Protofibril formation of amyloid beta-protein at low pH via a non-cooperative elongation mechanism.
Deposition of the amyloid beta-protein (Abeta) in senile or diffuse plaques is a distinctive feature of Alzheimer's disease. The role of Abeta aggregates in the etiology of the disease is still controversial. The formation of linear aggregates, known as amyloid fibrils, has been proposed as the onset and the cause of pathological deposition. Yet, recent findings suggest that a more crucial role is played by prefibrillar oligomeric assemblies of Abeta that are highly toxic in the extracellular environment. In the present work, the mechanism of protofibril formation is studied at pH 3.1, starting from a solution of oligomeric precursors. By combining static light scattering and photon correlation spectroscopy, the growth of the mass and the size of aggregates are determined at different temperatures. Analysis and scaling of kinetic data reveal that under the studied conditions protofibrils are formed via a single non-cooperative elongation mechanism, not prompted by nucleation. This process is well described as a linear colloidal aggregation due to diffusion and coalescence of growing aggregates. The rate of elongation follows an Arrhenius law with an activation enthalpy of 15 kcal mol(-1). Such a value points to a conformational change of peptides or oligomers being involved in binding to protofibrils or in general to a local reorganization of each aggregate. These results contribute to establishing a clearer relation at the molecular level between the fibrillation mechanism and fibrillar precursors. The observation of a non-cooperative aggregation pathway supports the hypothesis that amyloid formation may represent an escape route from a dangerous condition, induced by the presence of toxic oligomeric species.
Italian National Research Council, Institute of Biophysics at Palermo, via U. La Malfa 153, I-90146 Palermo, Italy.
Rita
R
Carrotta
Mauro
M
Manno
Donatella
D
Bulone
Vincenzo
V
Martorana
Pier Luigi
PL
San Biagio
D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D055592:Biophysical Phenomena; D001703:Biophysics; D004058:Diffusion; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008027:Light; D015233:Models, Statistical; D008962:Models, Theoretical; D010455:Peptides / Q000737:chemistry; D017785:Photons; D011485:Protein Binding; D012542:Scattering, Radiation; D013053:Spectrophotometry; D013696:Temperature; D013816:Thermodynamics; D013997:Time Factors
D016229:Amyloid beta-Peptides; D010455:Peptides