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Transthyretin Inhibits Primary and Secondary Nucleations of Amyloid‑β Peptide Aggregation and Reduces the Toxicity of Its Oligomers
Version 2 2020-02-24, 14:58
Version 1 2020-02-17, 17:03
journal contribution
posted on 2020-02-24, 14:58 authored by Seyyed
Abolghasem Ghadami, Sean Chia, Francesco Simone Ruggeri, Georg Meisl, Francesco Bemporad, Johnny Habchi, Roberta Cascella, Christopher M. Dobson, Michele Vendruscolo, Tuomas P. J. Knowles, Fabrizio ChitiAlzheimer’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 preformed 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, which are primary and secondary
nucleations, 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 of its overall
structure following such interactions with Aβ40 oligomers,
as well as with oligomers of Aβ42, while maintaining
its overall topology. Hence, it is likely that the predominant mechanism
by which TTR exerts its protective role lies in the binding of TTR
to the Aβ oligomers and in inhibiting primary and secondary
nucleation processes, which limits both the toxicity of Aβ oligomers
and the ability of the fibrils to proliferate.