Polymorph-specific kinetics and thermodynamics of ?-amyloid fibril growth.

ABSTRACT: Amyloid fibrils formed by the 40-residue ?-amyloid peptide (A?(1-40)) are highly polymorphic, with molecular structures that depend on the details of growth conditions. Underlying differences in physical properties are not well understood. Here, we investigate differences in growth kinetics and thermodynamic stabilities of two A?(1-40) fibril polymorphs for which detailed structural models are available from solid-state nuclear magnetic resonance (NMR) studies. Rates of seeded fibril elongation in the presence of excess soluble A?(1-40) and shrinkage in the absence of soluble A?(1-40) are determined with atomic force microscopy (AFM). From these rates, we derive polymorph-specific values for the soluble A?(1-40) concentration at quasi-equilibrium, from which relative stabilities can be derived. The AFM results are supported by direct measurements by ultraviolet absorbance, using a novel dialysis system to establish quasi-equilibrium. At 24 °C, the two polymorphs have significantly different elongation and shrinkage kinetics but similar thermodynamic stabilities. At 37 °C, differences in kinetics are reduced, and thermodynamic stabilities are increased significantly. Fibril length distributions in AFM images provide support for an intermittent growth model, in which fibrils switch randomly between an "on" state (capable of elongation) and an "off" state (incapable of elongation). We also monitor interconversion between polymorphs at 24 °C by solid-state NMR, showing that the two-fold symmetric "agitated" (A) polymorph is more stable than the three-fold symmetric "quiescent" (Q) polymorph. Finally, we show that the two polymorphs have significantly different rates of fragmentation in the presence of shear forces, a difference that helps explain the observed predominance of the A structure when fibrils are grown in agitated solutions.

SUBMITTER: Qiang W 

PROVIDER: S-EPMC3686096 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature