Ionic Strength Modulation of the Free Energy Landscape of Aβ40 Peptide Fibril Formation

J Am Chem Soc. 2016 Jun 1;138(21):6893-902. doi: 10.1021/jacs.6b04511. Epub 2016 May 23.

Abstract

Protein misfolding and formation of cross-β structured amyloid fibrils are linked to many neurodegenerative disorders. Although recently developed quantitative approaches have started to reveal the molecular nature of self-assembly and fibril formation of proteins and peptides, it is yet unclear how these self-organization events are precisely modulated by microenvironmental factors, which are known to strongly affect the macroscopic aggregation properties. Here, we characterize the explicit effect of ionic strength on the microscopic aggregation rates of amyloid β peptide (Aβ40) self-association, implicated in Alzheimer's disease. We found that physiological ionic strength accelerates Aβ40 aggregation kinetics by promoting surface-catalyzed secondary nucleation reactions. This promoted catalytic effect can be assigned to shielding of electrostatic repulsion between monomers on the fibril surface or between the fibril surface itself and monomeric peptides. Furthermore, we observe the formation of two different β-structured states with similar but distinct spectroscopic features, which can be assigned to an off-pathway immature state (Fβ*) and a mature stable state (Fβ), where salt favors formation of the Fβ fibril morphology. Addition of salt to preformed Fβ* accelerates transition to Fβ, underlining the dynamic nature of Aβ40 fibrils in solution. On the basis of these results we suggest a model where salt decreases the free-energy barrier for Aβ40 folding to the Fβ state, favoring the buildup of the mature fibril morphology while omitting competing, energetically less favorable structural states.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid / chemistry*
  • Amyloid / metabolism
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism
  • Entropy
  • Kinetics
  • Microscopy, Electron, Transmission
  • Nuclear Magnetic Resonance, Biomolecular
  • Osmolar Concentration
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism
  • Protein Aggregates
  • Protein Folding
  • Sodium Chloride / chemistry
  • Sodium Fluoride / chemistry

Substances

  • Amyloid
  • Amyloid beta-Peptides
  • Peptide Fragments
  • Protein Aggregates
  • amyloid beta-protein (1-40)
  • Sodium Chloride
  • Sodium Fluoride