title: Aβ40 and Aβ42 amyloid fibrils exhibit distinct molecular recycling properties.
abstract: A critical aspect to understanding the molecular basis of Alzheimer's disease (AD) is the characterization of the kinetics of interconversion between the different species present during amyloid-β protein (Aβ) aggregation. By monitoring hydrogen/deuterium exchange in Aβ fibrils using electrospray ionization mass spectrometry, we demonstrate that the Aβ molecules comprising the fibril continuously dissociate and reassociate, resulting in molecular recycling within the fibril population. Investigations on Aβ40 and Aβ42 amyloid fibrils reveal that molecules making up Aβ40 fibrils recycle to a much greater extent than those of Aβ42. By examining factors that could influence molecular recycling and by running simulations, we show that the rate constant for dissociation of molecules from the fibril (k(off)) is much greater for Aβ40 than that for Aβ42. Importantly, the k(off) values obtained for Aβ40 and Aβ42 reveal that recycling occurs on biologically relevant time scales. These results have implications for understanding the role of Aβ fibrils in neurotoxicity and for designing therapeutic strategies against AD.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Sánchez
authors.forename: Sergio
authors.initials: S
authors.lastname: Madurga
authors.forename: Tara
authors.initials: T
authors.lastname: Pukala
authors.forename: Marta
authors.initials: M
authors.lastname: Vilaseca
authors.forename: Carmen
authors.initials: C
authors.lastname: López-Iglesias
authors.forename: Carol V
authors.initials: CV
authors.lastname: Robinson
authors.forename: Ernest
authors.initials: E
authors.lastname: Giralt
authors.forename: Natàlia
authors.initials: N
authors.lastname: Carulla
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C538897:amyloid beta-protein (40-42)