Residues 17–20 and 30–35 of beta‐amyloid play critical roles in aggregation

Abstract

We examined the effects of co-incubating nine different Abeta peptide fragments with full-length Abeta1-40 (Abeta40) on protein aggregation. Six fragments enhanced aggregation of Abeta40 (Abeta1-28, 12-28, 17-28, 10-20, 25-35 and 17-40), while three others did not (Abeta1-11, 1-16, and 20-29). All of the peptides that enhanced aggregation contained either residues 17-20 or 30-35, indicating the importance of these regions for promoting aggregation of full-length Abeta. Abeta25-35 in particular increased both the rate and extent of aggregation of Abeta40 considerably as indicated by fluorescence staining. Atomic force microscope imaging (AFM) indicates the increase in fluorescence staining with Abeta25-35 is primarily due to increased formation of oligomers and protofibrils rather than formation of large amyloid fibrils. AFM images of Abeta25-35 when incubated alone also indicate formation of aggregates and long thin filaments. The increase in formation of the small toxic oligomeric morphology of Abeta40, along with formation of Abeta25-35 oligomers and thin filaments, represent two different potential pathways for Abeta25-35 toxicity. The critical roles of residues 17-20 and 30-35 of Abeta provide further insight into mechanism that underlie the formation of toxic aggregates in Alzheimer Disease (AD) and suggest targets for the design of beta-sheet breakers to modulate the aggregation and inhibit toxicity of full-length Abeta.

A comparative analysis of the aggregation behavior of amyloid‐β peptide variants

“…FAD mutations can thus either inhibit or induce aggregation depending on the suitability of the replacing amino acid to accommodate an amyloidogenic or aggregated structure. Molecular dynamics simulations have suggested the depletion of the E22-K28 salt bridge to explain the enhanced aggregation of E22Q Ab , while the switch of a bend motif to a turn in the region Ab [22][23][24][25][26][27][28] could result in slower aggregation of the D23N Ab 1-42 mutant [25]. Overall fibril morphology is however not affected, as has been shown previously for a subset of FAD mutants [23].…”

In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1–42) fibrillation process

“…[11][12][13] Although several theoretical and experimental studies have been conducted with the aim of explaining the interaction of Cu 21 and Ab, several contradictory results have emerged. 16 These contradictions might be explained by the different experimental conditions used by different research groups, which have included different pH values, 23 21 , Ab suffered conformational changes. At 5 ns of the MD simulation, the Ab adopted a U-turn shape that encouraged the interaction between Asp 23 and Lys 28, as reported previously.…”

“…19 To obtain an Ab dimer (lowest free energy), two of the same monomers were used. The ClusPro2.0 server, one of the top performers at CAPRI (Critical Assessment of Predicted Interactions) round [13][14][15][16][17][18][19]20 was used to predict the possible structure of the oligomers. We submitted to ClusPro two monomers to obtain the dimer, which was used to dock with another monomer to form a trimer, and so forth; this process was performed until an Ab pentamer was formed.…”

“…Furthermore, because the Cu 21 and His residues did not interact, the results from this MD simulation contradict those reported in the literature. 9,16,17 Consequently, we evaluated the amino acid residues that interacted with Cu 21 , Asp 23, and Glu 22, as displayed in Figure 4(B-D). The distance between Cu 21 and Asp 23 was lower (2.01 Å ) compared with that between Cu 21 and Glu22 (4.81 Å ) at the end of the simulation [ Fig.…”

“…16,17 Thus, for Ab 1242 in the a-helix conformation, Asp 23 did not interact with Lys 28, The RMSD, Rg, and RMSF values of the interaction between Ab 1-42 and galanthamine were calculated for the entire MD simulation. As displayed in Figure 6(E), the maximum RMSD value for all of the C a atoms was 9 Å .…”