age-related or pathological changes ("watering") of the extracellular environment.