Alzheimer's disease amyloid propagation by a template-dependent dock-lock mechanism

Amyloid plaques composed of the peptide A beta 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 A beta 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, A beta addition to the amyloid template is fully reversible (dissociation t(1/2) approximate to 10 min), while in the second phase, lock, the deposited peptide becomes irreversibly associated (dissociation t(1/2) much greater than 1000 min) with the template in a time-dependent manner. The most recently deposited peptide dissociates first while A beta previously deposited becomes irreversibly locked onto the template. Thus, the transition from monomer to neurstoxic amyloid is mediated by interaction with the template, a mechanism that has also been proposed for the prion diseases. Interestingly, two A beta peptides bearing primary sequence alterations implicated in heritable A beta amyloidoses displayed faster lock-phase kinetics than wild-type A beta. Inhibiting the initial weak docking interaction between depositing A beta and the template is a viable therapeutic target to prevent the critical conformational transition in the conversion of A beta((solution)) to A beta((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.