The hairpin conformation of the amyloid β peptide is an important structural motif along the aggregation pathway

Abstract

The amyloid β (Aβ) peptides are 39-42 residue-long peptides found in the senile plaques in the brains of Alzheimer's disease (AD) patients. These peptides self-aggregate in aqueous solution, going from soluble and mainly unstructured monomers to insoluble ordered fibrils. The aggregation process(es) are strongly influenced by environmental conditions. Several lines of evidence indicate that the neurotoxic species are the intermediate oligomeric states appearing along the aggregation pathways. This minireview summarizes recent findings, mainly based on solution and solid-state NMR experiments and electron microscopy, which investigate the molecular structures and characteristics of the Aβ peptides at different stages along the aggregation pathways. We conclude that a hairpin-like conformation constitutes a common motif for the Aβ peptides in most of the described structures. There are certain variations in different hairpin conformations, for example regarding H-bonding partners, which could be one reason for the molecular heterogeneity observed in the aggregated systems. Interacting hairpins are the building blocks of the insoluble fibrils, again with variations in how hairpins are organized in the cross-section of the fibril, perpendicular to the fibril axis. The secondary structure propensities can be seen already in peptide monomers in solution. Unfortunately, detailed structural information about the intermediate oligomeric states is presently not available. In the review, special attention is given to metal ion interactions, particularly the binding constants and ligand structures of Aβ complexes with Cu(II) and Zn(II), since these ions affect the aggregation process(es) and are considered to be involved in the molecular mechanisms underlying AD pathology.

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

“…Our observation of A␤ peptides adsorbing on the surfaces of hydrophobic carbon nanotubes appears to support this hypothesis (94). For A␤, the hydrophobic regions around residues 16 -21 and 29 -35 form the two legs of the A␤ hairpin, which is considered to be the basic unit for A␤ self-aggregation and co-aggregation with other molecules (5).…”

“…The amyloid form of A␤ aggregates is generally defined by in vitro observations: originally by the so-called cross-␤ x-ray diffraction pattern or by observation of fibril structures in microscopy (transmission electron microscopy or atomic force microscopy) (5). Molecular probes recognizing the formation of certain ordered molecular structures include Congo red and thioflavin T, which change their optical properties when bound to amyloid material (5). The terms "on-pathway" and "off-pathway" intermediates are used to differentiate between self-aggregated A␤ species that lead to amyloid formation and those that do not.…”

Phosphorylation Interferes with Maturation of Amyloid-β Fibrillar Structure in the N Terminus

“…Although a U-shaped strand-turn-strand conformation of A␤ is a structural motif commonly preserved along the aggregation pathway (27,28), a high level of conformational rearrangement underlying the interconversion of A␤ aggregates is essential for progression of A␤ aggregation (29). One striking example of the role of conformational plasticity in A␤ aggregation is observed in the turn region around Ser 26 where rigidification of this region by Ser 26 phosphorylation is connected to the prevention of fibrillar A␤ aggregates (26).…”

Different zinc(II) complex species and binding modes at Aβ N-terminus drive distinct long range cross-talks in the Aβ monomers

“…The first sixteen N-terminal segment (D1-K16) constitutes the hydrophilic tail. This is followed by one hydrophobic region L17-A21 and by a hydrophilic central region among the E22-G29 section, thereby reaching the C-terminal domain that is mainly hydrophobic [2]. The two hydrophobic A C C E P T E D M A N U S C R I P T…”

“…Amyloid-β protein (Aβ) is one of the main components of fibrils present in senile plaques, widely recognized as the pathological hallmark of Alzheimer's disease (AD) [1,2]. Aβ is a small protein typically 39-42 residues long.…”