Abstract
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.
Highlights
A clear hallmark of Alzheimer disease is the presence in the brain of extracellular amyloid plaques containing a certain amount of cleavage products of the transmembrane amyloid -protein precursor [1]
Obtained from amyloid deposits [11, 12], have been found to inhibit long term potentiation [9, 13], cause membrane damage [14, 15], alter membrane fluidity [16], and act as poreforming toxins [17]. These findings have changed the current perspective on the role of amyloid fibrils in neurodegenerative diseases to consider fibrils to be a means of removing dangerous toxic oligomeric species rather than an active pathogenic product (18 –20)
Stage of Kinetics: One Single, Non-cooperative Process—To unravel the mechanism of protofibril formation starting from oligomers, we focused on the early stage of aggregation kinetics, by measuring essentially two quantities: light scattered intensity, which is closely related to the average mass of aggregates, and hydrodynamic radius, which is related to the size and the diffusion properties of aggregates (Fig. 2)
Summary
A clear hallmark of Alzheimer disease is the presence in the brain of extracellular amyloid plaques containing a certain amount of cleavage products of the transmembrane amyloid -protein precursor [1] These are small peptides of 39 – 42 residues with a hydrophobic domain at the C terminus. To focus on the details of the assembly mechanism and to develop a reasonable model for protofibril formation, we chose to work at acid pH, a condition that allows easy seed-free preparations and, reproducible kinetics [35, 36] At this pH the overall process occurs on a time scale that is suitable to be studied over a wide range of temperatures [37]
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