Amyloid plaques composed of the
peptide Abeta are an integral part of
Alzheimer's disease (AD) pathogenesis. We have modeled the process of
amyloid plaque growth by monitoring the deposition of soluble Abeta onto
amyloid in AD brain tissue or synthetic
amyloid fibrils and show that it is mediated by two distinct kinetic processes. In the first phase, "dock", Abeta addition to the
amyloid template is fully reversible (dissociation t(1/2) approximately 10 min), while in the second phase, "lock", the deposited
peptide becomes irreversibly associated (dissociation t(1/2) >> 1000 min) with the template in a time-dependent manner. The most recently deposited
peptide dissociates first while Abeta previously deposited becomes irreversibly "locked" onto the template. Thus, the transition from monomer to neurotoxic
amyloid is mediated by interaction with the template, a mechanism that has also been proposed for the
prion diseases. Interestingly, two Abeta
peptides bearing primary sequence alterations implicated in heritable Abeta
amyloidoses displayed faster lock-phase kinetics than wild-type Abeta. Inhibiting the initial weak docking interaction between depositing Abeta and the template is a viable therapeutic target to prevent the critical conformational transition in the conversion of Abeta((
solution)) to Abeta((
amyloid)) and thus prevent stable
amyloid accumulation. While thermodynamics suggest that inhibiting
amyloid assembly would be difficult, the present study illustrates that the
protein misfolding diseases are kinetically vulnerable to intervention.