Two conformational states of amyloid β-peptide: implications for the pathogenesis of Alzheimer's disease

Abstract

Since the discovery of soluble amyloid-β (sAβ), it became clear that the same amino acid sequence can have both a fibrillar or a soluble state. In this work, we describe the isolation of two different species derived from synthetic Aβ(1–40) differing in their conformational and fibrillogenesis properties. The separation was performed taking advantage of the fact that only one species is sedimentable by centrifugation after 2 weeks of incubation at 1 mg/ml. One species is highly amyloidogenic (Aβac) and has an antiparallel β-sheet structure and the other one is poorly amyloidogenic (Aβnac) and contains mainly random coil or α-helix structure. Chemical changes were not detected in the primary structure of both species and the differences in the physical properties and very likely in biological behaviour are thought to have a conformational basis. We propose that the transformation of the non-amyloidogenic into the amyloidogenic conformation could be the fundamental event in the pathological polymerization of sAβ and in the development of Alzheimer's disease.