The toxicity of amyloid β oligomers

Abstract

In this review, we elucidate the mechanisms of Aβ oligomer toxicity which may contribute to Alzheimer's disease (AD). In particular, we discuss on the interaction of Aβ oligomers with the membrane through the process of adsorption and insertion. Such interaction gives rises to phase transitions in the sub-structures of the Aβ peptide from α-helical to β-sheet structure. By means of a coarse-grained model, we exhibit the tendency of β-sheet structures to aggregate, thus providing further insights to the process of membrane induced aggregation. We show that the aggregated oligomer causes membrane invagination, which is a precursor to the formation of pore structures and ion channels. Other pathological progressions to AD due to Aβ oligomers are also covered, such as their interaction with the membrane receptors, and their direct versus indirect effects on oxidative stress and intraneuronal accumulation. We further illustrate that the molecule curcumin is a potential Aβ toxicity inhibitor as a β-sheet breaker by having a high propensity to interact with certain Aβ residues without binding to them. The comprehensive understanding gained from these current researches on the various toxicity mechanisms show promises in the provision of better therapeutics and treatment strategies in the near future.

Keywords: Alzheimer’s disease; amyloid β oligomer toxicity mechanism; amyloid β peptide; curcumin; molecular dynamics simulation.

Figure 1

Partial density function along the Z-direction.

Figure 2

The residue contact map of each dimer. The coloring scheme is based on the inter-residue distance.

Figure 3

The density function of Aβ in the mixed bilayer environment along the Z-direction. Residues 1–27 are indicated by black line, and residues 28–42 by red line. The light yellow background shows the DPPC headgroup region. For detailed system information see Reference [18].

Figure 4

The cleavage of APP by α-, β- and γ-secretase and the production of Aβ peptides are shown on the left side of the figure. The following toxic mechanisms are illustrated in the figure: formation of Aβ oligomers and its further conversion to fibrils; disruption of membrane receptors; adsorption on membrane surface which alters the property of the membrane; formation of pore which causes the leakage of Ca²⁺; and the accumulation of intraneuronal Aβ.

Figure 5

Plots of α-β-coil secondary structure phase transition for a seven crank polyalanine. Solid line represents the number of hydrogen bonds; dotted line represents the corresponding heat capacity. The transition temperatures are T_α–β = 300 a.u, and T_β–coil = 950 a.u., respectively.

Figure 6

The binding propensity of curcumin towards the Aβ dimer.

Figure 7

The common pathways of curcumin in the diketone (a) and the keto-enol form (b) of Aβ dimer. The blue colored domains represent the residues from chain A, while the green colored domains represent the residues from chain B. The thickness of the arrow indicates the popularity of the pathway. This figure was generated by Graphviz [165].