Energy landscape theory for Alzheimer's amyloid beta-peptide fibril elongation

Recent experiments on the kinetics of deposition and fibril elongation of t he Alzheimer's beta -amyloid peptide on preexisting fibrils are analyzed, A mechanism is developed based on the dock-and-lock scheme recently proposed by Maggio and coworkers to organize their experimental observations of the kinetics of deposition of beta -peptide on preexisting amyloid fibrils and deposits. Our mechanism includes channels for (1) a one-step prion-like di rect deposition on fibrils of activated monomeric peptide in solution, and (2) a two-step deposition of unactivated peptide on fibrils and subsequent reorganization of the peptide-fibril complex. In this way, the mechanism an d implied "energy landscape" unify a number of schemes proposed to describe the process of fibril elongation. This beta -amyloid landscape mechanism ( beta ALM) is found to be in good agreement with existing experimental data. A number of experimental tests of the mechanism are proposed. The mechanis m leads to a clear definition of overall equilibrium or rate constants in t erms of the energetics of the elementary underlying processes. Analysis of existing experimental data suggests that fibril elongation occurs through a two-step mechanism of nonspecific peptide absorption and reorganization. T he mechanism predicts a turnover in the rate of fibril elongation as a func tion of temperature and denaturant concentration. Proteins 2001;42:217-229, (C) 2000 Wiley-Liss, Inc.