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 Alzh eimer's disease (AD) pathogenesis. We have modeled the process of amyloid p laque 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 addit ion to the amyloid template is fully reversible (dissociation t(1/2) approx imate 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 depos ited peptide dissociates first while A beta previously deposited becomes ir reversibly "locked" onto the template. Thus, the transition from monomer to neurstoxic amyloid is mediated by interaction with the template, a mechani sm 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 b eta. Inhibiting the initial weak docking interaction between depositing A b eta and the template is a viable therapeutic target to prevent the critical conformational transition in the conversion of A beta((solution)) to A bet a((amyloid)) and thus prevent stable amyloid accumulation. While thermodyna mics suggest that inhibiting amyloid assembly would be difficult, the prese nt study illustrates that the protein misfolding diseases are kinetically v ulnerable to intervention.