Amyloid β-protein oligomers and Alzheimer's disease

Abstract

The oligomer cascade hypothesis, which states that oligomers are the initiating pathologic agents in Alzheimer's disease, has all but supplanted the amyloid cascade hypothesis, which suggested that fibers were the key etiologic agents in Alzheimer's disease. We review here the results of in vivo, in vitro and in silico studies of amyloid β-protein oligomers, and discuss important caveats that should be considered in the evaluation of these results. This article is divided into four sections that mirror the main approaches used in the field to better understand oligomers: (1) attempts to locate and examine oligomers in vivo in situ; that is, without removing these species from their environment; (2) studies involving oligomers extracted from human or animal tissues and the subsequent characterization of their properties ex vivo; (3) studies of oligomers that have been produced synthetically and studied using a reductionist approach in relatively simple in vitro biophysical systems; and (4) computational studies of oligomers in silico. These multiple orthogonal approaches have revealed much about the molecular and cell biology of amyloid β-protein. However, as informative as these approaches have been, the amyloid β-protein oligomer system remains enigmatic.

Figure 1

The diverse nature of oligomers. Oligomeric assemblies ranging from two to six monomers. Each sphere represents a monomeric unit. Monomers (grey), dimers (red, diagonal lines) and trimers (white) can combine in different combinations comprising up to six monomers. Each small oligomer also could be a building block for larger oligomers. For simplicity and clarity, we only display basic units up to trimer. We note that the assemblies shown here, and others, are in rapid equilibrium, one that can be perturbed easily during experimental studies.

Figure 2

Simulation of amyloid β-protein hexamer formation. Formation of an amyloid β-protein (Aβ)40 hexamer from a tetramer (lower left) and a dimer (upper right). β-strands are depicted as yellow ribbons, turns as light blue ribbons and random coils as white ribbons. The N-termini are represented by red spheres. The C-terminal V39 and V40 are represented by orange spheres. Adapted with permission from [107], copyright 2010 American Chemical Society.