The Nature of the Amyloid-β Monomer and the Monomer-Oligomer Equilibrium

Abstract

Abstract:The monomer to oligomer transition initiates the aggregation and pathogenic transformation of Alzheimer's Amyloid-β (Aβ) peptide. However, the monomeric state of this aggregation-prone peptide has remained beyond the reach of most experimental techniques, and a quantitative understanding of this transition is yet to emerge. Here we employ single molecule level fluorescence tools to characterize the monomeric state and the monomer-oligomer transition at appropriately low concentrations in buffers mimicking the cerebrospinal fluid (CSF). Our measurements show the monomer to be a compact object with a hydrodynamic radius of 0.9 ± 0.1 nm, which confirms the prediction made by some of the in silico studies. Surprisingly, at equilibrium, both Aβ40 and Aβ42 remain predominantly monomeric up to 1.5 μM concentration. This concentration is much higher than their estimated concentrations in the CSF of either normal or diseased brains. However, we find that a strong kinetic barrier impedes the dissociation of pre-formed oligomers. Since Aβ oligomers in the CSF are generally accepted to be the key agents in Alzheimer's pathology, our results imply that these are released in the CSF as pre-formed entities, and their metastability allows them to remain toxic. We conclude that thermodynamic principles allow the development of pharmacological agents that can catalytically convert these metastable species to non-toxic monomers.