title: The air-water interface determines the outcome of seeding during amyloidogenesis.
abstract: Amyloid formation is a hallmark of protein misfolding diseases (e.g. Type II diabetes mellitus). The energetically unfavourable nucleation step of amyloidogenesis can be accelerated by seeding, during which pre-formed aggregates act as templates for monomer recruitment. Hydrophobic-hydrophilic interfaces [e.g. AWI (air-water interface)] can also catalyse amyloidogenesis due to the surfactant properties of amyloidogenic polypeptides. Using thioflavin T fluorescence and electron microscopy, we demonstrate that the outcome of seeding on human islet amyloid polypeptide amyloidogenesis is dependent upon whether the AWI is present or absent and is dictated by seed type. Seeding significantly inhibits (with AWI) or promotes (without AWI) plateau height compared with seedless controls; with short fibrils being more efficient seeds than their longer counterparts. Moreover, promotion of nucleation by increasing monomer concentrations can only be observed in the absence of an AWI. Using biophysical modelling, we suggest that a possible explanation for our results may reside in lateral interactions between seeds and monomers determining the fibril mass formed in seeded reactions at steady-state. Our results suggest that in vivo hydrophobic-hydrophilic interfaces (e.g. the presence of membranes and their turnover rate) may dictate the outcome of seeding during amyloidogenesis and that factors affecting the size of the pre-aggregate may be important.
authors.affiliation: *Department of Zoology, University of Oxford, Oxford OX1 3PS, U.K.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Trigg
authors.forename: Chiu Fan
authors.initials: CF
authors.lastname: Lee
authors.forename: David J
authors.initials: DJ
authors.lastname: Vaux
authors.forename: Létitia
authors.initials: L
authors.lastname: Jean
mesh_terms: D000388:Air; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D058228:Islet Amyloid Polypeptide / Q000737:chemistry*; D007700:Kinetics; D008954:Models, Biological; D014867:Water / Q000737:chemistry*
chemical_list: D058228:Islet Amyloid Polypeptide; D014867:Water