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Aβ40 and Aβ42 amyloid fibrils exhibit distinct molecular recycling

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dc.contributor.authorSanchez, L.
dc.contributor.authorMadurga, S.
dc.contributor.authorPukala, T.
dc.contributor.authorVilaseca, M.
dc.contributor.authorLopez-Iglesias, C.
dc.contributor.authorRobinson, C.
dc.contributor.authorGiralt, E.
dc.contributor.authorCarulla, N.
dc.date.issued2011
dc.description.abstractA 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.
dc.description.statementofresponsibilityLaia Sánchez, Sergio Madurga, Tara Pukala, Marta Vilaseca, Carmen López-Iglesias, Carol V. Robinson, Ernest Giralt, and Natàlia Carulla
dc.identifier.citationJournal of the American Chemical Society, 2011; 133(17):6505-6508
dc.identifier.doi10.1021/ja1117123
dc.identifier.issn0002-7863
dc.identifier.issn1520-5126
dc.identifier.orcidPukala, T. [0000-0001-7391-1436]
dc.identifier.urihttp://hdl.handle.net/2440/66162
dc.language.isoen
dc.publisherAmer Chemical Soc
dc.rights© 2011 American Chemical Society
dc.source.urihttps://doi.org/10.1021/ja1117123
dc.subjectHumans
dc.subjectAlzheimer Disease
dc.subjectAmyloid
dc.subjectPeptide Fragments
dc.subjectSpectrometry, Mass, Electrospray Ionization
dc.subjectAmyloid beta-Peptides
dc.titleAβ40 and Aβ42 amyloid fibrils exhibit distinct molecular recycling
dc.title.alternativeAbeta40 and Abeta42 amyloid fibrils exhibit distinct molecular recycling
dc.typeJournal article
pubs.publication-statusPublished

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