In vitro fibrillization of Alzheimer’s amyloid-β peptide (1-42)

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.

Copper(II) partially protects three histidine residues and the N‐terminus of amyloid‐β peptide from diethyl pyrocarbonate (DEPC) modification

“…Structural and metal‐binding studies have demonstrated that the metal binding to Aβ peptides is at large extent determined by His residues located in positions 6, 13 and 14 of human Aβ [2‐3,5,6]. Replacement of His13 with Arg in rat Aβ peptide is assumed to be responsible for its lower sensitivity towards Zn(II)‐induced aggregation as compared with human Aβ [7].…”

Protein folding, misfolding and aggregation: The importance of two-electron stabilizing interactions

“…(a) The Aβ 1-42 dimer obtained by modelling studies based on the SAXS data for the stoichiometric Aβ 1-42 complexes with 8-hydroxyquinolines [ 200 ]; (b) The FP i plot shows the anticipated ‘strand’ configurations in the Aβ homodimer at pH 5-6 i.e. under the conditions that accelerate fibrillization (light blue curve H + /E − , blue curve H + /E 0 ) [ 203 , 204 ]; (c) The antiparallel coiled coil as a model of Aβ dimer structure: the favoured antiparallel dimerization of Aβ in aqueous solutions matches the CHC and C-terminal segments that both adopt either the C 7eq or C 5 conformations. The antiparallel assembly could in addition be stabilized by H-bonding between the segments of consecutive ‘turns’ V24-G37 which may adopt the C 5 * fold in the dimer.…”

“…Fig 22B(b) shows the ‘strand’ configurations in the homodimer that favor fibrillization [ 203 , 204 ]. The sequence β0(C 7eq )-β1(C 5 )-β2(C 5 *)-β3(C 5 ) is crucial to the FP -directed molecular recognition in dimerization and subsequent pleiomorphic behavior of Aβ.…”

(Bio)chemical Strategies To Modulate Amyloid-β Self-Assembly

“…One of the observations is that A aggregation is a modifiable process. Environmental factors, such as peptide concentration, temperature, pH, ion strength, added solvents, agitation, etc., have been studied and are known to affect A fibrillization 9 . A great variety of molecules, chemical and biological, are able to modify as well the aggregation of A.…”