Low TGF-β1 plasma levels are associated with cognitive decline in Down syndrome

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• dc.contributor.author Grasso, Margherita
• dc.contributor.author Fidilio, Annamaria
• dc.contributor.author L'Episcopo, Francesca
• dc.contributor.author Recupero, Marilena
• dc.contributor.author Barone, Concetta
• dc.contributor.author Bacalini, Maria Giulia
• dc.contributor.author Benatti, Cristina
• dc.contributor.author Giambirtone, Maria Concetta
• dc.contributor.author Caruso, Giuseppe
• dc.contributor.author Greco, Donatella
• dc.contributor.author Di Nuovo, Santo
• dc.contributor.author Romano, Corrado
• dc.contributor.author Ferri, Raffaele
• dc.contributor.author Buono, Serafino
• dc.contributor.author Cuello, Claudio
• dc.contributor.author Blom, Johanna M. C.
• dc.contributor.author Tascedda, Fabio
• dc.contributor.author Piazza, Pier Vincenzo
• dc.contributor.author Torre Fornell, Rafael de la
• dc.contributor.author Caraci, Filippo
• dc.date.accessioned 2024-06-06T06:08:53Z
• dc.date.available 2024-06-06T06:08:53Z
• dc.date.issued 2024
• dc.description.abstract Almost all individuals with Down's syndrome (DS) show the characteristic neuropathological features of Alzheimer's disease (AD) by the age of 40, yet not every individual with DS experiences symptoms of AD later in life. Similar to neurotypical developing subjects, AD in people with DS lasts for a long preclinical phase in which biomarkers follow a predictable order of changes. Hence, a prolonged asymptomatic period precedes the onset of dementia, underscoring the importance of identifying new biomarkers for the early detection and monitoring of cognitive decline in individuals with DS. Blood-based biomarkers may offer an alternative non-invasive strategy for the detection of peripheral biological alterations paralleling nervous system pathology in an early phase of the AD continuum. In the last few years, a strong neurobiological link has been demonstrated between the deficit of transforming growth factor-β1 (TGF-β1) levels, an anti-inflammatory cytokine endowed with neuroprotective activity, and early pro-inflammatory processes in the AD brain. In this clinical prospective observational study, we found significant lower plasma TGF-β1 concentrations at the first neuropsychological evaluation (baseline = T0) both in young adult DS individuals (19-35 years) and older DS subjects without AD (35-60 years) compared to age- and sex-matched healthy controls. Interestingly, we found that the lower TGF-β1 plasma concentrations at T0 were strongly correlated with the following cognitive decline at 12 months. In addition, in young individuals with DS, we found, for the first time, a negative correlation between low TGF-β1 concentrations and high TNF-α plasma concentrations, a pro-inflammatory cytokine that is known to be associated with cognitive impairment in DS individuals with AD. Finally, adopting an ex vivo approach, we found that TGF-β1 concentrations were reduced in parallel both in the plasma and in the peripheral blood mononuclear cells (PBMCs) of DS subjects, and interestingly, therapeutic concentrations of fluoxetine (FLX) applied to cultured PBMCs (1 µM for 24 h) were able to rescue TGF-β1 concentrations in the culture media from DS PBMCs, suggesting that FLX, a selective serotonin reuptake inhibitor (SSRI) endowed with neuroprotective activity, might rescue TGF-β1 concentrations in DS subjects at higher risk to develop cognitive decline.
• dc.description.sponsorship The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This project has been funded by the Italian Ministry of Health, grant no: GR-2019-12369983-Theory-enhancing and partially supported with funds by project no. 3 of Ricerca Corrente 2022-2024-Linea 4 of Oasi Research Institute-IRCCS, Troina, Italy, and by FONDO DI ATENEO PER LA RICERCA ANNO 2020, Department of Life Sciences, UNIMORE. FC’s Lab at the Oasi Research Institute is also supported by the European Union’s Horizon 2020 research and innovation program under the grant agreement no. 899986 (ICOD).
• dc.format.mimetype application/pdf
• dc.identifier.citation Grasso M, Fidilio A, L'Episcopo F, Recupero M, Barone C, Bacalini MG, et al. Low TGF-β1 plasma levels are associated with cognitive decline in Down syndrome. Front Pharmacol. 2024 Mar 21;15:1379965. DOI: 10.3389/fphar.2024.1379965
• dc.identifier.doi http://dx.doi.org/10.3389/fphar.2024.1379965
• dc.identifier.issn 1663-9812
• dc.identifier.uri http://hdl.handle.net/10230/60364
• dc.language.iso eng
• dc.publisher Frontiers
• dc.relation.ispartof Front Pharmacol. 2024 Mar 21;15:1379965
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/899986
• dc.rights © 2024 Grasso, Fidilio, L’Episcopo, Recupero, Barone, Bacalini, Benatti, Giambirtone, Caruso, Greco, Di Nuovo, Romano, Ferri, Buono, Cuello, Blom, Tascedda, Piazza, De La Torre and Caraci. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms (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 Down’s syndrome
• dc.subject.keyword PBMCs
• dc.subject.keyword TGF-β1
• dc.subject.keyword Blood-based biomarker
• dc.subject.keyword Cognitive decline
• dc.title Low TGF-β1 plasma levels are associated with cognitive decline in Down syndrome
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion