Time dependence of NMR observables reveals salient differences in the accumulation of early aggregated species between human islet amyloid polypeptide and amyloid-β - Archive ouverte HAL Access content directly
Journal Articles Physical Chemistry Chemical Physics Year : 2018

Time dependence of NMR observables reveals salient differences in the accumulation of early aggregated species between human islet amyloid polypeptide and amyloid-β

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Abstract

Type 2 diabetes mellitus and Alzheimer's disease are characterized by the accumulation of fibrillar amyloid deposits consisting mainly of islet amyloid polypeptide (IAPP) and amyloid-b (Ab), respectively. Fibril formation is a multi-step nucleation process that involves the transient build-up of oligomeric species that are thought to be the most toxic components. To gain more insight into the molecular mechanism of early IAPP aggregated species formation, we performed a combination of direct and indirect biophysical approaches on IAPP and also on Ab42 for the sake of comparison. Thioflavin T fluorescence kinetics measurements revealed a stronger autocatalytic behaviour of IAPP and a weaker concentration dependence of fibrillization half-time t 1/2 , as compared to Ab42. Our NMR experiments highlight the absence of micelle reservoir or supercritical regime in the studied concentration range, indicating that the low concentration dependence of IAPP fibril formation can be ascribed to saturable pathways. IAPP and Ab42 displayed marked differences in formation of oligomeric species, as observed by 1D 1 H, pulsed-field gradient (PFG) diffusion and saturation transfer difference (STD) NMR experiments. A fast equilibrium between monomer and oligomeric species was detected in the case of Ab42 but not IAPP, with a significant build-up of aggregated species, as shown by the time dependence of diffusion coefficient and STD magnetization transfer efficiency during the aggregation process. Altogether our data show significant differences between IAPP and Ab42 regarding the microscopic events of amyloid species formation.
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hal-01840142 , version 1 (16-07-2018)

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Anais R. F. Hoffmann, Lucie Caillon, Lilian Shadai Salazar Vazquez, Pierre-Alexandre Spath, Ludovic Carlier, et al.. Time dependence of NMR observables reveals salient differences in the accumulation of early aggregated species between human islet amyloid polypeptide and amyloid-β. Physical Chemistry Chemical Physics, 2018, 20 (14), pp.9561 - 9573. ⟨10.1039/C7CP07516B⟩. ⟨hal-01840142⟩
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