Sequence‐based modeling of Aβ42 soluble oligomers

Abstract

Aβ fibrils, which are central to the pathology of Alzheimer's disease, form a cross‐β‐structure that contains likely parallel β‐sheets with a salt bridge between residues Asp23 and Lys28. Recent studies suggest that soluble oligomers of amyloid peptides have neurotoxic effects in cell cultures, raising the interest in studying the structures of these intermediate forms. Here, we present three models of possible soluble Aβ forms based on the sequences similarities, assumed to support local structural similarities, of the Aβ peptide with fragments of three proteins (adhesin, Semliki Forest virus capsid protein, and transthyretin). These three models share a similar structure in the C‐terminal region composed of two β‐strands connected by a loop, which contain the Asp23‐Lys28 salt bridge. This segment is also structurally well conserved in Aβ fibril forms. Differences between the three monomeric models occur in the N‐terminal region and in the C‐terminal tail. These three models might sample some of the most stable conformers of the soluble Aβ peptide within oligomeric assemblies, which were modeled here in the form of dimers, trimers, tetramers, and hexamers. The consistency of these models is discussed with respect to available experimental and theoretical data. © 2007 Wiley Periodicals, Inc. Biopolymers 85: 422–437, 2007.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

p3 peptide, a truncated form of Aβ devoid of synaptotoxic effect, does not assemble into soluble oligomers

“…Hepn sulfate proteoglycans [33], metals like Al(III), Fe(III), Zn[5] and Cu[5] [34–36] or proteins like CLAC (“Collagen‐like Alzheimer amyloid plaque component”) [37] bind to residues which are located in this region. Within the models of Aβ soluble oligomers we have recently proposed [13] that the N‐terminal domain, modelled by one or two β‐strands, is always accessible to solvent, which is consistent with available experimental data.…”

“…In these three models, the β‐hairpin constitutes the hydrophobic core of the oligomers which is always protected by the hydrophilic N‐terminal domain of the Aβ peptide. These water‐soluble oligomeric models might sample the possible conformations of the experimentally observed multimeric Aβ assemblies [13].…”

“…The coordinates of the three Aβ models were retrieved from a previous work [13]. The construction of the p3‐derived models was performed using Swiss‐PDB Viewer [18].…”

Probing the efficacy of peptide-based inhibitors against acid- and zinc-promoted oligomerization of amyloid-β peptide via single-oligomer spectroscopy

“…Recognition may be facilitated by β-character in the central hydrophobic region of the full-length peptides and the presence of a turn and/or salt bridge around residues 23–28, common features of the fibrils these compounds are designed to bind [65] which have recently been discovered in simulations of Aβ monomers and small oligomers [66–69]. …”

Manipulation of Microglial Activation as a Therapeutic Strategy in Alzheimers Disease

“…These appear to be directly neurotoxic and have received increasing attention as key mediators of pathogenic processes in AD [14][15][16]. Soluble higher-order structures of A , that appear to consist of dimeric, trimeric, and hexameric structures, as well as multiples thereof [17][18][19][20][21][22][23][24][25], have been isolated from human brain tissue and correlated with memory loss [18]. These oligomers have been shown to bind membranes of synaptic structures and at even very low concentrations in slice culture and animal models inhibit synaptic plasticity that underlies learning and memory [26,27].…”