Evidence of the Existence of Micelles in the Fibrillogenesis of β-Amyloid Peptide

Abstract

Alzheimer's disease (AD) is characterized by the deposition of fibrillar deposits formed by the amyloid beta (Abeta) peptide. The most widely accepted model of fibrillogenesis of Abeta affirms that fibrillogenesis occurs in two distinct stages, nucleation and elongation. A modification of the model includes the formation of micelles. We have demonstrated with accurate experimental determinations the existence of aggregates with micellar properties (namely, the critical micellar concentration, CMC, and aggregation number). Values of the CMC were obtained by analysis of surface tension (17.5 microM) and changes in the fluorescence of pyrene (17.6 microM), respectively. The average aggregation number determined by fluorescence quenching was 25, and it was independent of peptide concentration. The presence of micelles implies that above the CMC all excess peptide is incorporated into micelles, and consequently, the monomer concentration is kept almost constant. Thus, micelles act as a peptide reservoir. Micelles are located on-pathway, since they serves as nucleation centers. Experimental data support the model, since above 17.7 microM the time of half-aggregation is independent of peptide concentration, and the overall reaction of the conversion of monomer peptide into fibril can be treated as an apparent first-order reaction.

Oligomeric Intermediates in Amyloid Formation: Structure Determination and Mechanisms of Toxicity

“…39 FCS can even be applied in cellular environments, 48 and the relatively high structural dynamics of oligomers, their hydrophobicity and quasi-spherical structure relate these states to lipid or detergent micelles. 49,50 This conclusion has been further strengthened by small-angle neuron scattering. 49 Associated with these micelle-like properties are the observations of mixed oligomers that were made from mixtures of murine and human α-synuclein, 51 Aβ(1-40) and Aβ(1-42) peptides 52 or Aβ and α-synuclein.…”

Interpreting the Aggregation Kinetics of Amyloid Peptides

“…6 An unstructured peptide with a marginally stable β-prone state (e.g. Aβ40 32,36 or the islet amyloid polypeptide 37 ) as well as the α/β protein acylphosphatase 22 visit oligomeric systems in the lag phase, and have a very weak dependence of the elongation rate on concentration due to the monomermicelle equilibrium. This mechanism corresponds to the nucleated conformational conversion proposed by Serio et al 38 Other examples of the β-unstable model include phosphoglycerate kinase (PGK), an α/β protein, which was investigated by light scattering, circular dichroism and electron microscopy.…”

Time resolved structure analysis of growing β-amyloid fibers

“…Recent in vitro experiments on the aggregation behaviour of Ab in aqueous solution, both under physiological and non-physiological conditions support first insight into a general aggregation mechanism (Dobson, 2003;Lomakin et al, 1996;Lomakin et al, 1997;Naiki and Nakakuki, 1996;Nichols et al, 2002;Pallitto and Murphy, 2001;Sabaté and Estelrich, 2005;Sabaté et al, 2003;Shen et al, 1994;Teplow, 1998;Walsh et al, 1997Walsh et al, , 1999. In a primary step, active sites are formed, in partial analogy to the initiation step of a radical or ionic polymerisation.…”

“…If the concentration of monomers exceeds a critical value denoted as CMC, micelles are hypothesized by several groups. These micelles may also produce nuclei and provide a reservoir of monomers (Lomakin et al, 1996;Sabaté and Estelrich, 2005;Sabaté et al, 2003). In the second step, active monomers or multimers are added to nuclei.…”