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Lookup NU author(s): Professor Tiago OuteiroORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved. In Alzheimer's disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, and synaptic transmission and plasticity. Using cerebrospinal fluid and postmortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as a function of pathology severity. To explore the therapeutic potential of this disease mechanism, we designed small TAT-fused peptides and screened their ability to prevent TrkB-FL receptor cleavage. Among these, a TAT-TrkB peptide with a lysine-lysine linker prevented TrkB-FL cleavage both in vitro and in vivo and rescued synaptic deficits induced by oligomeric Aβ in hippocampal slices. Furthermore, this TAT-TrkB peptide improved the cognitive performance, ameliorated synaptic plasticity deficits and prevented Tau pathology progression in vivo in the 5XFAD mouse model of AD. No evidence of liver or kidney toxicity was found. We provide proof-of-concept evidence for the efficacy and safety of this therapeutic strategy and anticipate that this TAT-TrkB peptide has the potential to be a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD.
Author(s): Fonseca-Gomes J, Costa-Coelho T, Ferreira-Manso M, Inteiro-Oliveira S, Vaz SH, Aleman-Serrano N, Atalaia-Barbacena H, Ribeiro-Rodrigues L, Ramalho RM, Pinto R, Vicente Miranda H, Tanqueiro SR, de Almeida-Borlido C, Ramalho MJ, Miranda-Lourenco C, Belo RF, Ferreira CB, Neves V, Rombo DM, Viais R, Martins IC, Jeronimo-Santos A, Caetano A, Manso N, Makinen P, Marttinen M, Takalo M, Bremang M, Pike I, Haapasalo A, Loureiro JA, Pereira MC, Santos NC, Outeiro TF, Castanho MARB, Fernandes A, Hiltunen M, Duarte CB, Castren E, de Mendonca A, Sebastiao AM, Rodrigues TM, Diogenes MJ
Publication type: Article
Publication status: Published
Journal: Molecular Therapy
Year: 2024
Volume: 32
Issue: 10
Pages: 3372-3401
Online publication date: 27/08/2024
Acceptance date: 23/08/2024
Date deposited: 15/10/2024
ISSN (print): 1525-0016
ISSN (electronic): 1525-0024
Publisher: Elsevier
URL: https://doi.org/10.1016/j.ymthe.2024.08.022
DOI: 10.1016/j.ymthe.2024.08.022
Data Access Statement: All software used for the data analysis is either publicly or commercially available, and information is provided in each respective section. Sequencing data have been deposited at GEO and is accessible under GEO: GSE271487. The remaining data and code that support the findings of this study are available from the lead contacts (Tiago M. Rodrigues,tiago.rodrigues@iob.ch; Maria José Diógenes, diogenes@medicina.ulisboa.pt) upon reasonable request
PubMed id: 39205389
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