Radiochemical examination of transthyretin (TTR) brain penetration assisted by iododiflunisal, a TTR tetramer stabilizer and a new candidate drug for AD

Rios, Xabier; Gómez Vallejo, Vanessa; Martín, Abraham; Cossío, Unai; Morcillo, Miguel Ángel; Alemi, Mobina; Cardoso, Isabel; Quintana, Jordi; Jiménez-Barbero, Jesús J.; Cotrina, Ellen; Valencia, Gregorio; Arsequell, Gemma; Llop, Jordi

Radiochemical examination of transthyretin (TTR) brain penetration assisted by iododiflunisal, a TTR tetramer stabilizer and a new candidate drug for AD

Mostra el registre complet Registre parcial de l'ítem

dc.contributor.author Rios, Xabier
dc.contributor.author Gómez Vallejo, Vanessa
dc.contributor.author Martín, Abraham
dc.contributor.author Cossío, Unai
dc.contributor.author Morcillo, Miguel Ángel
dc.contributor.author Alemi, Mobina
dc.contributor.author Cardoso, Isabel
dc.contributor.author Quintana, Jordi
dc.contributor.author Jiménez-Barbero, Jesús J.
dc.contributor.author Cotrina, Ellen
dc.contributor.author Valencia, Gregorio
dc.contributor.author Arsequell, Gemma
dc.contributor.author Llop, Jordi
dc.date.accessioned 2020-07-27T06:19:56Z
dc.date.available 2020-07-27T06:19:56Z
dc.date.issued 2019
dc.description.abstract It is well settled that the amyloidogenic properties of the plasma protein transporter transthyretin (TTR) can be modulated by compounds that stabilize its native tetrameric conformation. TTR is also present in cerebrospinal fluid where it can bind to Aβ-peptides and prevent Aβ aggregation. We have previously shown that treatment of Alzheimer's Disease (AD) model mice with iododiflunisal (IDIF), a TTR tetramer stabilizing compound, prevents AD pathologies. This evidence positioned IDIF as a new lead drug for AD. In dissecting the mechanism of action of IDIF, we disclose here different labeling strategies for the preparation of 131I-labeled IDIF and 131I- and 124I-labeled TTR, which have been further used for the preparation of IDIF-TTR complexes labeled either on the compound or the protein. The biodistribution of all labeled species after intravenous administration has been investigated in mice using ex vivo and in vivo techniques. Our results confirm the capacity of TTR to cross the blood brain barrier (BBB) and suggest that the formation of TTR-IDIF complexes enhances BBB permeability of both IDIF and TTR. The increased TTR and IDIF brain concentrations may result in higher Aβ-peptide sequestration capacity with the subsequent inhibition of AD symptoms as we have previously observed in mice.
dc.format.mimetype application/pdf
dc.identifier.citation Rios X, Gómez-Vallejo V, Martín A, Cossío U, Morcillo MÁ, Alemi M, Cardoso I, Quintana J, Jiménez-Barbero J, Cotrina EY, Valencia G, Arsequell G, Llop J. Radiochemical examination of transthyretin (TTR) brain penetration assisted by iododiflunisal, a TTR tetramer stabilizer and a new candidate drug for AD. Sci Rep. 2019; 9(1):13672. DOI: 10.1038/s41598-019-50071-w
dc.identifier.doi http://dx.doi.org/10.1038/s41598-019-50071-w
dc.identifier.issn 2045-2322
dc.identifier.uri http://hdl.handle.net/10230/45195
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Sci Rep. 2019; 9(1):13672
dc.rights © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Blood–brain barrier
dc.subject.keyword Proteins
dc.title Radiochemical examination of transthyretin (TTR) brain penetration assisted by iododiflunisal, a TTR tetramer stabilizer and a new candidate drug for AD
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

Col·leccions

Articles (Departament de Medicina i Ciències de la Vida)