Transthyretin inhibits primary and secondary nucleation of amyloid-β peptide aggregation and reduces the toxicity of its oligomers

Alzheimer’s disease is associated with the deposition of the amyloid-β peptide (Aβ) into extracellular senile plaques in the brain. In vitro and in vivo observations have indicated that transthyretin (TTR) acts as an Aβ scavenger in the brain, but the mechanism has not been fully resolved. We have monitored the aggregation process of Aβ40 by thioflavin T fluorescence, in the presence or absence of different concentrations of pre-formed seed aggregates of Aβ40, of wild-type tetrameric TTR (WT-TTR) and of a variant engineered to be stable as a monomer (M-TTR). Both WT-TTR and M-TTR were found to inhibit specific steps of the process of Aβ40 fibril formation, that are primary and secondary nucleation, without affecting the elongation of the resulting fibrils. Moreover, the analysis shows that both WT-TTR and M-TTR bind to Aβ40 oligomers formed in the aggregation reaction, and inhibit their conversion into the shortest fibrils able to elongate. Using biophysical methods, TTR was found to change some aspects o...