In vitro characterization of conditions for amyloid-β peptide oligomerization and fibrillogenesis

Extensive research causally links amyloid-beta peptide (Abeta) to Alzheimer's disease, although the pathologically relevant Abeta conformation remains unclear. Abeta spontaneously aggregates into the fibrils that deposit in senile plaques. However, recent in vivo and in vitro reports describe a potent biological activity for oligomeric assemblies of Abeta. To consistently prepare in vitro oligomeric and fibrillar forms of Abeta1-42, a detailed knowledge of how solution parameters influence structure is required. This manuscript represents the first study using a single chemically and structurally homogeneous unaggregated starting material to demonstrate that the formation of oligomers, fibrils, and fibrillar aggregates is determined by time, concentration, temperature, pH, ionic strength, and Abeta species. We recently reported that oligomers inhibit neuronal viability 10-fold more than fibrils and similar to40-fold more than unaggregated peptide, with oligomeric Abeta1-42-induced neurotoxicity significant at 10 nM. In addition, we were able to differentiate by structure and neurotoxic activity wild-type Abeta1-42 from isoforms containing familial mutations (Dahlgren, K. N., Manelli, A. M., Stine, W. B., Jr., Baker, L. K., Krafft, G. A., and LaDu, M. J. (2002) J. Biol. Chem. 277, 32046-32053). Understanding the biological role of specific Abeta conformations may define the link between Abeta and Alzheimer's disease, re-focusing therapeutic approaches by identifying the pernicious species of Abeta ultimately responsible for the cognitive dysfunction that defines the disease.