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Quartz Crystal Microbalance Studies of Multilayer Glucagon Fibrillation at the Solid-Liquid Interface

Mads Bruun Hovgaard ^* , Mingdong Dong ^* , Daniel Erik Otzen ^*  and Flemming Besenbacher ^* 

^* Interdisciplinary Nanoscience Center and Department of Physics and Astronomy, University of Aarhus, DK-8000 Aarhus C, Denmark; and Centre for Insoluble Protein Structures, Department of Life Sciences, Aalborg University, DK–9000 Aalborg, Denmark

Correspondence: Address reprint requests to Flemming Besenbacher, Interdisciplinary Nanoscience Center, University of Aarhus, DK-8000 Aarhus C, Denmark. Tel.: 45-8942-3604; Fax: 45-8942-3690; E-mail: fbe{at}inano.dk.

We have used a quartz crystal microbalance with dissipation (QCM-D) to monitor the changes in layer thickness and viscoelastic properties accompanying multilayer amyloid deposition in situ for the first time. By means of atomic force microscope imaging, an unequivocal correlation is established between the interfacial nucleation and growth of glucagon fibrils and the QCM-D response. The combination of the two techniques allows us to study the temporal evolution of the interfacial fibrillation process. We have modeled the QCM-D data using an extension to the Kelvin-Voigt viscoelastic model. Three phases were observed in the fibrillation process: 1), a rigid multilayer of glucagon monomers forms and slowly rearranges; 2), this multilayer subsequently evolves into a dramatically more viscoelastic layer, containing a polymorphic network of micrometer-long fibrils growing from multiple nucleation sites; and 3), the fibrillar formation effectively stops as a result of the depletion of bulk-phase monomers, although the process can be continued without a lag phase by subsequent addition of fresh monomers. The robustness of the QCM-D technique, consolidated by complementary atomic force microscope studies, should make it possible to combine different components thought to be involved in the plaque formation process and thus build up realistic models of amyloid plaque formation in vitro.

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