Amyloid β-Peptide 25–35 Self-Assembly and Its Inhibition: A Model Undecapeptide System to Gain Atomistic and Secondary Structure Details of the Alzheimer’s Disease Process and Treatment

Abstract

Combined results of theoretical molecular dynamic simulations and in vitro spectroscopic (circular dichroism and fluorescence) studies are presented, providing the atomistic and secondary structure details of the process by which a selected small molecule may destabilize the β-sheet ordered "amyloid" oligomers formed by the model undecapeptide of amyloid β-peptide 25-35 [Aβ(25-35)]. Aβ(25-35) was chosen because it is the shortest fragment capable of forming large β-sheet fibrils and retaining the toxicity of the full length Aβ(1-40/42) peptides. The conformational transition, that leads to the formation of β-sheet fibrils from soluble unordered structures, was found to depend on the environmental conditions, whereas the presence of myricetin destabilizes the self-assembly and antagonizes this conformational shift. In parallel, we analyzed several molecular dynamics trajectories describing the evolution of five monomer fragments, without inhibitor as well as in the presence of myricetin. Other well-known inhibitors (curcumin and (-)-tetracycline), found to be stronger and weaker Aβ(1-42) aggregation inhibitors, respectively, were also studied. The combined in vitro and theoretical studies of the Aβ(25-35) self-assembly and its inhibition contribute to understanding the mechanism of action of well-known inhibitors and the peptide amino acid residues involved in the interaction leading to a rational drug design of more potent new molecules able to antagonize the self-assembly process.

Study of early stages of amyloid Aβ13-23 formation using molecular dynamics simulation in implicit environments

“…Only some other amyloids of different length were tested both in experimental and in silico methods (Kirkitadze et al, 2001;Cecchini et al, 2006;Zheng et al, 2007;Urbanc et al, 2006;Naldi et al, 2012). Our results stayed in accordance with present literature data (Shea and Urbanc, 2012) and confirmed an important role of hydrophobic interactions and salt bridges in the formation of b-amyloid oligomers.…”

“…They included mainly MD simulations of many amyloid structures of different lengths (Cecchini et al, 2006;Zheng et al, 2007;Naldi et al, 2012) and different initial conformation in various environments, including aqueous solutions, micelles and water/organic solvent mixtures (Lee and Ham, 2011;Zhao et al, 2011). The influence of different membranes on aggregation process was also studied (Davis and Berkowitz, 2009a,b;Lemkul and Bevan, 2013).…”

Synthesis of chemically-tethered amyloid-β segment trimer possessing amyloidogenic properties

“…Curcumin, 29,30 EGCG,18,31 NQTrp (1,4-naphthoquinon-2-yl-L-tryptophan), 32,33 and thionin 34 had strong inhibitory effects on aggregation of 1, whereas tetracycline 35 and D-H-KLVFF-OH 36 had no inhibitory activity ( Table 1). As curcumin 30 and EGCG 18 is known to inhibit the aggregation of Ab [25][26][27][28][29][30][31][32][33][34][35] , these inhibitions on 1 imply that the aggregation pattern of the original Ab 25-35 is preserved in 1. In addition, as EGCG and thionin did not exhibit such high inhibitory activities on Ab 1-42 , these two compounds might have the potential to specifically inhibit aggregation of the trimers.…”

“…2). As the Ab chain, we used the pathogenic segment Ab [25][26][27][28][29][30][31][32][33][34][35] , which has been used in both in vitro [16][17][18] and in vivo [19][20][21] experiments, and which retains the same toxic effect in rat hippocampal compared to Ab To synthesize 1, we prepared the following two peptides by Fmoc chemistry-based solid phase peptide synthesis: cyclic peptide 2 and azide functionalized Ab 25-35 3 (for their structures, see Fig. S1).…”

“…25 To compare the amount of cross b-sheet structures between 1 and the corresponding monomers Ab [25][26][27][28][29][30][31][32][33][34][35] (6), we performed a thioflavin-T (ThT) fluorescence assay; cross b-sheet structures are recognized by ThT, leading to an increase in its fluorescence intensity (FI) (Fig. 4a).…”