A尾40 and A尾42 Amyloid Fibrils Exhibit Distinct Molecular Recycling Properties

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• 作者：Laia S谩nchez ; Sergio Madurga ; Tara Pukala ; Marta Vilaseca ; Carmen L贸pez-Iglesias ; Carol V. Robinson ; Ernest Giralt ; Nat脿lia Carulla
• 刊名：Journal of the American Chemical Society
• 出版年：2011
• 出版时间：May 4, 2011
• 年：2011
• 卷：133
• 期：17
• 页码：6505-6508
• 全文大小：752K
• 年卷期：v.133,no.17(May 4, 2011)
• ISSN：1520-5126

文摘

A critical aspect to understanding the molecular basis of Alzheimer鈥檚 disease (AD) is the characterization of the kinetics of interconversion between the different species present during amyloid-尾 protein (A尾) aggregation. By monitoring hydrogen/deuterium exchange in A尾 fibrils using electrospray ionization mass spectrometry, we demonstrate that the A尾 molecules comprising the fibril continuously dissociate and reassociate, resulting in molecular recycling within the fibril population. Investigations on A尾40 and A尾42 amyloid fibrils reveal that molecules making up A尾40 fibrils recycle to a much greater extent than those of A尾42. 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 A尾40 than that for A尾42. Importantly, the k_off values obtained for A尾40 and A尾42 reveal that recycling occurs on biologically relevant time scales. These results have implications for understanding the role of A尾 fibrils in neurotoxicity and for designing therapeutic strategies against AD.