Multiple aggregation mechanism in Abeta(1-40) fibril formation

Risultato della ricerca: Other

Abstract

A general characteristic of aggregation is the multiple interaction and cross-feedback among distinct mechanisms occurring at different hierarchical levels. The comprehension of the different species interconversion during aggregation is very important since emerging evidences indicate intermediate oligomeric aggregates as primary toxic species.In this context, Aβ amyloid peptide provides a challenging model for studying aggregation phenomena both for the complexity of its association process and for the direct implications in Alzheimer’s Disease. Indeed, aggregates growth conditions strongly affect their final morphology and their molecular structure as well as the time evolution of aggregation pathway which is characterised by the occurrence of multiple transient species. We here present an experimental study on Aβ(1-40) peptide fibrillation kinetics at pH 7.4 as a function of temperature and concentration. Light scattering, Thioflavin T (ThT) fluorescence emission, Circular Dichroism, two photon fluorescence microscopy and Fluorescence recovery after photo-bleaching measurements, were used in a kinetic fashion to highlight different aspects and critical phases of the aggregation pathway. This approach gives detailed information on the time evolution of conformational changes at molecular level, on different aggregate species growth and their morphologies. Our data suggest that Aβ(1-40) fibrillation process involves at least three different aggregation mechanisms acting in competition. In the first step of aggregation, small oligomers which bind ThT are formed via non nucleated polymerisation mechanism representing an activated state to proceed towards fibril growth. This process which implies a conformational conversion constitutes the rate limiting step for two distinct fibril nucleation mechanisms probably affected by an high degree of spatial heterogeneity.
Lingua originaleEnglish
Numero di pagine1
Stato di pubblicazionePublished - 2011

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