Insights on the Interaction between Transthyretin and Aβ in Solution. A Saturation Transfer Difference (STD) NMR Analysis of the Role of Iododiflunisal

Ana Gimeno, Luis M. Santos, Mobina Alemi, Josep Rivas, Daniel Blasi, Ellen Y. Cotrina, Jordi Llop, Gregorio Valencia, Isabel Cardoso, Jordi Quintana, Gemma Arsequell, Jesús Jiménez-Barbero

Several strategies against Alzheimer Disease (AD) are directed to target Aβ-peptides. The ability of transthyretin (TTR) to bind Aβ-peptides and the positive effect exerted by some TTR stabilizers for modulating the TTR-Aβ interaction have been previously studied. Herein, key structural features of the interaction between TTR and the Aβ(12-28) peptide (3), the essential recognition element of Aβ, have been unravelled by STD-NMR spectroscopy methods in solution. Molecular aspects related with the role of the TTR stabilizer iododiflunisal (IDIF, 5) on the TTR-Aβ complex have been also examined. The NMR results, assisted by molecular modeling protocols, have provided a structural model for the TTR-Aβ interaction, as well as for the ternary complex formed in the presence of IDIF. This basic structural information could be relevant for providing light on the mechanisms involved in the ameliorating effects of AD symptoms observed in AD/TTR(+/-) animal models after IDIF treatment and eventually for designing new molecules towards AD therapeutic drugs.