In Vitro Characterization of Conditions for Amyloid-β Peptide Oligomerization and Fibrillogenesis

摘要: Abstract Extensive research causally links amyloid-β peptide (Aβ) to Alzheimer's disease, although the pathologically relevant Aβ conformation remains unclear. spontaneously aggregates into fibrils that deposit in senile plaques. However, recent vivo and vitroreports describe a potent biological activity for oligomeric assemblies of Aβ. To consistently prepare vitro fibrillar forms Aβ1–42, detailed knowledge how solution parameters influence structure is required. This manuscript represents first study using single chemically structurally homogeneous unaggregated starting material demonstrate formation oligomers, fibrils, determined by time, concentration, temperature, pH, ionic strength, species. We recently reported oligomers inhibit neuronal viability 10-fold more than ∼40-fold peptide, with Aβ1–42-induced neurotoxicity significant at 10 nm. In addition, we were able differentiate neurotoxic wild-type Aβ1–42 from isoforms containing familial mutations (Dahlgren, K. N., Manelli, A. M., Stine, W. B., Jr., Baker, L. K., Krafft, G. A., LaDu, M. J. (2002) Biol. Chem. 277, 32046–32053). Understanding role specific conformations may define link between re-focusing therapeutic approaches identifying pernicious species ultimately responsible cognitive dysfunction defines disease.