Abstract
The amyloid deposition in the form of extracellular fibrillar aggregates of amyloid-β (Aβ) peptide is a critical pathological event in Alzheimer’s disease. Here, we report a systematic investigation of the effects of environmental factors on the kinetics of Aβ fibrillization in vitro. The effects of Aβ42 peptide concentration, temperature, pH, added solvents and the ratio of Aβ40 and Aβ42 on the peptide fibrillization under agitated conditions was studied. The analysis show that the rate of fibril growth by monomer addition is not limited by diffusion but by rearrangement in the monomer structure, which is enhanced by low concentrations of fluorinated alcohols and characterized by the activation energy of 12 kcal/mol. Fibrillization rate decreases at pH values below 7.0 where simultaneous protonation of His 13 and 14 inhibits fibril formation. The lag period for Aβ42 was only twofold shorter and the fibril growth rate twofold faster than those of Aβ40. Lag period was shortened and the fibrillization rate was increased only at 90% content of Aβ42.
Highlights
The assembly of peptides and proteins into fibrillar aggregates plays an essential role in the onset of several pathologies known as amyloid diseases[1] including Alzheimer’s disease (AD), Parkinson’s disease, type II diabetes as well as prion diseases
The analysis show that the rate of fibril growth by monomer addition is not limited by diffusion but by rearrangement in the monomer structure, which is enhanced by low concentrations of fluorinated alcohols and characterized by the activation energy of 12 kcal/mol
In this paper we have studied the effects of multiple environmental factors on the aggregation of amyloid-β 1− 42 (Aβ42) peptide, the main component of amyloid plaques, characteristic to AD
Summary
The assembly of peptides and proteins into fibrillar aggregates plays an essential role in the onset of several pathologies known as amyloid diseases[1] including Alzheimer’s disease (AD), Parkinson’s disease, type II diabetes as well as prion diseases. Recent studies have shown the importance of secondary nucleation events in the fibril growth process. For example the fragmentation of fibrils, can dominate in the propagation of amyloid growth.[4] several recent studies have shown that amyloid formation in vivo is initiated by the formation of a limited number of seeds that spread from a single nucleation site and start the formation of plaques e.g. the process involves a secondary nucleation step.[5,6]. It has been shown that agitation enhances the fibrillization of Aβ42 peptide only in the initial exponential phase and this has been suggested to be related with the significant role of secondary nucleation.[7]. The decrease in the fibrillization rate at lower pH values is caused by the concurrent protonation of H13 and H14 residues that stabilizes the soluble monomer
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