Diverse Structural Conversion and Aggregation Pathways of Alzheimer's Amyloid-beta (1-40)

Abstract

Complex amyloid aggregation of amyloid-beta (1-40) (A beta(1-40)) in terms of monomer structures has not been fully understood. Herein, we report the microscopic mechanism and pathways of A beta(1-40) aggregation with macroscopic viewpoints through tuning its initial structure and solubility. Partial helical structures of A beta(1-40) induced by low solvent polarity accelerated cytotoxic A beta(1-40) amyloid fibrillation, while predominantly helical folds did not aggregate. Changes in the solvent polarity caused a rapid formation of beta-structure-rich protofibrils or oligomers via aggregation-prone helical structures. Modulation of the pH and salt concentration transformed oligomers to protofibrils, which proceeded to amyloid formation. We reveal diverse molecular mechanisms underlying A beta(1-40) aggregation with conceptual energy diagrams and propose that aggregation-prone partial helical structures are key to inducing amyloidogenesis. We demonstrate that context-dependent protein aggregation is comprehensively understood using the macroscopic phase diagram, which provides general insights into differentiation of amyloid formation and phase separation from unfolded and folded structures.