His6, His13, and His14 residues in Aβ 1–40 peptide significantly and specifically affect oligomeric equilibria

Abstract

Oligomers of Aβ peptide are implicated as the most probable causative agent in Alzheimer’s disease. However, their structural properties remain elusive due to the dynamic and heterogeneous character of oligomeric species coexisting in solution. Nevertheless, new approaches, mainly based on mass spectrometry, provide unique access to these different structural forms. Using these methods, we previously showed that the N-terminal, non-amyloidogenic region of Aβ is involved in the network of interactions specifically stabilizing oligomers. In the present study, we identified three histidine residues as active participants in this network. Detailed knowledge of the structural features that are potentially important for oligomer-mediated neurotoxicity is a prerequisite for the rational design of oligomerization modifiers.

The Aggregation Pattern of Aβ1–40 is Altered by the Presence of N‐Truncated Aβ4–40 and/or CuII in a Similar Way through Ionic Interactions

“…This effect cannot stem just from the addition of the less negatively charged Aβ 4–40 , but rather on the concentration of positive charge on the N terminus of Aβ 4–40 . Although details of these interactions can be explained only in the course of further experimental and theoretical structural studies, our results reinforce the concept of the catalytic role of the N termini in the initial stages of Aβ aggregation and underscore the relevance of electrostatic interactions [26, 27] …”

“…Copper, along with zinc and iron, has been found in amyloid plaques in abnormally high amounts [18–20] . Cu II modulates the aggregation of Aβ peptides in vitro, likely stabilizing oligomers, [21–27] whereas Aβ‐bound Cu II can undergo redox cycling, producing a sustainable Cu I /Cu II couple that generates reactive oxygen species (ROS) contributing to the oxidative stress observed in the pathology [28] . Together, these findings gave rise to the modified amyloid cascade hypothesis, which puts copper at the center of AD pathology [29, 30] …”

How very small changes in the peptide sequence of β-amyloids influence their redox properties. Electrochemical studies of copper complexes with Aβ(11-16) and pAβ(11-16)

“…UV-Vis spectra recorded at pH 3.01 up to 5.0 exhibit the characteristic abortion band with maximum at 812 nm corresponding to the free copper ion. [41] At higher pH values of the solution, we observed precipitation of copper ions. Because of this, an increase in the baseline was registered, which was not visible in the case of the pAβ(11-16)-Cu(II) complex.…”

“…The absorption spectra registered below pH 4.50 (both solutions) exhibit a characteristic abortion band with maximum at 812 nm corresponding to the free copper ion (not bound to the peptide). [41] Further increase of the pH (pH 4.50 and 5.0) results in the appearance of a new absorption band with maximum at 520 nm corresponding to the 4N complex formation. [9][42] In phosphate buffer at pH 5, we can still observe the presence of a band between 600 and 900 nm while in KNO3 solution (at pH 5.0) the spectral shoulder between 600-900 nm is gone, and the 4N complex is solely present.…”

Glucosylceramide Associated with Gaucher Disease Forms Amyloid-like Twisted Ribbon Fibrils That Induce α-Synuclein Aggregation

“…The size distribution results obtained from DLS were supported by the ACFs of the scattered light, extracted from DLS analysis ( Figure S17 ). In the absence of GlcCer PFFs, the αSyn aggregates quickly as evident from the rapid change in initial slope of ACF, which reflects the presence of small size oligomers, 61 from 2 h to 5 h and the slope of the ACF remains stable after 10 h ( Figure S17a ). Likewise, the ACF curves at 10–60 h exhibited higher values in the time domain at the midpoint of the transition, indicating larger aggregates compared to the values of 2 h and 5 h samples.…”