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

Complex amyloid aggregation of amyloid-β (1-40) (Aβ) in terms of monomer structures has not been fully understood. Herein, we report the microscopic mechanism and pathways of Aβ aggregation with macroscopic viewpoints through tuning its initial structure and solubility. Partial helical structures of Aβ induced by low solvent polarity accelerated cytotoxic Aβ amyloid fibrillation, while predominantly helical folds did not aggregate. Changes in the solvent polarity caused a rapid formation of β-structure-rich protofibrils or oligomers 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 Aβ 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.