Biophysical Studies of the Amyloid β‐Peptide: Interactions with Metal Ions and Small Molecules

Abstract

Alzheimer's disease is the most common of the protein misfolding ("amyloid") diseases. The deposits in the brains of afflicted patients contain as a major fraction an aggregated insoluble form of the so-called amyloid β-peptides (Aβ peptides): fragments of the amyloid precursor protein of 39-43 residues in length. This review focuses on biophysical studies of the Aβ peptides: that is, of the aggregation pathways and intermediates observed during aggregation, of the molecular structures observed along these pathways, and of the interactions of Aβ with Cu and Zn ions and with small molecules that modify the aggregation pathways. Particular emphasis is placed on studies based on high-resolution and solid-state NMR methods. Theoretical studies relating to the interactions are also included. An emerging picture is that of Aβ peptides in aqueous solution undergoing hydrophobic collapse together with identical partners. There then follows a relatively slow process leading to more ordered secondary and tertiary (quaternary) structures in the growing aggregates. These aggregates eventually assemble into elongated fibrils visible by electron microscopy. Small molecules or metal ions that interfere with the aggregation processes give rise to a variety of aggregation products that may be studied in vitro and considered in relation to observations in cell cultures or in vivo. Although the heterogeneous nature of the processes makes detailed structural studies difficult, knowledge and understanding of the underlying physical chemistry might provide a basis for future therapeutic strategies against the disease. A final part of the review deals with the interactions that may occur between the Aβ peptides and the prion protein, where the latter is involved in other protein misfolding diseases.

Effects of aluminum on amyloid-beta aggregation in the context of Alzheimer’s disease

“…The value of K a is qualitatively similar to values reported in the literature, in which other techniques were applied (Asandei et al, 2014). It should be kept in mind that although previously reported metal affinities of the various Ab peptides seemed to vary appreciably, this can be accounted for by taking into considerations the different experimental conditions used in different studies, e.g., different models reported the use of different buffers to influence the binding of metals, and the initial aggregation states of the peptide (Warmlander et al, 2013). From the finally resolved pure spectra (Fig.…”

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

“…These aggregates have a linear structure, stronger binding affinity toward PrP, and a stronger inhibitory effect on longterm potentiation than non-fibrillar A␤ oligomers (14). The presence of PrP enhances A␤ accumulation, and vice versa (15). Thus, in transgenic mice, the two proteins mutually accelerate the progression of both pathologies (16).…”

“…Various metal ions are known to bind A␤ and interfere with its aggregation process (15,81). Recent work has shown that multiple amyloid protein molecules may share coordination of a single metal ion, promoting protein aggregation and possibly also crossinteractions (82).…”

“…For instance, the A␤ N terminus (residues 1-15) interacts with many different small charged molecules (15,84). Interaction between two heterogeneous amyloid proteins may prevent fibrillation of one of them, but may also be the precursor of a cross-amyloid interaction.…”

Metal-dependent amyloid β-degrading catalytic antibody construct

“…EDTA and 1,10-phenanthroline also inhibited the IgV hydrolytic activity completely, suggesting that a metal ion is required for the hydrolytic reaction. Aβ is known to bind certain metal ions (Warmlander et al 2013). To exclude metal binding to Aβ as a factor, we repeated the 125 I-Aβ40 hydrolysis test after removing EDTA from the chelator-pretreated IgV 2E6.…”