In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis.
Extensive research causally links amyloid-beta peptide (A beta) to Alzheimer's disease, although the pathologically relevant A beta conformation remains unclear. A beta 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 A beta. To consistently prepare in vitro oligomeric and fibrillar forms of A beta 1-42, 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 A beta species. We recently reported that oligomers inhibit neuronal viability 10-fold more than fibrils and approximately 40-fold more than unaggregated peptide, with oligomeric A beta 1-42-induced neurotoxicity significant at 10 nm. In addition, we were able to differentiate by structure and neurotoxic activity wild-type A beta1-42 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 A beta conformations may define the link between A beta and Alzheimer's disease, re-focusing therapeutic approaches by identifying the pernicious species of A beta ultimately responsible for the cognitive dysfunction that defines the disease.
Stine
W Blaine
WB
Department of Medicine, Division of Geriatrics, Evanston Northwestern Healthcare Research Institute, Evanston, Illinois 60201, USA.
Dahlgren
Karie N
KN
Krafft
Grant A
GA
LaDu
Mary Jo
MJ
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001704:Biopolymers / Q000737:chemistry*; D015153:Blotting, Western; D002942:Circular Dichroism; D004591:Electrophoresis, Polyacrylamide Gel; D010446:Peptide Fragments / Q000737:chemistry*; D012995:Solubility
D016229:Amyloid beta-Peptides; D001704:Biopolymers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)