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

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Abstract
Recent experiments on the kinetics of deposition and fibril elongation of the Alzheimer's β-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 β-peptide on preexisting amyloid fibrils and deposits. Our mechanism includes channels for (1) a one-step prion-like direct 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 and implied “energy landscape” unify a number of schemes proposed to describe the process of fibril elongation. This β-amyloid landscape mechanism (βALM) is found to be in good agreement with existing experimental data. A number of experimental tests of the mechanism are proposed. The mechanism leads to a clear definition of overall equilibrium or rate constants in terms 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. The mechanism predicts a turnover in the rate of fibril elongation as a function of temperature and denaturant concentration. Proteins 2001;42:217–229.